(Circulation. 1999;100:2359.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Dilated and Failing Cardiomyopathy in Bradykinin B2 Receptor Knockout Mice
From the National Laboratory of the National Institute of Biostructures and Biosystems (C.E., M.B.S., P.M.), Osilo; Laboratorio di Patologia Vascolare (C.E., A.M., S.S., M.C.C.), Istituto Dermopatico dell’Immacolata, Rome; Department of Pathology (R.M., D.C., R.M., G.O.), University of Parma, Parma; and Institutes of Biochemistry (M.G.T.), Internal Medicine and Department of Biomedical Sciences (P.M.), University of Sassari, Sassari, Italy.
Correspondence to Paolo Madeddu, MD, Institute of Internal Medicine, University of Sassari, Viale S. Pietro 8, 07100 Sassari, Italy. E-mail madeddu{at}ssmain.uniss.it
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Background—The activation of B2 receptors by kinins could exert cardioprotective effects in myocardial ischemia and heart failure.
Methods and Results—To test whether the absence of bradykinin B2 receptors may affect cardiac structure and function, we examined the developmental changes in blood pressure (BP), heart rate, and heart morphology of bradykinin B2 receptor gene knockout (B2-/-), heterozygous (B2+/-), and wild-type (B2+/+) mice. The BP of B2-/- mice, which was still normal at 50 days of age, gradually increased, reaching a plateau at 6 months (136±3 versus 109±1 mm Hg in B2+/+, P<0.01). In B2+/- mice, BP elevation was delayed. At 40 days, the heart rate was higher (P<0.01) in B2-/- and B2+/- than in B2+/+ mice, whereas the left ventricular (LV) weight and chamber volume were similar among groups. Thereafter, the LV growth rate of B2-/- and B2+/- mice was accelerated, leading at 360 days to a LV weight–to–body weight ratio that was 9% and 17% higher, respectively, than that of B2+/+ mice. In B2-/- mice, hypertrophy was associated with a marked chamber dilatation (42% larger than that of B2+/+ mice), an elevation in LV end-diastolic pressure (25±3 versus 5±1 mm Hg in B2+/+ mice, P<0.01), and reparative fibrosis.
Conclusions—The disruption of the bradykinin B2 receptor leads to hypertension, LV remodeling, and functional impairment, implying that kinins are essential for the functional and structural preservation of the heart.
Key Words: bradykinin • angiotensin • myocardium • hypertrophy • heart failure • blood pressure • genes
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Heart failure remains the leading cause of death in the industrialized countries and represents the emerging epidemics of the third millennium.1 In ischemic and idiopathic dilated cardiomyopathies, in addition to extensive myocardial scarring and despite huge myocyte hypertrophy, a disproportion has been found between myocardial growth and left ventricular (LV) chamber enlargement, leading to a significant reduction in myocardial mass–to–chamber volume ratio.2 3 4 5 6 Hypertension, myocardial hypertrophy, and ischemia accelerate the physiological drop-off of cardiomyocytes occurring with age,3 4 7 8 9 and it can be assumed that cardiac dysfunction and failure may supervene when the number of remaining viable hypertrophied cells is too low to maintain cardiac performance. The mechanisms that provoke the ongoing myocyte loss remain unknown. Endocrine and paracrine factors, including catecholamines and angiotensin II (Ang II), may cause myocyte hypertrophy and myocyte death through apoptosis and necrosis.10 11 12 13 14 15
Furthermore, the presence and functional relevance of a kallikrein-kinin system in the heart are firmly established16 17 18 19 Kinins, cleaved by kallikrein from substrate kininogen, stimulate the release of NO and prostacyclin through the activation of bradykinin (BK) B2 receptors. This action opposes Ang II–induced vasoconstriction and exerts anti-ischemic, antiproliferative, and antiatherosclerotic effects, preserving myocardial stores of energy-rich phosphates and glycogen.16 20 21 22 23 24 Conversely, a dysfunctional kallikrein-kinin system may contribute to the pathogenesis of heart failure. In fact, reduced local kinin generation and blunted NO formation have been reported in failing human hearts.20 Furthermore, icatibant, a selective antagonist of the BK B2 receptor, reduces coronary blood flow and contractility and increases LV end-diastolic pressure in pacing-induced heart failure.25
Thus, to test the hypothesis that the absence of the BK B2 receptor may lead to cardiac dysfunction, we examined the functional and structural changes occurring in the hearts of BK B2 receptor knockout mice (B2-/-) during development. This genetic model has similarity with the natural history of patients with hypertension and ventricular hypertrophy, who are at high risk for cardiovascular complications and death.26 27 28 The informative potential of heterozygous mice (B2+/-), resembling a condition of partial deficiency, has been added to test whether a gene-dose effect on the cardiovascular phenotype may be present.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
All procedures complied with the standards for the care and use of animal subjects as stated in the Guide for the Care and Use of Laboratory Animals (Institute of Laboratory Animal Resources, National Academy of Sciences, Bethesda, Md).
