(Circulation. 1996;93:1087-1094.)
© 1996 American Heart Association, Inc.
Articles |
Expression of Inducible Nitric Oxide Synthase in Human Heart Failure
From the Department of Cardiological Sciences (P.J.K., W.J.M.), St George's Hospital, London, UK; and Division of Cardiovascular Medicine (G.A.H., P.S.T., H.E.vdL., M.J.M., P.T.T., N.P.L., C.D.B., P.R.R., N.H.B., J.P.C., M.B.F.), Stanford University, Stanford, Calif.
Correspondence to Guy Haywood, MD, MRCP, or Michael Fowler, MB, MRCP, Falk Cardiovascular Research Center, Stanford University School of Medicine, 300 Pasteur Dr, Stanford, CA 94305-5246.
 |
Abstract |
|---|
 Top Abstract IntroductionMethods Results Discussion References |
|---|
Background There is increasing evidence that alterations in nitric oxide synthesis are of pathophysiological importance in heart failure. A number of studies have shown altered nitric oxide production by the endothelial constitutive isoform of nitric oxide synthase (NOS), but there is very little information on the role of the inducible isoform.
Methods and Results We analyzed inducible NOS (iNOS) expression in ventricular myocardium taken from 11 control subjects (who had died suddenly from noncardiac causes), from 10 donor hearts before implantation, and from 51 patients with heart failure (24 with dilated cardiomyopathy [DCM], 17 with ischemic heart disease [IHD], and 10 with valvular heart disease [VHD]). Reverse transcription–polymerase chain reaction was used to confirm the presence of intact mRNA and to detect expression of iNOS and atrial natriuretic peptide (ANP). ANP was used as a molecular phenotypic marker of ventricular failure. iNOS was expressed in 36 of 51 biopsies (71%) from patients with heart failure and in none of the control patients (P<.0001). iNOS expression could also be detected in 50% of the donor hearts. All samples that expressed iNOS also expressed ANP. iNOS gene expression occurred in 67% of patients with DCM, 59% of patients with IHD, and 100% of patients with VHD. To determine whether iNOS protein was expressed in failing ventricles, immunohistochemistry was performed on three donor hearts and nine failing hearts with iNOS mRNA expression. Staining for iNOS was almost undetectable in the donor myocardium and in control sections, but all failing hearts showed diffuse cytoplasmic staining in cardiac myocytes. Expression of iNOS could be observed in all four chambers. Western blot analysis with the same primary antibody showed a specific positive band for iNOS protein in the heart failure specimens; minimal iNOS protein expression was seen in donor heart samples.
Conclusions iNOS expression occurs in failing human cardiac myocytes and may be involved in the pathophysiology of DCM, IHD, and VHD.
Key Words: heart failure • myocardium • molecular biology • immunohistochemistry • polymerase chain reaction
|
Introduction |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
It is becoming apparent that NO is one of the most important regulatory factors in physiological processes throughout the body.1 It can be generated by three different isoforms of the enzyme NOS: brain (type I), ecNOS (type III), and iNOS (type II). Recent research in heart failure has focused on alterations in NO production by ecNOS2 3 4 ; far less is known about the behavior of the inducible isoform in this condition. iNOS is expressed in a wide range of tissues in response to stimulation by lipopolysaccharide.5 6 In adult rats in vivo, injection of lipopolysaccharide results in expression of mRNA by myocytes cultured from the ventricular myocardium7 and in increased calcium-independent NOS activity in homogenized ventricular myocardium.8 In humans, iNOS has been cloned from cultured hepatocytes stimulated with lipopolysaccharide combined with the cytokines IL-1ß, TNF-
, and IFN-
9 and from
cultured chondrocytes stimulated with IL-1ß.10 There
also is evidence that IL-2 infusions in patients receiving cancer
chemotherapy can cause expression of iNOS,11 and the
enzyme has been proposed as the mediator of the
catecholamine-resistant hypotension
characteristic of septic shock.12
Because circulating cytokine13 14 and total
nitrate15 levels are elevated in some patients with heart
failure, the question has been raised of whether iNOS can be induced in
failing myocardium. Initial reports have suggested that
iNOS is induced in the ventricular myocardium
of patients with dilated
cardiomyopathy16 and with "focal
healing myocarditis."17 It has been suggested that
inflammatory processes in the myocardium of such patients
may be responsible for the induction of iNOS. However, levels of
circulating cytokines such as TNF- are elevated in patients
with end-stage heart failure regardless of origin14
and in myocardial infarction.18 Recently, a wider role has
been proposed for the pathophysiological
effects of cytokines beyond what are usually considered to be
inflammatory cardiac diseases.19 Thus, there may be
mechanisms that result in the induction of iNOS in the failing
ventricle other than local inflammation.
Interest in whether iNOS is expressed in failing myocardium has been heightened by observations that NO can exert negative inotropic20 21 22 and cytolytic23 effects on myocytes. Beyond the effects on intracellular second messengers such as cGMP, NO is known to bind to iron-containing proteins such as those in the respiratory chain and to complex with oxygen free radicals to form the highly toxic peroxynitrite radical.24 25 iNOS generates higher and more sustained levels of NO than ecNOS, and it appears likely that high local concentrations of NO in cardiac myocytes exert important pathophysiological effects.
The aim of the present study was to determine whether there was evidence for iNOS mRNA and protein expression in the ventricular myocardium of patients with heart failure secondary to idiopathic dilated cardiomyopathy, ischemic heart disease, and valvular heart disease and to compare the findings with control tissue.
|
Methods |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Subjects
Right ventricular myocardium from the endocardial surface of the intraventricular septum was obtained at the time of cardiac transplantation or at diagnostic endomyocardial biopsy from patients being treated for heart failure. In addition, samples were taken during cardiopulmonary bypass from the interventricular septum of patients undergoing valve replacement surgery who were being treated for mild-to-moderate heart failure. Control myocardium was obtained from two sources: donor hearts before implantation (donor hearts) and after autopsies performed on victims of sudden death from a noncardiac cause within 6 hours of the time of death (controls).
In a subgroup of patients with end-stage heart failure undergoing cardiac transplantation, myocardial tissue was taken from all four cardiac chambers. The sites sampled were the right and left atrial appendages, the left ventricular free wall, and the right side of the interventricular septum.
Clinical information on the
subjects studied is shown in Tables 1
and 2. All
living patients who
underwent biopsy gave informed consent before the procedure in
accordance with the hospitals' human subjects review boards.
|
|
RT-PCR
In all cases, the myocardial tissue obtained was
immediately
frozen in liquid nitrogen and stored at -80°C. Total RNA was
isolated from tissue samples according to the method of Chomozynski and
Sacchi26 with Trizol reagent (GIBCO-BRL Life Technologies
Inc). RNA was extracted with the use of chloroform and precipitated by
isopropanol. The RNA was washed in 75% ethanol, dried, and stored
under 100% ethanol at -70°C until required. RNA was quantified by
spectrophotometry with the A260/280 method.
Before use, samples were centrifuged at 4°C and resuspended
in RNAse-free water. First-strand cDNA was synthesized from
total RNA with monkey Moloney leukemia virus RT (Perkin-Elmer Cetus)
and random hexamers. Amplification by PCR was carried out in a total
reaction volume of 50 µL. The sequences of the primers and the
conditions used are shown in Table 3. Three microliters
of cDNA from the 30-µL product of the RT step was added to each
reaction mix. Thermal cycling was performed with a PTC 100 thermal
cycler (MJ Research). Electrophoresis of the amplified products was
performed on 1.5% agarose gel containing Tris acetate/EDTA and
ethidium bromide. A HaeIII digest of 
174 DNA (GIBCO-BRL
Life Technologies) was used as a molecular size standard. Gels were
visualized with UV irradiation and photographed.
|
Amplification of ß-actin was used to demonstrate the presence of intact mRNA in each total RNA sample and to help demonstrate approximate equivalence of mRNA loading in each RT-PCR. Atrial natriuretic peptide gene expression is normally undetectable in healthy ventricular myocardium but is induced under the conditions associated with heart failure27 and was used as a sensitive molecular marker of disturbed gene expression in human ventricular myocardium.