B2-/- mice were kindly provided by Dr. Fred Hess (Merck Laboratories), and wild-type control animals (B2+/+) were obtained from Jackson Laboratories. B2+/- mice were derived through the mating of B2+/+ and B2-/-. Two days after birth, the sex of the pups from B2-/-, B2+/+, and B2+/- groups was determined, and each litter was culled to 5 male pups. The animals were identified and housed at a constant room temperature (24±1°C) and humidity (60±3%).
Hemodynamic Measurements
Body weight (BW), systolic blood pressure (SBP), and
heart rate (HR) of unanesthetized
B2+/+ (n=33),
B2+/- (n=12), and
B2-/- (n=38) mice were
measured from 40 to 360 days of age with the use of tail-cuff
plethysmography.27 At the end of the experiments, in
unanesthetized mice, mean blood pressure was measured with the
use of an intra-aortic catheter (PE-10; Clay Adams) with a Statham
transducer (Gould). In six anesthetized mice
(2,2,2-tribromoethanol, 88 mmol/100 g body wt IP; Sigma Chemical
Co) of each group, LV pressure and dP/dt at 40 mm Hg were
measured with a high-sensitivity pressure transducer (World Precision
Instruments) in a closed-chest preparation.
Heart Morphology
In B2+/+,
B2+/-, and
B2-/- mice at 40 (n=23, 28,
and 20, respectively), 180 (n=10, 16, and 18, respectively), and 360
days of age (n=5, 5, and 7, respectively), hearts were arrested in
diastole with cadmium chloride (100 nmol), excised from
blood vessels, dissected free, rinsed in saline, blotted, weighed, and
fixed in 10% buffered formalin. Lung wet weight was also determined
(n=6 each group).
Ventricular Wall and Chamber Diameter
Measurements
The free walls of the right ventricle (RV) and the LV, including
the septum, were dissected free, and their weights were recorded.
Myocardial volume was calculated by dividing its weight by the specific
gravity of muscle tissue (ie, 1.06 g/mL). The major cavitary axis of
the LV from the apex to the aortic valve was measured under a stereo
microscope (Wild M 600) with a calibrated ocular accurate to 0.1
mm. Transverse chamber diameters and LV wall thickness were determined
with an analyzer (Image Pro Plus 3.0; accuracy 0.01 mm)
with images acquired with a videocamera (Sony) through the stereo
microscope (magnification x16). The cavitary volume was computed with
use of the Dodge equation.29
Analysis of Ventricular Fibrosis
Transverse slices were embedded in paraffin, and 5-µm-thick
sections were cut and stained with Masson’s trichrome. Sections were
examined at a calibrated magnification of x100 with an ocular reticle
containing 42 sampling points (Wild Heerbrugg Instruments). This
reticle defines a sectional area of 0.85
µm2. The points overlying the foci of
perivascular or reparative fibrosis were counted separately to compute
the volume fraction of myocardial fibrosis.
Myocyte Transverse Diameter and Sarcomere Length
The transverse diameter of longitudinally oriented myocytes of
the LV was measured at the level of the nucleus at a magnification of
x1000. One hundred measurements were collected in each LV. At the same
magnification, the lengths of 
10 sarcomeres were evaluated, for a
total of 200 measurements.
Reverse-Transcription Polymerase Chain Reaction Analysis
Total RNA was isolated from frozen hearts (n=3 each group)
according to the RNAzol B method. cDNA was made from total RNA
according to the manufacturer’s instructions (Stratagene).
The primers for amplification of a 157-bp product of the
-skeletal actin transcript were -actin L (5'-GCT CTC TCT CCT CAG
GAC C-3') and -actin R (5'-GGA GCA AAA CAG AAT GGC TGG C-3'). These
primers are specific to the 3' untranslated region of -actin RNA.
Polymerase chain reaction amplification was performed under the
following conditions: denaturing for 1 minute at 94°C, annealing for
1 minute at 61°C, and elongation for 1 minute at 72°C for 35
cycles. The primers used for amplification of a 287-bp product of
angiotensin AT1a receptor isoform
were AT1a L (GAT AAT TAT GGC GAT TGT GC) and
AT1a R (TGC TCA TTT TCG TAG ACA GG). For
amplification of a 303-bp product of angiotensin
AT1b receptor isoform, the primers were
AT1b L (ATT CAG TTT TCT GGA TGT GC) and
AT1b R (TCC ACT TCA AAA CAA TAC GC). For both
sets of primers, the conditions were denaturation at 95°C, annealing
at 56°C, and elongation at 72°C for 30 cycles. RNA levels were
normalized through amplification of
glyceraldehyde-3-phosphate dehydrogenase.
Biochemical Assays
To determine the myocardial adenylate concentration,
hearts (B2+/+, n=6;
B2+/-, n=6; and
B2-/-, n=9) were washed in
saline, frozen, and then stored at -80°C until assay. Pulverized
samples were suspended in 60% methanol (in 100 mmol/L Tris
· HCl buffer), homogenized, and then centrifuged
for 20 minutes at 10 000g. The supernatant was dried,
resuspended in 25 µL of ultrapure water, and analyzed with
capillary electrophoresis (P/ACE 2100 System; Beckman Instruments).
Protein concentration was determined according to Lowry et
al.30
Plasma concentration of atrial natriuretic factor and endothelin-1 (ET-1) was determined (n=6 each group) with the use of radioimmunoassays (Phoenix) after extraction of the peptides with Sep-Pack C-18 Cartridges (Waters).
Statistical Analysis
Data are expressed as mean±SEM. Multivariate
repeated measures ANOVA was performed to test for interaction between
time and grouping factor. In multiple comparisons among independent
groups in which ANOVA and F test indicated significant
differences, the statistical value was determined according to the
Bonferroni method. Differences within and between groups were
determined with paired or unpaired Student’s t tests,
respectively. A P value of <0.05 was considered
statistically significant.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Hemodynamic Measurements
The SBP of B2-/- mice was normal at 50 days of age and gradually increased, reaching a plateau at 6 months (Figure 1A
). In
B2+/- mice, SBP elevation was
delayed and matched the hypertensive levels of
B2-/- mice after 6 months of
age. Intra-arterial measurements confirmed the elevated BP
of B2-/- and
B2+/- mice (136±2 and 134±1
versus 115±1 mm Hg in
B2+/+ at 360 days,
P<0.01 for both comparisons). Tachycardia was
observed in B2-/- and
B2+/- mice since the early
phases of life through adulthood (Figure 1B). Initially, BW gain
was slightly accelerated in
B2+/- mice,
but this trend was lost at 7 months (Figure 1C). LV end-diastolic pressure increased in
B2-/- mice at 180 days (13±2
versus 6±1 mm Hg in
B2+/+, P<0.05) and
increased even more at 360 days (25±3 versus 5±1 mm Hg in
B2+/+, P<0.01). At
180 days, the dP/dt at 40 mm Hg was similar in
B2-/- and
B2+/+ mice (1725±73 versus
1704±112 mm Hg/s, respectively, P=NS), but at 360
days, it was reduced in B2-/-
mice (1201±104 versus 1803±72 mm Hg/s in
B2+/+, P<0.05).
|
), and B2-/- (
) mice. Values are
mean±SEM. *P<0.05 vs B2+/+.
+P<0.05 vs B2+/-.
Heart Morphology
Cross sections of the hearts of knockout and wild-type mice are
shown in Figure 2. Due to a differential
growth rate (Table), at 180 days,
the LV weight (LVW) of B2-/-
and B2+/- mice was 51% and
29% higher than that of B2+/+
mice (P<0.01); at 360 days, however, no significant
difference was detected among groups. A similar pattern was observed in
RV weight (RVW). The early acceleration in LV growth of
B2-/- mice was confirmed after
normalization by body weight (BW): at 180 days, the LVW/BW ratio was
13% (P<0.01) and 28% (P<0.001) higher than
that of B2+/- and
B2+/+ mice, respectively (Figure 3A). In the second interval, a 2.2-fold
increase was seen only in B2+/-
mice (P<0.05). Thus, at 360 days, the LV/BW ratio was 9%
higher in B2-/- and 17%
higher in B2+/- than in
B2+/+ mice. No difference in
RVW/BW ratio was observed among groups with maturation (Figure 3B). At 360 days, lung weight was greater in
B2-/- than in
B2+/+ mice (7.97±0.53 versus
5.49±0.21 mg/g body wt, P<0.002)
|
|
|
A conspicuous increase in LV transverse chamber diameter occurred
in B2-/- mice (1.8-fold),
equally distributed in the 2 intervals (Figure 4A). This increase was greater
(P<0.05) than that of
B2+/+ or
B2+/- mice (1.4- and 1.5-fold,
respectively). A slight elongation in LV chamber length was observed in
both B2+/+ and
B2-/- mice, with no further
change later (Figure 4B). As a result of the changes in these
linear dimensions, a 4.0-fold enlargement of LV chamber was found in
B2-/- mice compared with 2.6-
and 2.3-fold increases in B2+/-
and B2-/- mice, respectively
(P<0.001 for both comparisons).
|
At variance with the compensatory remodeling found in
heterozygous mice, in B2-/-
mice, the growth in wall thickness and myocardial mass was inadequate
to compensate chamber enlargement (Table
). In fact, at
360 days, the ratio of mass to chamber volume for knockout mice was
27% (P<0.01) and 24% (P<0.05) lower than that
for B2+/+ and
B2+/- mice, respectively
(Figures 4C and 4D). Diastolic LV wall stress,
calculated from hemodynamic and anatomic data, was
114% higher in B2-/- mice
than in B2+/+ mice at 180 days
(54±9 versus 25±6 dynes/mm2;
P<0.001), and at 360 days, it reached 126±15
dynes/mm2, a value 655% higher
(P<0.001) than that of
B2+/+ mice (17±8
dynes/mm2).
As shown in the Table, at 360 days, the myocytes of
B2+/- and
B2-/- mice were 17% and 15%
thinner than those of B2+/+ mice
(P<0.05 for both comparisons). Sarcomere length was similar
among groups at all ages examined.