RT-PCR Control Experiments
Absence of genomic contamination
in the cDNA samples was
confirmed by the use of a PCR reaction with primers that amplify the
promoter region of apolipoprotein (a)–related gene C, a nontranscribed
region of genomic DNA.28 These primers were designed to
sensitively and specifically amplify genomic DNA only, and the
technique was validated against serial dilutions of genomic DNA and
total RNA with or without RNAse pretreatment before RT-PCR (G.A.
Haywood, C.D. Byrne, unpublished data, 1994). This method allows
screening of cDNA for genomic contamination without the need to use
RT-negative RNA controls, thus saving on the consumption of total RNA.
If any genomic contamination were present, the samples were also
tested with PCR for human skeletal -actin to ensure that a
false-positive result had not been obtained by amplification of an
intronless ß-actin pseudogene. Any false-positive results
were excluded from the analysis. The ANP, human skeletal
-actin, and iNOS primers each spanned intron
sequences29 30 31 to enable
identification of amplification
of cDNA from any genomic DNA amplification by the size of the
product. Selected samples were also pretreated with RNAse before
RT-PCR to confirm complete elimination of the product bands. In
addition, a number of samples were treated with DNAse 1 before RT and
PCR to ensure that normalization to equivalent ß-actin band
intensity had not been affected by the amplification of any genomic
contamination. Amplification of mRNA for ß-actin and human
skeletal -actin was confirmed in all control samples.
Western Blot Analysis
Total protein was extracted from
ventricular
myocardium with the Trizol method according to
manufacturer's instructions (GIBCO-BRL Life Technologies Inc)
solubilized with 1% SDS and separated on 8% denaturing SDS
polyacrylamide gels (15 to 25 µg/lane). Proteins were then
transferred onto a nitrocellulose membrane (Hybond-ECL, Amersham) by
wet electroblotting for 4 hours. Blots were blocked for 1 hour at room
temperature with 5% nonfat dry milk in TBS-T (20 mmol/L Tris-HCl, 200
mmol/L NaCl, 0.1% Tween-20) before incubation with mouse
anti-macrophage NOS monoclonal IgG (Transduction
Laboratories). Incubation with the primary antibody was at a dilution
of 1:500 for 1 hour at room temperature and, after washing, with the
second antibody (horseradish peroxidase–conjugated sheep
anti-mouse immunoglobulin antibody [Amersham]) at 1:1500
for 1 hour. Specific proteins (131 kD) were detected by enhanced
chemiluminescence (Amersham) according to the manufacturer's
instructions. Prestained protein markers (Sigma) were used for
molecular mass determinations. Two micrograms of mouse
macrophage cell lysate stimulated with IFN- (10 ng/mL) and
lipopolysaccharide (1 µg/mL) for 12 hours (Transduction
Laboratories) were used as a positive control.
Immunohistochemistry
Fresh, unfixed tissue frozen in OCT
(Miles Inc) was sectioned
with a cryostat. Adjacent sections were placed on duplicate slides.
Sections were fixed with acetone at 4°C for 10 minutes, air-dried
at room temperature for 20 minutes, and rehydrated in PBS for 15
minutes. They were then treated with 3% H2O2
for 10 minutes and washed again in PBS for 15 minutes. Sections were
then blocked with 5% rabbit serum for 15 minutes. Detection of iNOS
was performed with the same primary antibody as used for Western
blotting in a 1:10 dilution. Adjacent sections were treated
with a 1:20 dilution of an anti-desmin mouse monoclonal primary
antibody (Sigma) to allow colocalization to cardiac myocytes. The
sections were then incubated for 1 hour at room temperature and then
washed in PBS for 15 minutes. Control sections for each patient were
incubated with mouse ascites (Sigma). Secondary antibody (rabbit
anti-mouse, biotinylated; DAKO) was applied as a 1:50 dilution,
incubated at room temperature for 30 minutes, and washed for 15 minutes
in PBS. Streptavidin-peroxidase conjugate was applied for 15
minutes, followed by AEC chromagen. Counterstaining was done with
hematoxylin.
In addition, a subgroup of donor heart and left ventricular failing heart sections were analyzed with a fluorescent double-staining technique. Sections were fixed in acetone for 10 minutes at 4°C, air-dried, and rehydrated with PBS. They were then blocked with 10% horse serum in 0.3% Tween-20 and 0.85% NaCl in 10 mmol/L phosphate buffer at room temperature for 15 minutes. Sections were then incubated with 1:10 mouse anti-macrophage NOS monoclonal IgG (Transduction Laboratories) in a 1:5 dilution of blocking solution in PBS at room temperature for 1 hour. After washes with PBS, the sections were incubated with biotinylated anti-mouse IgG 1:200 (Vector Labs) and rabbit polyclonal anti-desmin 1:20 (Sigma) for 1 hour. After being washed again in PBS, they were then incubated with fluorescein avidin D 1:250 (Vector Laboratories) and goat anti-rabbit Texas red 1:100 (Vector Laboratories) in PBS, pH 8.2. Sections were then washed, dried, and mounted.
Statistical Analysis
Statistical analysis was performed with
the statistical
software package STATVIEW (Abacus) on an Apple Macintosh
computer. Age differences between the experimental groups were compared
with ANOVA, and posthoc testing was done with Scheffé's F test.
The frequency of positive PCR results from the different groups was
compared with the use of multiple-comparison contingency table
analysis with the 
2 test.
|
Results |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Patient Characteristics
The age, method of tissue sampling, and severity of heart failure of the patients in the different etiological groups are shown in Tables 1
and 2. The age of the control subjects was not
significantly
different than that of the other groups (F=6.563 and
P=.013;
P=.517, P=.972, P=.117, and
P=.132 for donors, dilated
cardiomyopathy, ischemic heart disease, and
valvular heart disease, respectively). However, heart donors
were significantly younger than patients with ischemic heart
disease (P=.002) or with valvular heart disease
(P=.004), whereas not different from those with dilated
cardiomyopathy (P=.175).
PCR Results
The frequency of gene expression for iNOS and ANP
in the different
patient groups analyzed by RT-PCR amplification to 35 cycles is
shown in Fig 1. All patients who expressed iNOS also
expressed ANP. The presence of intact mRNA was confirmed in all
samples. The difference in the frequency of expression of iNOS between
the control patients' biopsies and the explanted hearts was highly
significant overall and for each of the etiological subgroups (dilated
cardiomyopathy, ischemic heart disease, and
valvular heart disease; P<.0001 overall and for
each pairwise comparison). A representative
electrophoretic gel for patients from the different subgroups is shown
in Fig 2.
|
|
Amplification of cDNA from the control patients to 40 cycles still failed to result in any detectable iNOS PCR product bands. In contrast cDNA from nonfailing donor hearts showed amplification bands at 35 cycles in 5 of 10 patients.
Negative Controls
No iNOS PCR product bands could be detected
when RT-PCR was
performed on total RNA from unstimulated cultured human monocytes (THP1
cells, American Type Culture Collection). Similarly, iNOS message was
undetectable in a human heart cDNA library taken from four normal
hearts and with characteristics indicating that the library is a
suitable source for the detection of low-abundance mRNAs (Clontech
Laboratories).
Frequency of iNOS Expression Compared With NYHA Class
When
patients with heart failure from the different etiological
groups were pooled, iNOS expression was present in all 11 patients
in NYHA class II, in 17 of 24 patients in NYHA class III, and in 8 of
14 patients in NYHA class IV. Thus, iNOS expression appeared to be
significantly more common in NYHA class II heart failure patients than
in either class III (P<.05) or class IV (P<.02)
heart failure patients.
Regional Expression of iNOS
Total RNA was analyzed from each
of the four chambers of
the hearts of six patients with end-stage heart failure and
positive iNOS expression in the right ventricle. PCR product bands
specific for iNOS were detectable in all four chambers at varying
intensities. In some cases, iNOS mRNA expression appeared to be most
prominent in the left ventricle.