At 40 days, the structure of ventricular
myocardium did not reveal pathological alterations in any
group. Later, distinct foci of fibrosis were present in the LV,
mainly in the subendocardium but also scattered throughout the wall
(Figure 5). Compared with
B2+/+ mice (Figure 6),
B2-/- mice showed an increase
in perivascular and reparative fibrosis at 180 days (178% and 930%,
respectively, P<0.05) and an even greater increase at 360
days (1013% and 1397%, respectively, P<0.01). No
reparative fibrosis was seen in the RV.
|
|
Gene Expression in Heart
At 40 days, the mRNA levels of -skeletal actin were 8.0- and
4.1-fold greater in the hearts of
B2-/- and
B2+/-, respectively, than
B2+/+ mice (Figure 7). This pattern persisted in adult
animals. By contrast, the expression of AT1
receptor isoforms was similar among groups at all ages examined (data
not shown).
|
Biochemical Assays
At 360 days, the adenylate content was significantly
(P<0.01) reduced in the hearts of
B2-/- mice (22.62±1.04 versus
30.22±2.15 and 32.66±1.77 nmol/mg protein in
B2+/- and
B2+/+, respectively). At the
same age, plasma concentrations of ANF were increased in
B2-/- mice (222±46 versus
18±11 pg/mL in B2+/+,
P<0.05), whereas no group difference was detected regarding
circulating ET-1 levels (3.34±1.31 versus 4.15±0.87 pg/mL,
P=NS).
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The relevance of kinins in the regulation of BP has been described repeatedly.31 32 In particular, the importance of the BK B2 receptor has been demonstrated in genetically modified murine models. Transgenic mice in which the human B2 receptor gene has been added to the murine gene are hypotensive,33 whereas B2-/- mice have mildly elevated BP levels.27 Furthermore, B2+/- mice, which mimic a condition of partial deficiency, are normotensive until 5 months of age,27 but with maturation, as demonstrated here, they show a delayed progressive elevation of BP. These data indicate that genetically determined changes in the level of expression of the BK B2 receptor directly affect the BP of mice during development.
The tachycardia observed in B2-/-, similar to that found in rats with prenatal blockade of the BK B2 receptor,34 confirms that kinins are involved in the early programming of the cardiovascular phenotype. Because norepinephrine release is diminished in B2-/- mice,35 the elevated basal HR might be the consequence of sensitization of sinoatrial ß-adrenoceptors to catecholamines. Other possible explanations include perturbation in the activity of intrinsic cardiac cholinergic neurons,36 perturbation of transduction mechanisms linked to ß-adrenoceptors, and alteration in the central baroreflex control of HR.37 38
It appears likely that Ang II contributes to the development of
cardiac remodeling in mice with partial or total deficiency of the BK
B2 receptor. The results of our previous studies
demonstrated that in B2-/-
mice, the interrupted receptor signaling leads to
blunted basal activation of NO pathway, leaving unbalanced Ang
II–induced vasoconstriction.27 However, the elevation in
BP was only moderate in B2-/-
mice, and a load-independent mechanism may be operative.39
The observation that myocardial hypertrophy was present
in heterozygous mice at 180 days, when BP was just starting to diverge
from normal, is consistent with this hypothesis. In addition,
reactivation of fetal -skeletal actin expression (an immediate-early
gene response reportedly induced by Ang II independent of its
vasoconstrictor action)40 41 in the heart of
B2-/- mice precedes any
increase in BP. The counterregulatory influence of kinins on Ang
II–induced myocardial growth has been documented in animal models with
renin-dependent hypertension42 43 and in in vitro
preparations of cardiomyocytes cocultured with
endothelial cells.44 Consistently,
we found that early, lifelong administration of an
AT1 receptor antagonist prevents
myocardial hypertrophy and fibrosis in
B2-/- mice while only
temporarily blunting the tendency to develop hypertension (Paolo
Madeddu, unpublished results, 1999). Interestingly, plasma renin
activity and cardiac expression of the renin gene are not altered in
B2-/- mice at 6
months,27 and as demonstrated here,
AT1 receptor expression is also unaffected by the
mutation even at later stages of the life. ET-1 is well known to play a
role in myocyte growth,45 and the formation of ET-1 can be
inhibited with BK via the B2
receptor.46 However, we found that circulating levels of
ET-1 are normal in B2-/-
mice.
The development of ventricular dysfunction and failure in this knockout model is documented by anatomic, functional, and biochemical data. Combined, these abnormalities simulate the characteristic findings of decompensated cardiac hypertrophy seen in humans.47 In accordance with Laplace’s law, the hearts of B2-/- mice are exposed to a substantial increase in the diastolic circumferential wall stress. It should be pointed out, however, that computed data may underestimate the stress on a per-cell basis due to the amount of myocyte replaced by reparative fibrosis. The distribution of myocardial fibrosis mainly in the subendocardium, the layer most exposed to the increased intraventricular diastolic pressure, again seems to confirm the importance of mechanical factors in the development of heart failure in this model. The decrease in myocardial adenylate content suggests an intrinsic alteration in energy buildup in the failing hearts of B2-/- mice. A shortage of myocardial energy reserves might have exaggerated the consequences of the pressure overload on the heart, leading to an abnormal growth response and accelerated myocyte death. A gene-dose effect influenced the severity of myocardial changes in mutant animals. Heterozygosity, in fact, was characterized by proportional increases in chamber volume and myocardial mass without cardiac dysfunction.
In conclusion, our results indicate that a partial deficiency of the BK B2 receptor causes LV hypertrophy and that total deficiency induces decompensated hypertrophy and failure similar to the hypertrophic hypertensive cardiomyopathy seen in humans, demonstrating the essential role of kinins in the preservation of myocardial structure and function.
Note Added in Proof
After the accpetance of this article, on the occasion of
the 53rd Annual Fall Conference of the Council for High Blood Pressure
Research, Pierra Meneton et al showed that disruption of tissue
kallikrein gene triggers dilated cardiomyopathy in mice (Meneton P,
Block-Favre M, Hagege A, Gasc JM, Huang W, Neubauer M, Duffy J, Menard
J, Alhenc-Galas F. Targeted disruption of the tissue kallikrien gene
triggers cardiac abnormalities typical of a dilated cardiomyopathy.
Hypertension. 1999;34:333. Abstract.) These data reinforce
the view that the kallikrein kinin system is important for normal heart
maturation.
|
Acknowledgments |
|---|
This work was supported in part by grants from the Minister of Universities and Scientific Research (Area Scienze Mediche: Il Cuore Insufficiente; grant F07C/1997-98, Department of Biomedical Sciences). In addition, the financial support of Telethon-Italy (grant A.105) is gratefully acknowledged.
|
Footnotes |
|---|
1 These authors contributed equally to this work.
Received May 12, 1999; revision received June 24, 1999; accepted July 13, 1999.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Braunwald E. Cardiovascular medicine at the turn of the millennium: triumphs, concerns, and opportunities. N Engl J Med. 1997;337:1360–1369.
2. Roberts WC, Siegel RJ, McManus BM. Idiopathic dilated cardiomyopathy: analysis of 152 necropsy patients. Am J Cardiol. 1987;60:1340–1355.[Medline] [Order article via Infotrieve]
3. Beltrami CA, Finato N, Rocco M, Feruglio GA, Puricelli C, Cigola E, Sonneblick EH, Olivetti G, Anversa P. The cellular basis of dilated cardiomyopathy in humans. J Mol Cell Cardiol. 1995;27:291–305.[Medline] [Order article via Infotrieve]
4.
Beltrami CA, Finato N, Rocco M, Feruglio GA,
Puricelli C, Cigola E, Quaini F, Sonnenblick EH, Olivetti G, Anversa P.
Structural basis of end-stage failure in ischemic
cardiomyopathy in humans. Circulation. 1994;89:151–163.
5. Waller TA, Hiser WL, Copeheart JE, Roberts WC. Comparison of clinical and morphologic cardiac findings in patients having cardiac transplantation for ischemic cardiomyopathy, idiopathic dilated cardiomyopathy and dilated hypertrophic cardiomyopathy. Am J Cardiol. 1998;81:884–894.[Medline] [Order article via Infotrieve]
6.
Olivetti G, Abbi R, Quaini F, Kajstura J, Cheng
W, Nitahara JA, Quaini E, Di Loreto C, Beltrami CA, Krajewsky S, Reed
J, Anversa P. Apoptosis in the failing human heart.
N Engl J Med. 1997;336:1131–1141.
7.
Olivetti G, Melissari M, Capasso JM, Anversa P.
Cardiomyopathy of the aging human heart. Circ
Res. 1991;68:1560–1568.
8. Olivetti G, Cigola E, Maestri R, Corradi D, Lagrasta C, Gambert SR, Anversa P. Aging, cardiac hypertrophy and ischemic cardiomyopathy do not affect the proportion of mononucleated and multinucleated myocytes in the human heart. J Mol Cell Cardiol. 1996;28:1463–1477.[Medline] [Order article via Infotrieve]
9.
Li Z, Bing OHL, Long X, Robinson KG, Lakatta EG.
Increased cardiomyocyte apoptosis during the
transition to heart failure in the spontaneously hypertensive rat.
Am J Physiol. 1997;272:H2313–H2319.
10.
Communal C, Singh K, Pimentel DR, Colucci WS.
Norepinephrine stimulates apoptosis in adult rat
ventricular myocytes by activation of the beta-adrenergic
pathway. Circulation. 1998;98:1329–1334.