Immunohistochemistry Results
Sections were analyzed from the
right ventricle of three
nonfailing donor hearts and from three patients with dilated
cardiomyopathy, three patients with
ischemic heart disease, and one patient with valvular
heart disease. Myocardial sections were also taken from all four
chambers of the heart of one patient from each of the etiological
groups. Representative sections with staining for iNOS
and for desmin (to allow myocyte localization) are shown in Fig
3. In Fig 3A through Fig 3D,
pinkish-brown staining
indicates binding of the primary antibody-secondary
antibody/chromagen complex. In Fig E and Fig F, the green
fluorescence indicates iNOS, and the red fluorescence
indicates desmin. Detection of iNOS protein could be clearly
colocalized, with desmin indicating iNOS expression in the cytoplasm of
cardiac myocytes. Only minimal positive staining was observed on
sections from nonfailing donor hearts, including that from tissue that
had been positive for iNOS mRNA expression. To test for nonspecific
staining by the secondary antibody/chromagen complex, mouse ascites was
substituted for the primary antibody on control sections from patients
with failing ventricular myocardium. No
significant nonspecific staining was observed with the chromagen
complex; background levels of fluorescence were also markedly
lower than the levels of fluorescence seen in the sections that
stained positive for either iNOS or desmin. No obvious differences were
observed in the pattern of staining among the subjects in each
etiological group, and there were no clear differences in the pattern
or intensity of staining present in myocardium from the
different cardiac chambers. All hearts from patients with heart failure
that were analyzed showed positive staining.
|
Western Blot Analysis
Protein was extracted from two of the
donor hearts and four of the
failing hearts examined by immunohistochemistry. The primary antibody
used for immunohistochemical staining specifically recognized the
130-kD iNOS protein in the heart failure samples. A mouse
stimulated-macrophage cell lysate was used as a positive
control. Stronger bands were seen in failing hearts positive for iNOS
mRNA by RT-PCR than in positive donor hearts (Fig 4).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Results of the present study provide evidence that heart failure is associated with induction of iNOS gene expression in the ventricular myocardium and that iNOS protein is present in ventricular myocytes from patients with end-stage heart failure secondary to dilated cardiomyopathy, ischemic heart disease, or valvular heart disease.
Unlike the brain and ec isoforms of NOS, iNOS is not considered to be expressed in healthy tissues.12 The finding that iNOS gene expression was undetectable in control samples was therefore anticipated. It appears, however, that iNOS mRNA expression parallels induction of atrial natriuretic peptide gene expression in ventricular myocardium and, like atrial natriuretic peptide,27 32 is associated with early as well as end-stage heart failure. It has been suggested that inducible iNOS is part of a primitive but evolutionarily conserved inflammatory response.9 The patients in this study did not have systemic sepsis but may have had chronically elevated levels of proinflammatory cytokines. Alternatively, it may be that other abnormal stimuli, such as altered mechanical stresses on myocytes, are capable of inducing expression of iNOS independent of cytokine activation.
Not all ventricular samples from failing hearts analyzed in the present study were positive by RT-PCR. This may reflect that gene expression for iNOS is triggered by factors or conditions that are not universally present in end-stage heart failure. The group with the highest frequency of detectable expression was the patients with valvular heart disease, most of whom had mild-to-moderate (NYHA class II) heart failure. It may be that iNOS mRNA expression is phasic during the progression of heart failure and that analysis of samples taken at a single time point in the course of the disease underestimates the overall frequency of gene expression. Other explanations for the nonuniformity of iNOS gene expression in end-stage heart failure are that there may be negative feedback on gene transcription or that there may be negative regulation at the transcriptional or pretranslational level by cellular factors such as TGF-ß.33 34
One of the difficulties in studying diseased human
myocardium is the absence of a readily obtainable source of
normal control tissue. We overcame this problem by using tissue
obtained at autopsy from patients without cardiac disease who had died
suddenly from a noncardiac cause. Autopsies were performed close to the
time of death, while good-quality mRNA was still present. There
must still be a theoretical possibility that iNOS mRNA undergoes more
rapid degradation than mRNA for ß-actin or human skeletal
-actin and that this could have resulted in the absence of iNOS
amplification from these control samples. The absence of iNOS mRNA in
the control ventricular myocardium is, however,
in accord with the more general observation of a lack of iNOS
expression in healthy tissues in mammals, and iNOS expression could not
be detected in a normal human heart cDNA library. Insufficient
quantities of control subjects' myocardium were available
for protein analysis in addition to RT-PCR, and we therefore
used donor heart myocardium for the control tissue in our
analysis of protein expression. Nonfailing donor heart tissue
is by far the most common source of control myocardium
reported in the literature by groups studying human heart failure. It
was, however, of interest to note that iNOS mRNA expression was
detectable in some donors (50%). This may have been due to the
abnormal conditions associated with brain death, ventilation,
explanation of the donor heart, and transportation. The particular
component of these events that results in induction of the iNOS gene
cannot be identified from this study. The expression of iNOS mRNA in
donor myocardium did not, however, result in significant
levels of protein expression. The explanation for this may be
quantitative, with too little iNOS protein synthesized by the donor
hearts to be detected by immunohistochemical staining. Alternatively,
it may be that iNOS gene expression occurs late in the sequence of
abnormal events to which donor hearts are subjected, resulting in
insufficient time for significant protein translation to occur. It is
also possible that abnormal gene expression can occur under the
metabolic conditions that are present during
transportation of the donor heart but that these conditions prevent
translation of the protein.
One concern in interpreting the results is that the process of cardiothoracic surgery or explantation might be sufficient to account for the induction of iNOS in the explanted failing and nonfailing hearts. It seems unlikely, however, that this accounts for the positive results in the failing hearts because endomyocardial biopsies removed at cardiac catheterization from patients with end-stage heart failure, in which the interval between biopsy and snap-freezing in liquid nitrogen was 10 to 15 seconds, were as positive for iNOS gene expression as the explanted failing hearts.
It could also be argued that the absence of iNOS protein in the donor hearts was a function of the younger age of this group, but this would be contrary to the considerable literature indicating that iNOS is not constitutively expressed. Furthermore, some patients with failing ventricles expressing iNOS were younger than some donors of hearts that were negative for iNOS protein.
The observations arising from this study showed some differences compared with previous reports.16 17 With the arginine-citrulline activity assay, these investigators inferred the relative contributions to total NO synthesis from ecNOS and iNOS by measuring the effect of calcium chelators. They concluded that iNOS was induced in dilated cardiomyopathy and "focal healing myocarditis" but not in ischemic heart disease or aortic regurgitation. The enzymatic activity of the murine equivalent of iNOS, mouse mac-NOS, shows almost complete calcium independence, and the effect on NO and citrulline generation of chelating agents such as EDTA allows effective discrimination between iNOS and ecNOS. However, it has been demonstrated that transfection of embryonic kidney cells with a human iNOS construct resulted in NOS catalytic activity that was lowered by 70% in the presence of calcium-chelating agents. A murine mac-NOS construct transfected in the same cells produced NOS activity that showed classic calcium independence.9 It is therefore possible that the interpretation of whether iNOS or ecNOS was responsible for NO production in the different etiological groups in the studies by De Belder and colleagues16 17 may have been misleading. It seems unlikely that the calcium sensitivity displayed by human iNOS expressed in embryonic kidney cells would differ substantially from human iNOS expression in cardiac myocytes; the human iNOS gene is a single copy gene,31 and there is no evidence to suggest that different iNOS proteins are synthesized in different organs.
We did not attempt to measure or correlate the presence of iNOS with the severity of ventricular dysfunction in the patients with heart failure. NO donors have been shown to reduce isolated guinea pig myocyte contraction amplitude at concentrations of 3x10-5 mol/L22 and to reduce developed tension in human atrial muscle strips at 10-3 mol/L.21 These effects may be mediated via cGMP or by cytotoxic effects on iron-containing enzymes of the respiratory chain.35 The concentration of NO that is present in the cytosol of human ventricular myocytes in failing hearts is unknown and cannot be directly determined, and correlations in patients between total NO synthesis, calcium-independent NO synthesis, cGMP levels, and ventricular function will be subject to large numbers of uncontrolled variables. It is also possible that chronic elevation of intracellular levels of NO results in cell death through cytolysis or apoptosis,36 37 resulting in left ventricular dysfunction through depletion of the total myocyte population. Studies of the functional significance of the induction of iNOS in failing myocardium may require the development of animal models and the chronic use of specific iNOS inhibitors such as aminoguanidine.38
Conclusions
Evidence of iNOS gene expression was present in
ventricular myocardium of patients with both
mild-to-moderate and severe heart failure regardless of
etiology but was virtually undetectable in nondiseased
myocardium. Expression of iNOS mRNA appears to be an early
event paralleling expression of atrial natriuretic peptide.