11. Kajstura J, Cigola E, Malhotra A, Li P, Cheng W, Meggs LG, Anversa P. Angiotensin II induces apoptosis in adult ventricular myocytes in vitro. J Mol Cell Cardiol. 1997;29:859–870.[Medline] [Order article via Infotrieve]
12. Cigola E, Kajstura J, Li B, Meggs LG, Anversa P. Angiotensin II activates programmed myocyte cell death in vitro. Exp Cell Res. 1997;231:363–371.[Medline] [Order article via Infotrieve]
13. Sadoshima J, Xu Y, Slayter HS, Izumo S. Autocrine release of angiotensin II mediates stretch-induced hypertrophy of cardiac myocytes in vitro. Cell. 1993;75:977–984.[Medline] [Order article via Infotrieve]
14.
Shunkert H, Sadoshima J, Cornelius T, Kagaya Y,
Weinberg EO, Izumo S, Riegger G, Lorell BH. Angiotensin
II-induced growth responses in isolated adult rat hearts: evidence for
load-independent induction of cardiac protein synthesis by
angiotensin II. Circ Res. 1995;76:489–497.
15.
Tan LB, Jalil JE, Pick R, Janicki JS, Weber KT.
Cardiac myocyte necrosis induced by angiotensin II.
Circ Res. 1991;69:1185–1195.
16. Linz W, Wiemer G, Gohlke P, Unger T, Scholkens BA. Contribution of kinins to the cardiovascular actions of angiotensin-converting enzyme inhibitors. Pharmacol Rev. 1995;47:25–49.[Abstract]
17.
Nolly H, Carbini LA, Scicli G, Carretero
OA, Scicli AG. A local kallikrein-kinin system is present in rat
hearts. Hypertension. 1994;23:919–923.
18. Clements J, Mukhtar A, Ehrlich A, Fuller P. A re-evaluation of the tissue-specific pattern of expression of the rat kallikrein gene family. Agents Actions. 1992;38:34–41.
19.
Minshall RD, Nakamura F, Becker RP, Rabito SF.
Characterization of the bradykinin B2 receptors
in adult myocardium and neonatal rat
cardiomyocytes. Circ Res. 1995;76:773–780.
20.
Kichuk MR, Seyedi N, Zhang X, Marboe CC, Michler
RE, Addonzio LJ, Kaley G, Nasjletti A, Hintze TH. Regulation of nitric
oxide production in human coronary microvessels and the
contribution of local kinin formation. Circulation. 1996;94:44–51.
21.
Gohlke P, Kuwer I, Schnell A, Amman K, Mall
G, Unger T. Blockade of the bradykinin B2
receptors prevents the increase in capillary density induced by chronic
angiotensin-converting enzyme inhibitor
treatment in stroke-prone spontaneously hypertensive rats.
Hypertension. 1997;29:478–482.
22. Lochner A, Parratt JR. A comparison of the effects of locally and systemically administered kinins on coronary blood flow and myocardial metabolism. Br J Pharmacol. 1966;26:17–26.[Medline] [Order article via Infotrieve]
23. Yang XP, Liu YH, Peterson E, Carretero OA. Effect of neutral endopeptidase 24.11 inhibition on myocardial ischemia/reperfusion injury: role of kinins. J Cardiovasc Pharmacol. 1997;29:250–256.[Medline] [Order article via Infotrieve]
24. Martorana PA, Kettenbach B, Breipohl G, Linz W, Scholkens BA. Reduction of infarct size by local angiotensin-converting enzyme inhibition is abolished by a bradykinin antagonist. Eur J Pharmacol. 1990;182:395–396.[Medline] [Order article via Infotrieve]
25.
Cheng CP, Onishi K, Ohte N, Suzuki M, Little WC.
Functional effects of endogenous bradykinin in congestive
heart failure. J Am Coll Cardiol. 1998;31:1679–1686.
26. Borkowski JA, Ransom RW, Seabrook GR, Trumbauer M, Chen H, Hill RG, Strader CD, Hess JF. Targeted disruption of a B2 bradykinin receptor gene in mice eliminates bradykinin action in smooth muscle and neurons. J Biol Chem. 1995;23:13706–13710.
27.
Madeddu P, Varoni MV, Palomba D, Emanueli C,
Demontis MP, Glorioso N, Dessì-Fulgheri P, Sarzani R, Anania V.
Cardiovascular phenotype of a mouse strain with
disruption of the bradykinin B2-receptor gene.
Circulation. 1997;96:3570–3578.
28. Schmieder RE, Messerli FH. Is the decrease in arterial pressure the sole factor for reduction of left ventricular hypertrophy? Am J Med. 1992;92(suppl 4B):S28–S34.
29. Dodge HT, Baxley WA. Left ventricular volume and mass and their significance in heart disease. Am J Cardiol. 1969;23:528–537.[Medline] [Order article via Infotrieve]
30.
Lowry OH, Rosebrough N, Farr A, Randall RJ.
Protein measurement with the Folin phenol reagent. J Biol
Chem. 1951;193:265–275.
31. Berry TD, Hasstedt SJ, Hunt SC, Wu LL, Smith JB, Ash KO, Kuida H, Williams RR. A gene for high urinary kallikrein may protect against hypertension in Utah kindreds. Hypertension. 1989;13:3–8.[Abstract]
32.