These observations raise the possibility that autocrine and paracrine
actions of iNOS may be of pathophysiological
importance in patients with failing ventricles.
|
Selected Abbreviations and Acronyms |
|---|
|
|
Acknowledgments |
|---|
We are most grateful to Dr Margaret Billingham for discussion and advice related to the immunohistochemical data, Barbara Sato for expert technical assistance with the fluorescent double-staining technique, and Dr Byron W. Brown, Jr, for statistical advice. We also thank the surgical staff at Stanford, London, and Hanover, who assisted us in the collection of the myocardial samples, and in particular we thank Hermann Reichenspurner and John Stevens.
Received April 17, 1995; revision received September 7, 1995; accepted September 10, 1995.
|
References |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
1. Vallance P, Moncada S. Nitric oxide: from mediator to medicines. J Roy Coll Phys (Lond). 1994;28:209-219.
2. Drexler H, Hayoz D, Münzel T, Hornig B, Jüst H, Brunner HR, Zelis R. Endothelial function in chronic congestive heart failure. Am J Cardiol. 1992;69:1596-1601. [Medline] [Order article via Infotrieve]
3. Kubo SH, Rector TS, Bank AJ, Raij L, Kraemer MD, Tadros P, Beardslee M, Garr MD. Lack of contribution of nitric oxide to basal vasomotor tone in heart failure. Am J Cardiol. 1994;74:1133-1136. [Medline] [Order article via Infotrieve]
4. O'Murchu B, Miller V, Perrella M, Burnett JC Jr. Increased production of nitric oxide in coronary arteries during congestive heart failure. J Clin Invest. 1994;93:165-171.
5. Hibbs J, Taintor R, Vavrin Z, Rachlin E. Nitric oxide: a cytotoxic activated macrophage effector molecule. Biochem Biophys Res Commun. 1988;157:87-94. [Medline] [Order article via Infotrieve]
6. Liu S, Adcock I, Old R, Barnes P, Evans T. Lipopolysaccharide treatment in vivo induces widespread tissue expression of inducible nitric oxide synthase mRNA. Biochem Biophys Res Commun. 1993;196:1208-1213. [Medline] [Order article via Infotrieve]
7.
Balligand J-L, Ungureanu-Longrois D, Simmons W,
Pimental D, Malinski TA, Kapturczak M, Taha Z, Lowenstein CJ, Davidoff
AJ, Kelly RA, Smith TW, Michel T. Cytokine-inducible
nitric oxide synthase (iNOS) expression in cardiac myocytes.
J Biol Chem. 1994;269:27580-27588.
8. Schulz R, Nava E, Moncada S. Induction and potential biological relevance of a Ca2+ independent nitric oxide synthase in the myocardium. Br J Pharmacol. 1992;105:575-580. [Medline] [Order article via Infotrieve]
9.
Geller D, Lowenstein C, Shapiro R, Nussler AK, Di
Silvio M, Wang SC, Nakayama DK, Simmons RL, Snyder SH, Billiar TR.
Molecular cloning and expression of inducible nitric oxide
synthase from human hepatocytes. Proc Natl
Acad Sci U S A. 1993;90:3491-3495.
10.
Charles I, Palmer R, Hickery M, Bayliss MT, Chubb AP,
Hall VS, Moss DW, Moncada S. Cloning characterization and
expression of a cDNA encoding an inducible nitric oxide synthase from
the human chondrocyte. Proc Natl Acad Sci U S A. 1993;90:11419-11423.
11. Hibbs JJ, Westenfelder C, Taintor R, Vavrin Z, Kablitz C, Baranowski RL, Ward JH, Menlove RL, McMurray MP, Kushner JP, Samlowski WE. Evidence for cytokine-inducible nitric oxide synthesis from L-arginine in patients receiving interleukin-2 therapy. J Clin Invest. 1992;89:867-877.
12. Moncada S, Palmer R, Higgs E. Nitric oxide: physiology, pathophysiology and pharmacology. Pharmacol Rev. 1991;43:109-142. [Medline] [Order article via Infotrieve]
13. Levine B, Kalman J, Mayer L, Fillit H, Packer M. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med. 1990;223:236-241.
14.
McMurray J, Abdullah I, Dargie H, Shapiro D.
Increased concentrations of tumour necrosis factor in
`cachectic' patients with severe chronic heart failure.
Br Heart J. 1991;66:356-358.
15. Winslaw D, Smythe G, Keogh A, Schyvens C, Spratt P, MacDonald P. Increased nitric oxide production in heart failure. Lancet. 1994;1:373-374.
16. De Belder A, Radomski M, Why H, Richardson PJ, Bucknall CA, Salas E, Martin JF, Moncada S. Nitric oxide synthase activities in human myocardium. Lancet. 1993;1:84-85.
17. De Belder A, Radomski M, Why H, Richardson P, Martin J, Moncada S. Expression of an inducible NO synthase in heart tissue from patients with inflammatory heart disease. J Am Coll Cardiol. 1994;263A. Abstract.
18.
Maury C, Teppo A. Circulating tumour necrosis
factor- (cachectin) in myocardial infarction. J
Intern Med. 1989;225:333-336. [Medline]
[Order article via Infotrieve]
19.
Mann D, Young J. Basic mechanisms in congestive
heart failure: recognizing the role of proinflammatory
cytokines. Chest. 1994;105:897-904.
20.
Finkel M, Odis C, Jacob T, Watkins S, Hattler B,
Simmons R. Negative inotropic effects of cytokines on
the heart mediated by nitric oxide. Science. 1992;257:387-389.
21. Smith R, Desai J, Forsyth A, Martin J. Nitric oxide reduces contractility of isolated human myocardium. Br Heart J. 1994;71:P71. Abstract.
22.
Brady A, Warren J, Poole-Wilson P, Williams T, Harding
S. Nitric oxide attenuates cardiac myocyte contraction.
Am J Physiol. 1993;265:H176-H182.
23. Pinsky D, Cai B, Yang X, Rodriguez C, Sciacca R, Cannon P. Nitric oxide–dependent killing of cardiac myocytes by adjacent macrophages. Circulation. 1994;90(suppl I):I-192. Abstract.
24. Bolanos J, Peuchen S, Heales S, Land J, Clark J. Nitric oxide-mediated inhibition of the mitochondrial respiratory chain in cultured astrocytes. J Neurochem. 1994;63:910-916. [Medline] [Order article via Infotrieve]
25. Kooy N, Royall J, Ye Y, Kelly D, Beckman J. Evidence for in vivo peroxynitrite production in human acute lung injury. Am J Resp Crit Care Med. 1995;151:1250-1254. [Abstract]
26. Chomzynski P, Sacchi N. Single step method of RNA isolation by acid guanidinium-thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987;162:156-159. [Medline] [Order article via Infotrieve]
27.
Feldman A, Ray P, Silan C, Mercer J, Minobe W, Bristow
M. Selective gene expression in failing human heart:
quantification of steady-state levels of messenger RNA in
endomyocardial biopsies using the polymerase chain
reaction. Circulation. 1991;83:1866-1872.
28.
Byrne C, Schwartz K, Meer K, Cheng J-F, Lawn R.
The human apolipoprotein (a)/plasminogen gene
cluster contains a novel homologue transcribed in liver.
Arterioscler Thromb. 1994;14:534-541.
29. Greenberg B, Bencen G, Seilhamer J, Lewicki J, Fiddes J. Nucleotide sequence of the gene encoding human atrial natriuretic factor precursor. Nature. 1984;312:656-658. [Medline] [Order article via Infotrieve]
30. Taylor A, Erba H, Muscat G, Kedes L. Nucleotide sequence and expression of the human skeletal alpha-actin gene: evolution of functional and regulatory domains. Genomics. 1988;3:323-336. [Medline] [Order article via Infotrieve]
31.
Chartrain N, Geller D, Koty P, Sitrin NF, Nussler AK,
Hoffman EP, Billiar TR, Hutchinson NI, Mudgett JS. Molecular
cloning, structure and chromosomal localization of the human inducible
nitric oxide synthase gene. J Biol Chem. 1994;269:6765-6772.