Pravanec M, Kren V, Kunes J, Scicli AG, Carretero
OA, Simonet L, Kurtz TW. Cosegregation of blood pressure with
kallikrein gene family polymorphism. Hypertension. 1991;17:242–246.
33. Wang DZ, Chao L, Chao J. Hypotension in transgenic mice overexpressing human bradykinin B2 receptor. Hypertension. 1997;29:499–493.
34.
Madeddu P, Pinna Parpaglia P, Demontis MP,
Varoni MV, Fattaccio MC, Anania V, Glorioso N. Early blockade of
bradykinin B2-receptors alters the adult
cardiovascular phenotype in rats.
Hypertension. 1995;25:453–459.
35. Chulak C, Couture R, Foucart S. Modulatory effects of bradykinin on noradrenaline release in isolated atria from normal and B2 knockout transgenic mice. Eur J Pharmacol. 1998;346:167–174.[Medline] [Order article via Infotrieve]
36.
Izrailtyan I, Kresh JY. Bradykinin modulation of
isolated rabbit heart function is mediated by intrinsic cardiac
neurons. Cardiovasc Res. 1997;33:641–649.
37. Madeddu P, Glorioso N, Varoni MV, Demontis MP, Fattaccio MC, Anania V. Cardiovascular effects of brain kinin receptor blockade in spontaneously hypertensive rats. Hypertension. 1994;23(suppl I):I-189–I-192.
38. Gerken VMV, Santos RAS. Centrally infused bradykinin increases baroreceptor reflex sensitivity. Hypertension. 1992;19(suppl II):II-176–I-181.
39. Dostal DE, Baker KM. Angiotensin II stimulation of left ventricular hypertrophy in adult rat heart: mediation by the AT1 receptor. Am J Hypertens. 1992;5:276–280.[Medline] [Order article via Infotrieve]
40.
Mazzolai L, Nussberger J, Aubert J-F, Brunner DB,
Gabbiani G, Brunner HR, Pedrazzini T. Blood pressure-independent
cardiac hypertrophy induced by locally activated
renin-angiotensin system. Hypertension. 1998;31:1324–1330.
41.
Kent RL, MacDermott PJ. Passive load and
angiotensin evoke differential responses of gene expression
and protein synthesis in cardiac myocytes. Circ Res. 1996;78:829–838.
42.
Yayama K, Wang C, Chao L, Chao J. Kallikrein gene
delivery attenuates hypertension and cardiac hypertrophy
and enhances renal function in Goldblatt hypertensive rats.
Hypertension. 1998;31:1104–1110.
43.
Madeddu P, Milia AF, Salis MB, Gaspa L, Gross W,
Lippoldt A, Emanueli C. Renovascular hypertension in bradykinin
B2-receptor knockout mice.
Hypertension. 1998;32:503–509.
44.
Ritchie RH, Marsh JD, Lancaster WD, Diglio CA,
Schiebinger RJ. Bradykinin blocks angiotensin II induced
hypertrophy in the presence of endothelial
cells. Hypertension. 1998;31:39–44.
45. Kramer BK, Ittner KP, Beyer ME, Hoffmeister HM, Riegger GA. Circulatory and myocardial effects of endothelin. J Mol Med. 1997;75:886–890.[Medline] [Order article via Infotrieve]
46.
Mamose N, Fukuo K, Morimoto S, Ogihara T.
Captopril inhibit endothelin-1 secretion from
endothelial cells through bradykinin.
Hypertension. 1993;21:921–924.
47. Cheng W, Li B, Kajstura J, Li P, Wolin MS, Sonnenblick EH, Hintze TH, Olivetti G, Anversa P. Stretch-induced programmed myocyte cell death. J Clin Invest. 1995;96:2247–2259.