32. Redfield M, Stevens T, Aarhus L, Meyer L, Burnett J. Differential role of circulating and ventricular ANP as a marker for cardiac filling pressures and ventricular remodeling in a model of pacing induced heart failure and cardiac hypertrophy. J Am Coll Cardiol. 1995;25:133A. Abstract.
33.
Roberts A, Vodovotz Y, Roche N, Sporn M, Nathan C.
Role of nitric oxide in antagonistic effects of
transforming growth factor-ß and interleukin-1 ß on the beating
rate of cultured cardiac myocytes. Mol Endocrinol. 1992;6:1921-1930.
34. Shindo T, Ikeda U, Ohkawa F, Takahashi M, Funayama H, Nishinaga M, Kawahara Y, Yokoyama M, Kasahara T, Shimada K. Nitric oxide synthesis in rat cardiac myocytes and fibroblasts. Life Sci. 1994;55:1101-1108. [Medline] [Order article via Infotrieve]
35. Drapier J, Hibbs JJ. Differentiation of murine macrophages to express nonspecific cytotoxicity for tumor cells results in L-arginine-dependent inhibition of mitochondrial iron-sulfur enzymes in the macrophage effector cells. J Immunol. 1988;140:2829-2838. [Abstract]
36. Albina J, Cui S, Mateo R, Reichner J. Nitric oxide mediated apoptosis in murine peritoneal macrophages. J Immunol. 1993;150:5080-5085. [Abstract]
37. Blanco F, Ochs R, Schwarz H, Lotz M. Chondrocyte apoptosis induced by nitric oxide. Am J Pathol. 1995;146:75-85. [Abstract]
38. McAllister R, Whitley G, Vallance P. Effects of guanidino and uremic compounds on nitric oxide pathways. Kidney Int. 1994;45:737-742.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  A. Maffei and G. Lembo Nitric oxide mechanisms of nebivolol Therapeutic Advances in Cardiovascular Disease, August 1, 2009; 3(4): 317 - 327. [Abstract] [PDF]
|
|
|
|
 |
|
 J. L. Durand, S. Mukherjee, F. Commodari, A. P. De Souza, D. Zhao, F. S. Machado, H. B. Tanowitz, and L. A. Jelicks Role of NO Synthase in the Development of Trypanosoma cruzi-Induced Cardiomyopathy in Mice Am J Trop Med Hyg, May 1, 2009; 80(5): 782 - 787. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Yang, Z. Fang, Y. Liu, H. Zhang, X. Shi, Q. Ji, Q. Lin, and R. Lin Protective Effects of Chinese Traditional Medicine Buyang Huanwu Decoction on Myocardial Injury Evid. Based Complement. Altern. Med., February 8, 2009; (2009) nep013v1. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Krenek, J. Kmecova, D. Kucerova, Z. Bajuszova, P. Musil, A. Gazova, P. Ochodnicky, J. Klimas, and J. Kyselovic Isoproterenol-induced heart failure in the rat is associated with nitric oxide-dependent functional alterations of cardiac function Eur J Heart Fail, February 1, 2009; 11(2): 140 - 146. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Sun, O. A. Carretero, J. Xu, N.-E. Rhaleb, J. J. Yang, P. J. Pagano, and X.-P. Yang Deletion of Inducible Nitric Oxide Synthase Provides Cardioprotection in Mice With 2-Kidney, 1-Clip Hypertension Hypertension, January 1, 2009; 53(1): 49 - 56. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. R. Heinzel, P. Gres, K. Boengler, A. Duschin, I. Konietzka, T. Rassaf, J. Snedovskaya, S. Meyer, A. Skyschally, M. Kelm, et al. Inducible Nitric Oxide Synthase Expression and Cardiomyocyte Dysfunction During Sustained Moderate Ischemia in Pigs Circ. Res., November 7, 2008; 103(10): 1120 - 1127. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. M. El-Mas, M. Fan, and A. A. Abdel-Rahman Endotoxemia-Mediated Induction of Cardiac Inducible Nitric-Oxide Synthase Expression Accounts for the Hypotensive Effect of Ethanol in Female Rats J. Pharmacol. Exp. Ther., January 1, 2008; 324(1): 368 - 375. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. G. Williams, T. Rincon-Skinner, D. Sun, Z. Wang, S. Zhang, X. Zhang, and T. H. Hintze Role of nitric oxide in the coupling of myocardial oxygen consumption and coronary vascular dynamics during pregnancy in the dog Am J Physiol Heart Circ Physiol, October 1, 2007; 293(4): H2479 - H2486. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Maffei, A. Di Pardo, R. Carangi, P. Carullo, R. Poulet, M. T. Gentile, C. Vecchione, and G. Lembo Nebivolol Induces Nitric Oxide Release in the Heart Through Inducible Nitric Oxide Synthase Activation Hypertension, October 1, 2007; 50(4): 652 - 656. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Fu, Z. Wang, W. L. Chen, P. K. Moore, and Y. Z. Zhu Cardioprotective effects of nitric oxide-aspirin in myocardial ischemia-reperfused rats Am J Physiol Heart Circ Physiol, September 1, 2007; 293(3): H1545 - H1552. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Zhang, X. Xu, X. Hu, E. D. van Deel, G. Zhu, and Y. Chen Inducible Nitric Oxide Synthase Deficiency Protects the Heart From Systolic Overload-Induced Ventricular Hypertrophy and Congestive Heart Failure Circ. Res., April 13, 2007; 100(7): 1089 - 1098. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Shiroshita-Takeshita, B. J.J.M. Brundel, B. Burstein, T.-K. Leung, H. Mitamura, S. Ogawa, and S. Nattel Effects of simvastatin on the development of the atrial fibrillation substrate in dogs with congestive heart failure Cardiovasc Res, April 1, 2007; 74(1): 75 - 84. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. N. Mazzadi, X. Andre-Fouet, N. Costes, P. Croisille, D. Revel, and M. F. Janier Mechanisms leading to reversible mechanical dysfunction in severe CAD: alternatives to myocardial stunning Am J Physiol Heart Circ Physiol, December 1, 2006; 291(6): H2570 - H2582. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Hu, X. Jiao, E. Gao, W. J. Koch, S. Sharifi-Azad, Z. Grunwald, X. L. Ma, and J.-Z. Sun Chronic beta-Adrenergic Receptor Stimulation Induces Cardiac Apoptosis and Aggravates Myocardial Ischemia/Reperfusion Injury by Provoking Inducible Nitric-Oxide Synthase-Mediated Nitrative Stress J. Pharmacol. Exp. Ther., August 1, 2006; 318(2): 469 - 475. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Steppan, S. Ryoo, K. H. Schuleri, C. Gregg, R. K. Hasan, A. R. White, L. J. Bugaj, M. Khan, L. Santhanam, D. Nyhan, et al. Arginase modulates myocardial contractility by a nitric oxide synthase 1-dependent mechanism PNAS, March 21, 2006; 103(12): 4759 - 4764. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Z. Zhu, C. L. Chong, S. C. Chuah, S. H. Huang, H. S. Nai, H. T. Tong, M. Whiteman, and P. K. Moore Cardioprotective effects of nitroparacetamol and paracetamol in acute phase of myocardial infarction in experimental rats Am J Physiol Heart Circ Physiol, February 1, 2006; 290(2): H517 - H524. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Li, Y. Guo, W. Tan, A. B. Stein, B. Dawn, W.-J. Wu, X. Zhu, X. Lu, X. Xu, T. Siddiqui, et al. Gene therapy with iNOS provides long-term protection against myocardial infarction without adverse functional consequences Am J Physiol Heart Circ Physiol, February 1, 2006; 290(2): H584 - H589. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Godecke On the impact of NO-globin interactions in the cardiovascular system Cardiovasc Res, February 1, 2006; 69(2): 309 - 317. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-H. Liu, O. A. Carretero, O. H. Cingolani, T.-D. Liao, Y. Sun, J. Xu, L. Y. Li, P. J. Pagano, J. J. Yang, and X.-P. Yang Role of inducible nitric oxide synthase in cardiac function and remodeling in mice with heart failure due to myocardial infarction Am J Physiol Heart Circ Physiol, December 1, 2005; 289(6): H2616 - H2623. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Ozguner, A. Altinbas, M. Ozaydin, A. Dogan, H. Vural, A N. Kisioglu, G. Cesur, and N. G. Yildirim Mobile phone-induced myocardial oxidative stress: protection by a novel antioxidant agent caffeic acid phenethyl ester Toxicology and Industrial Health, August 1, 2005; 21(7-8): 223 - 230. [Abstract] [PDF]
|
|
|
|
|
|
A. Borbely, A. Toth, I. Edes, L. Virag, J. G. Papp, A. Varro, W. J. Paulus, J. van der Velden, G. J.M. Stienen, and Z. Papp Peroxynitrite-induced {alpha}-actinin nitration and contractile alterations in isolated human myocardial cells Cardiovasc Res, August 1, 2005; 67(2): 225 - 233. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M Vanderheyden, W J Paulus, M Voss, P Knuefermann, N Sivasubramanian, D Mann, and G Baumgarten Myocardial cytokine gene expression is higher in aortic stenosis than in idiopathic dilated cardiomyopathy Heart, July 1, 2005; 91(7): 926 - 931. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. D. Patten, D. DeNofrio, M. El-Zaru, R. Kakkar, J. Saunders, F. Celestin, K. Warner, H. Rastegar, K. R. Khabbaz, J. E. Udelson, et al. Ventricular Assist Device Therapy Normalizes Inducible Nitric Oxide Synthase Expression and Reduces Cardiomyocyte Apoptosis in the Failing Human Heart J. Am. Coll. Cardiol., May 3, 2005; 45(9): 1419 - 1424. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. C. Starling Inducible Nitric Oxide Synthase in Severe Human Heart Failure: Impact of Mechanical Unloading J. Am. Coll. Cardiol., May 3, 2005; 45(9): 1425 - 1427. [Full Text] [PDF]
|
|
|
|
|
|
J. Niebauer, A. L. Clark, K. M. Webb-Peploe, R. Boger, and A. J.S. Coats Home-based exercise training modulates pro-oxidant substrates in patients with chronic heart failure Eur J Heart Fail, March 2, 2005; 7(2): 183 - 188. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. J. Lokuta, N. A. Maertz, S. V. Meethal, K. T. Potter, T. J. Kamp, H. H. Valdivia, and R. A. Haworth Increased Nitration of Sarcoplasmic Reticulum Ca2+-ATPase in Human Heart Failure Circulation, March 1, 2005; 111(8): 988 - 995. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. P. Jones, J. J. M. Greer, P. D. Ware, J. Yang, K. Walsh, and D. J. Lefer Deficiency of iNOS does not attenuate severe congestive heart failure in mice Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H365 - H370. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. J. Paulus and J. G. F. Bronzwaer Nitric oxide's role in the heart: control of beating or breathing? Am J Physiol Heart Circ Physiol, July 1, 2004; 287(1): H8 - H13. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. D. Prabhu Nitric Oxide Protects Against Pathological Ventricular Remodeling: Reconsideration of the Role of NO in the Failing Heart Circ. Res., May 14, 2004; 94(9): 1155 - 1157. [Full Text] [PDF]
|
|
|
|
|
|
M. T. Ziolo, L. S. Maier, V. Piacentino III, J. Bossuyt, S. R. Houser, and D. M. Bers Myocyte Nitric Oxide Synthase 2 Contributes to Blunted {beta}-Adrenergic Response in Failing Human Hearts by Decreasing Ca2+ Transients Circulation, April 20, 2004; 109(15): 1886 - 1891. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. FOGLI, P. NIERI, and M. C. BRESCHI The role of nitric oxide in anthracycline toxicity and prospects for pharmacologic prevention of cardiac damage FASEB J, April 1, 2004; 18(6): 664 - 675. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Dayoub, V. Achan, S. Adimoolam, J. Jacobi, M. C. Stuehlinger, B.-y. Wang, P. S. Tsao, M. Kimoto, P. Vallance, A. J. Patterson, et al. Dimethylarginine Dimethylaminohydrolase Regulates Nitric Oxide Synthesis: Genetic and Physiological Evidence Circulation, December 16, 2003; 108(24): 3042 - 3047. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Feldman The emerging role of pharmacogenomics in the treatment of patients with heart failure Ann. Thorac. Surg., December 1, 2003; 76(6): S2246 - 2253. [Full Text] [PDF]
|
|
|
|
|
|
P. P. A. Mammen, S. B. Kanatous, I. S. Yuhanna, P. W. Shaul, M. G. Garry, R. S. Balaban, and D. J. Garry Hypoxia-induced left ventricular dysfunction in myoglobin-deficient mice Am J Physiol Heart Circ Physiol, November 1, 2003; 285(5): H2132 - H2141. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Peschel, M. Schonauer, H. Thiele, S. Anker, G. Schuler, and J. Niebauer Invasive assessment of bacterial endotoxin and inflammatory cytokines in patients with acute heart failure Eur J Heart Fail, October 1, 2003; 5(5): 609 - 614. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Marfella, K. Esposito, D. Giugliano, F. Cosentino, M. Eto, B. van der Loo, A. Kouroedov, C. Delli Gatti, H. Joch, T. F. Luscher, et al. Effect of High Glucose on Vasculature * Response Circulation, September 9, 2003; 108 (10): e74 - e74. [Full Text] [PDF]
|
|
|
|
|
|
C. Wunderlich, U. Flogel, A. Godecke, J. Heger, and J. Schrader Acute Inhibition of Myoglobin Impairs Contractility and Energy State of iNOS-Overexpressing Hearts Circ. Res., June 27, 2003; 92(12): 1352 - 1358. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Godecke, A. Molojavyi, J. Heger, U. Flogel, Z. Ding, C. Jacoby, and J. Schrader Myoglobin Protects the Heart from Inducible Nitric-oxide Synthase (iNOS)-mediated Nitrosative Stress J. Biol. Chem., June 6, 2003; 278(24): 21761 - 21766. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Heineke, T. Kempf, T. Kraft, A. Hilfiker, H. Morawietz, R. J. Scheubel, P. Caroni, S. M. Lohmann, H. Drexler, and K. C. Wollert Downregulation of Cytoskeletal Muscle LIM Protein by Nitric Oxide: Impact on Cardiac Myocyte Hypertrophy Circulation, March 18, 2003; 107(10): 1424 - 1432. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. L. Brutsaert Cardiac Endothelial-Myocardial Signaling: Its Role in Cardiac Growth, Contractile Performance, and Rhythmicity Physiol Rev, January 1, 2003; 83(1): 59 - 115. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Kaye, M. M. Parnell, and B. A. Ahlers Reduced Myocardial and Systemic L-Arginine Uptake in Heart Failure Circ. Res., December 13, 2002; 91(12): 1198 - 1203. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J M Cotton, M T Kearney, and A M Shah Nitric oxide and myocardial function in heart failure: friend or foe? Heart, December 1, 2002; 88(6): 564 - 566. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Tian, J. Liu, P. B. Bitterman, and R. J. Bache Mechanisms of cytokine induced NO-mediated cardiac fibroblast apoptosis Am J Physiol Heart Circ Physiol, November 1, 2002; 283(5): H1958 - H1967. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Ikeda, Y. Maeda, K. Yamamoto, and K. Shimada C-Reactive protein augments inducible nitric oxide synthase expression in cytokine-stimulated cardiac myocytes Cardiovasc Res, October 1, 2002; 56(1): 86 - 92. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Linke, W. Li, H. Huang, Z. Wang, and T. H. Hintze Role of cardiac eNOS expression during pregnancy in the coupling of myocardial oxygen consumption to cardiac work Am J Physiol Heart Circ Physiol, September 1, 2002; 283(3): H1208 - H1214. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Hunt, G. M. Aru, M. R. Hayden, C. K. Moore, B. D. Hoit, and S. C. Tyagi Induction of oxidative stress and disintegrin metalloproteinase in human heart end-stage failure Am J Physiol Lung Cell Mol Physiol, August 1, 2002; 283(2): L239 - L245. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. T Stark, D. J Schaeffer, and D. R Gross Response to: endomyocardial nitric oxide synthase and the hemodynamic phenotypes of human dilated cardiomyopathy and of athlete's heart Cardiovasc Res, August 1, 2002; 55(2): 225 - 228. [Full Text] [PDF]
|
|
|
|
|
|
J. G.F Bronzwaer, C. Zeitz, C. A Visser, and W. J Paulus Endomyocardial nitric oxide synthase and the hemodynamic phenotypes of human dilated cardiomyopathy and of athlete's heart Cardiovasc Res, August 1, 2002; 55(2): 270 - 278. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Chen, J. H. Traverse, R. Du, M. Hou, and R. J. Bache Nitric Oxide Modulates Myocardial Oxygen Consumption in the Failing Heart Circulation, July 9, 2002; 106(2): 273 - 279. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Saito, F. Hu, L. Tayara, L. Fahas, H. Shennib, and A. Giaid Inhibition of NOS II prevents cardiac dysfunction in myocardial infarction and congestive heart failure Am J Physiol Heart Circ Physiol, July 1, 2002; 283(1): H339 - H345. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. H. Traverse, Y. Chen, M. Hou, and R. J. Bache Inhibition of NO production increases myocardial blood flow and oxygen consumption in congestive heart failure Am J Physiol Heart Circ Physiol, June 1, 2002; 282(6): H2278 - H2283. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S Chowdhary, D Harrington, R S Bonser, J H Coote, and J N Townend Chronotropic effects of nitric oxide in the denervated human heart J. Physiol., June 1, 2002; 541(2): 645 - 651. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y.-H. Liu, J. Xu, X.-P. Yang, F. Yang, E. Shesely, and O. A. Carretero Effect of ACE Inhibitors and Angiotensin II Type 1 Receptor Antagonists on Endothelial NO Synthase Knockout Mice With Heart Failure Hypertension, February 1, 2002; 39(2): 375 - 381. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Saito, K. Maehara, K. Tamagawa, Y. Oikawa, T. Niitsuma, S.-I. Saitoh, and Y. Maruyama Alterations of endothelium-dependent and -independent regulation of coronary blood flow during heart failure Am J Physiol Heart Circ Physiol, January 1, 2002; 282(1): H80 - H86. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. T. Ziolo, H. Katoh, and D. M. Bers Expression of Inducible Nitric Oxide Synthase Depresses {beta}-Adrenergic-Stimulated Calcium Release From the Sarcoplasmic Reticulum in Intact Ventricular Myocytes Circulation, December 11, 2001; 104(24): 2961 - 2966. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Post, R. Schulz, P. Gres, and G. Heusch No involvement of nitric oxide in the limitation of beta -adrenergic inotropic responsiveness during ischemia Am J Physiol Heart Circ Physiol, December 1, 2001; 281(6): H2392 - H2397. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Cotton, M. T. Kearney, P. A. MacCarthy, R. M. Grocott-Mason, D. R. McClean, C. Heymes, P. J. Richardson, and A. M. Shah Effects of Nitric Oxide Synthase Inhibition on Basal Function and the Force-Frequency Relationship in the Normal and Failing Human Heart In Vivo Circulation, November 6, 2001; 104(19): 2318 - 2323. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Ishibashi, T. Shimada, Y. Murakami, N. Takahashi, T. Sakane, T. Sugamori, S. Ohata, S.-i. Inoue, Y. Ohta, K. Nakamura, et al. An inhibitor of inducible nitric oxide synthase decreases forearm blood flow in patients with congestive heart failure J. Am. Coll. Cardiol., November 1, 2001; 38(5): 1470 - 1476. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Mayers, T. Hurst, L. Puttagunta, A. Radomski, T. Mycyk, G. Sawicki, D. Johnson, and M. W. Radomski Cardiac surgery increases the activity of matrix metalloproteinases and nitric oxide synthase in human hearts J. Thorac. Cardiovasc. Surg., October 1, 2001; 122(4): 746 - 752. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Sarkar, P. Vallance, and S. E. Harding Nitric oxide: not just a negative inotrope Eur J Heart Fail, October 1, 2001; 3(5): 527 - 534. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. E. Hill The Inflammatory Response to Cardiopulmonary Bypass-- Should It Be Treated? Seminars in Cardiothoracic and Vascular Anesthesia, September 1, 2001; 5(3): 229 - 235. [Abstract] [PDF]
|
|
|
|
|
|
Q. Feng, X. Lu, D. L. Jones, J. Shen, and J. M. O. Arnold Increased Inducible Nitric Oxide Synthase Expression Contributes to Myocardial Dysfunction and Higher Mortality After Myocardial Infarction in Mice Circulation, August 7, 2001; 104(6): 700 - 704. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Valen, Z.-q. Yan, and G.o. K. Hansson Nuclear factor kappa-B and the heart J. Am. Coll. Cardiol., August 1, 2001; 38(2): 307 - 314. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. S. Wittstein, D. A. Kass, P. H. Pak, W. L. Maughan, B. Fetics, and J. M. Hare Cardiac nitric oxide production due to angiotensin-converting enzyme inhibition decreases beta-adrenergic myocardial contractility in patients with dilated cardiomyopathy J. Am. Coll. Cardiol., August 1, 2001; 38(2): 429 - 435. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. SENZAKI, C. J. SMITH1, G. J. JUANG, T. ISODA, S. P. MAYER, A. OHLER, N. PAOLOCCI, G. F. TOMASELLI, J. M. HARE, and D. A. KASS Cardiac phosphodiesterase 5 (cGMP-specific) modulates {beta}-adrenergic signaling in vivo and is down-regulated in heart failure FASEB J, August 1, 2001; 15(10): 1718 - 1726. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. O. Stojanovic, M. T. Ziolo, G. M. Wahler, and B. M. Wolska Anti-adrenergic effects of nitric oxide donor SIN-1 in rat cardiac myocytes Am J Physiol Cell Physiol, July 1, 2001; 281(1): C342 - C349. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Y. T. Hart, E. L. Hahn, D. M. Meyer, J. C. Burnett Jr., and M. M. Redfield Differential effects of natriuretic peptides and NO on LV function in heart failure and normal dogs Am J Physiol Heart Circ Physiol, July 1, 2001; 281(1): H146 - H154. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M Bryant, C. E Sears, L. Rigg, D. A Terrar, and B. Casadei Nitric oxide does not modulate the hyperpolarization-activated current, If, in ventricular myocytes from spontaneously hypertensive rats Cardiovasc Res, July 1, 2001; 51(1): 51 - 58. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Vandecasteele, I. Verde, C. Rucker-Martin, P. Donzeau-Gouge, and R. Fischmeister Cyclic GMP regulation of the L-type Ca2+ channel current in human atrial myocytes J. Physiol., June 1, 2001; 533(2): 329 - 340. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A.C. Mendes Ribeiro, T.M.C. Brunini, J.C. Ellory, and G.E. Mann Abnormalities in L-arginine transport and nitric oxide biosynthesis in chronic renal and heart failure Cardiovasc Res, March 1, 2001; 49(4): 697 - 712. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Abe, M. Tokumura, T. Ito, T. Murai, A. Takashima, and N. Ibii Involvement of iNOS in postischemic heart dysfunction of stroke-prone spontaneously hypertensive rats Am J Physiol Heart Circ Physiol, February 1, 2001; 280(2): H668 - H673. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. B. Stathopulos, X. Lu, J. Shen, J. A. Scott, J. R. Hammond, D. G. McCormack, J. M. O. Arnold, and Q. Feng Increased L-arginine uptake and inducible nitric oxide synthase activity in aortas of rats with heart failure Am J Physiol Heart Circ Physiol, February 1, 2001; 280(2): H859 - H867. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Zieman, G. Gerstenblith, E. G. Lakatta, G. O. Rosas, K. Vandegaer, K. M. Ricker, and J. M. Hare Upregulation of the Nitric Oxide-cGMP Pathway in Aged Myocardium : Physiological Response to l-Arginine Circ. Res., January 19, 2001; 88(1): 97 - 102. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D B. Sanders, D. F Larson, K. Hunter, M. Gorman, and B. Yang Comparison of tumor necrosis factor-effect on the expression of iNOS in macrophage and cardiac myocytes Perfusion, January 1, 2001; 16(1): 67 - 74. [Abstract] [PDF]
|
|
|
|
|
|
H. Tsutsui, T. Ide, S. Hayashidani, N. Suematsu, H. Utsumi, R. Nakamura, K. Egashira, and A. Takeshita Greater susceptibility of failing cardiac myocytes to oxygen free radical-mediated injury Cardiovasc Res, January 1, 2001; 49(1): 103 - 109. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Sarkar, P. Vallance, C. Amirmansour, and S. E. Harding Positive inotropic effects of NO donors in isolated guinea-pig and human cardiomyocytes independent of NO species and cyclic nucleotides Cardiovasc Res, December 1, 2000; 48(3): 430 - 439. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Ishibashi, T. Shimada, T. Sakane, N. Takahashi, T. Sugamori, S. Ohhata, S.-i. Inoue, H. Katoh, K. Sano, Y. Murakami, et al. Contribution of endogenous nitric oxide to basal vasomotor tone of peripheral vessels and plasma B-Type natriuretic peptide levels in patients with congestive heart failure J. Am. Coll. Cardiol., November 1, 2000; 36(5): 1605 - 1611. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Badorff, B. Fichtlscherer, R. E. Rhoads, A. M. Zeiher, A. Muelsch, S. Dimmeler, and K. U. Knowlton Nitric Oxide Inhibits Dystrophin Proteolysis by Coxsackieviral Protease 2A Through S-Nitrosylation : A Protective Mechanism Against Enteroviral Cardiomyopathy Circulation, October 31, 2000; 102(18): 2276 - 2281. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Kalra, G. Baumgarten, Z. Dibbs, Y. Seta, N. Sivasubramanian, and D. L. Mann Nitric Oxide Provokes Tumor Necrosis Factor-{alpha} Expression in Adult Feline Myocardium Through a cGMP-Dependent Pathway Circulation, September 12, 2000; 102(11): 1302 - 1307. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Valen, G. Paulsson, A. M. Bennet, G. K. Hansson, and J. Vaage Gene expression of inflammatory mediators in different chambers of the human heart Ann. Thorac. Surg., August 1, 2000; 70(2): 562 - 567. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. M. Weinstein, M. J. Mihm, and J. A. Bauer Cardiac Peroxynitrite Formation and Left Ventricular Dysfunction following Doxorubicin Treatment in Mice J. Pharmacol. Exp. Ther., July 1, 2000; 294(1): 396 - 401. [Abstract] [Full Text]
|
|
|
|
|
|
J. M. Hare, R. A. Lofthouse, G. J. Juang, L. Colman, K. M. Ricker, B. Kim, H. Senzaki, S. Cao, R. S. Tunin, and D. A. Kass Contribution of Caveolin Protein Abundance to Augmented Nitric Oxide Signaling in Conscious Dogs With Pacing-Induced Heart Failure Circ. Res., May 26, 2000; 86(10): 1085 - 1092. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. D. Prabhu, B. Chandrasekar, D. R. Murray, and G. L. Freeman {beta}-Adrenergic Blockade in Developing Heart Failure : Effects on Myocardial Inflammatory Cytokines, Nitric Oxide, and Remodeling Circulation, May 2, 2000; 101(17): 2103 - 2109. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Shinke, H. Takaoka, M. Takeuchi, K. Hata, H. Kawai, H. Okubo, Y. Kijima, T. Murata, and M. Yokoyama Nitric Oxide Spares Myocardial Oxygen Consumption Through Attenuation of Contractile Response to {beta}-Adrenergic Stimulation in Patients With Idiopathic Dilated Cardiomyopathy Circulation, April 25, 2000; 101(16): 1925 - 1930. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Jung, L. A. Palmer, N. Zhou, and R. A. Johns Hypoxic Regulation of Inducible Nitric Oxide Synthase via Hypoxia Inducible Factor-1 in Cardiac Myocytes Circ. Res., February 18, 2000; 86(3): 319 - 325. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Ide, H. Tsutsui, S. Kinugawa, N. Suematsu, S. Hayashidani, K. Ichikawa, H. Utsumi, Y. Machida, K. Egashira, and A. Takeshita Direct Evidence for Increased Hydroxyl Radicals Originating From Superoxide in the Failing Myocardium Circ. Res., February 4, 2000; 86(2): 152 - 157. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. N. Sack, R. M. Smith, and L. H. Opie Tumor necrosis factor in myocardial hypertrophy and ischaemia -- an anti-apoptotic perspective Cardiovasc Res, February 1, 2000; 45(3): 688 - 695. [Full Text] [PDF]
|
|
|
|
|
|
K. J. Osterziel, S. M Bode-Boger, O. Strohm, A. E Ellmer, N. Bit-Avragim, D. Hanlein, M. B Ranke, R. Dietz, and R. H Boger Role of nitric oxide in the vasodilator effect of recombinant human growth hormone in patients with dilated cardiomyopathy Cardiovasc Res, January 14, 2000; 45(2): 447 - 453. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Tiret, C. Mallet, O. Poirier, V. Nicaud, A. Millaire, J.-B. Bouhour, G.e. Roizes, M. Desnos, R. Dorent, K. Schwartz, et al. Lack of association between polymorphisms of eight candidate genes and idiopathic dilated cardiomyopathy: The CARDIGENE study J. Am. Coll. Cardiol., January 1, 2000; 35(1): 29 - 35. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Isenovic and M. C. LaPointe Role of Ca2+-Independent Phospholipase A2 in the Regulation of Inducible Nitric Oxide Synthase in Cardiac Myocytes Hypertension, January 1, 2000; 35(1): 249 - 254. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. M Shah Inducible nitric oxide synthase and cardiovascular disease Cardiovasc Res, January 1, 2000; 45(1): 148 - 155. [Full Text] [PDF]
|
|
|
|
|
|
N. Kobayashi, T. Higashi, K. Hara, H. Shirataki, and H. Matsuoka Effects of imidapril on NOS expression and myocardial remodelling in failing heart of Dahl salt-sensitive hypertensive rats Cardiovasc Res, December 1, 1999; 44(3): 518 - 526. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Yang, D. F. Larson, and R. Watson Age-related left ventricular function in the mouse: analysis based on in vivo pressure-volume relationships Am J Physiol Heart Circ Physiol, November 1, 1999; 277(5): H1906 - H1913. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Arstall, D. B. Sawyer, R. Fukazawa, and R. A. Kelly Cytokine-Mediated Apoptosis in Cardiac Myocytes : The Role of Inducible Nitric Oxide Synthase Induction and Peroxynitrite Generation Circ. Res., October 29, 1999; 85(9): 829 - 840. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M Tendera and H Wysocki TNF-{alpha} in patients with chronic failure is not only a proinflammatory cytokine Eur. Heart J., October 2, 1999; 20(20): 1445 - 1446. [PDF]
|
|
|
|
|
|
M. V. Brahmajothi and D. L. Campbell Heterogeneous Basal Expression of Nitric Oxide Synthase and Superoxide Dismutase Isoforms in Mammalian Heart : Implications for Mechanisms Governing Indirect and Direct Nitric Oxide-Related Effects Circ. Res., October 1, 1999; 85(7): 575 - 587. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. de Frutos, L. S. de Miguel, M. Garcia-Duran, F. Gonzalez-Fernandez, J. A. Rodriguez-Feo, M. Monton, J. Guerra, J. Farre, S. Casado, and A. Lopez-Farre NO from smooth muscle cells decreases NOS expression in endothelial cells: role of TNF-alpha Am J Physiol Heart Circ Physiol, October 1, 1999; 277(4): H1317 - H1325. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Pinsky, W. Aji, M. Szabolcs, E. S. Athan, Y. Liu, Y. M. Yang, R. P. Kline, K. E. Olson, and P. J. Cannon Nitric oxide triggers programmed cell death (apoptosis) of adult rat ventricular myocytes in culture Am J Physiol Heart Circ Physiol, September 1, 1999; 277(3): H1189 - H1199. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. J Paulus and A. M Shah NO and cardiac diastolic function Cardiovasc Res, August 15, 1999; 43(3): 595 - 606. [Full Text] [PDF]
|
|
|
|
|
|
M. Nagashima, U. Stock, G. Nollert, J. Sperling, D. Shum-Tim, S. Hatsuoka, and J. E. Mayer Jr Effects of cyanosis and hypothermic circulatory arrest on lung function in neonatal lambs Ann. Thorac. Surg., August 1, 1999; 68(2): 499 - 504. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||