This article has been cited by other articles:
 |
|
 |
|
  M. A. Mori, R. C. Araujo, F. C.G. Reis, D. G. Sgai, R. G. Fonseca, C. C. Barros, V. F. Merino, M. Passadore, A. M. Barbosa, B. Ferrari, et al. Kinin B1 Receptor Deficiency Leads to Leptin Hypersensitivity and Resistance to Obesity Diabetes, June 1, 2008; 57(6): 1491 - 1500. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. C. Isbell, S. Voros, Z. Yang, J. M. DiMaria, S. S. Berr, B. A. French, F. H. Epstein, S. P. Bishop, H. Wang, R. J. Roy, et al. Interaction between bradykinin subtype 2 and angiotensin II type 2 receptors during post-MI left ventricular remodeling Am J Physiol Heart Circ Physiol, December 1, 2007; 293(6): H3372 - H3378. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Helske, M. Laine, M. Kupari, J. Lommi, H. Turto, L. Nurmi, I. Tikkanen, K. Werkkala, K. A. Lindstedt, and P. T. Kovanen Increased expression of profibrotic neutral endopeptidase and bradykinin type 1 receptors in stenotic aortic valves Eur. Heart J., August 1, 2007; 28(15): 1894 - 1903. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Cayla, M. Todiras, R. Iliescu, V. V. Saul, V. Gross, B. Pilz, G. Chai, V. F. Merino, J. B. Pesquero, O. C. Baltatu, et al. Mice deficient for both kinin receptors are normotensive and protected from endotoxin-induced hypotension FASEB J, June 1, 2007; 21(8): 1689 - 1698. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Liesmaa, A. Kuoppala, N. Shiota, J. O. Kokkonen, K. Kostner, M. Mayranpaa, P. T. Kovanen, and K. A. Lindstedt Increased expression of bradykinin type-1 receptors in endothelium of intramyocardial coronary vessels in human failing hearts Am J Physiol Heart Circ Physiol, May 1, 2005; 288(5): H2317 - H2322. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Chao and L. Chao Kallikrein-kinin in stroke, cardiovascular and renal disease Exp Physiol, May 1, 2005; 90(3): 291 - 298. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. M. F. Leeb-Lundberg, F. Marceau, W. Muller-Esterl, D. J. Pettibone, and B. L. Zuraw International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: from Molecular Mechanisms to Pathophysiological Consequences Pharmacol. Rev., March 1, 2005; 57(1): 27 - 77. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. W. Booz Putting the Brakes on Cardiac Hypertrophy: Exploiting the NO-cGMP Counter-Regulatory System Hypertension, March 1, 2005; 45(3): 341 - 346. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Strecker, K. Messlinger, M. Weyand, and P. W. Reeh Role of different proton-sensitive channels in releasing calcitonin gene-related peptide from isolated hearts of mutant mice Cardiovasc Res, February 1, 2005; 65(2): 405 - 410. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Funabiki, K. Onishi, K. Dohi, T. Koji, K. Imanaka-Yoshida, M. Ito, H. Wada, N. Isaka, T. Nobori, and T. Nakano Combined angiotensin receptor blocker and ACE inhibitor on myocardial fibrosis and left ventricular stiffness in dogs with heart failure Am J Physiol Heart Circ Physiol, December 1, 2004; 287(6): H2487 - H2492. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Tonduangu, L. Hittinger, B. Ghaleh, P. Le Corvoisier, L. Sambin, S. Champagne, T. Badoual, F. Vincent, A. Berdeaux, B. Crozatier, et al. Chronic Infusion of Bradykinin Delays the Progression of Heart Failure and Preserves Vascular Endothelium-Mediated Vasodilation in Conscious Dogs Circulation, January 6, 2004; 109(1): 114 - 119. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. I. McFarlane, N. Winer, and J. R. Sowers Role of the Natriuretic Peptide System in Cardiorenal Protection Arch Intern Med, December 8, 2003; 163(22): 2696 - 2704. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Bledsoe, L. Chao, and J. Chao Kallikrein gene delivery attenuates cardiac remodeling and promotes neovascularization in spontaneously hypertensive rats Am J Physiol Heart Circ Physiol, October 1, 2003; 285(4): H1479 - H1488. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Meune, J.-J. Mourad, J.-F. Bergmann, and C. Spaulding Interaction between cyclooxygenase and the renin-angiotensin-aldosterone system: rationale and clinical relevance Journal of Renin-Angiotensin-Aldosterone System, September 1, 2003; 4(3): 149 - 154. [Abstract] [PDF]
|
|
|
|
 |
|
 A. H. Schmaier The kallikrein-kinin and the renin-angiotensin systems have a multilayered interaction Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2003; 285(1): R1 - R13. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. D. Xiao, S. Fuchs, J. M. Cole, K. M. Disher, R. L. Sutliff, and K. E. Bernstein Regulation of Cardiovascular Signaling by Kinins and Products of Similar Converting-Enzyme Systems: Role of bradykinin in angiotensin-converting enzyme knockout mice Am J Physiol Heart Circ Physiol, June 1, 2003; 284(6): H1969 - H1977. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Maestri, A. F. Milia, M. B. Salis, G. Graiani, C. Lagrasta, M. Monica, D. Corradi, C. Emanueli, and P. Madeddu Cardiac Hypertrophy and Microvascular Deficit in Kinin B2 Receptor Knockout Mice Hypertension, May 1, 2003; 41(5): 1151 - 1155. [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]
|
|
|
|
 |
|
 L. Murphey, D. Vaughan, and N. Brown Contribution of bradykinin to the cardioprotective effects of ACE inhibitors Eur. Heart J. Suppl., January 1, 2003; 5(suppl_A): A37 - A41. [Abstract] [PDF]
|
|
|
|
|
|
A. C. Rosenkranz, S. G. Hood, R. L. Woods, G. J. Dusting, and R. H. Ritchie Acute Antihypertrophic Actions of Bradykinin in the Rat Heart: Importance of Cyclic GMP Hypertension, October 1, 2002; 40(4): 498 - 503. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. F. Milia, M. B. Salis, T. Stacca, A. Pinna, P. Madeddu, M. Trevisani, P. Geppetti, and C. Emanueli Protease-Activated Receptor-2 Stimulates Angiogenesis and Accelerates Hemodynamic Recovery in a Mouse Model of Hindlimb Ischemia Circ. Res., August 23, 2002; 91(4): 346 - 352. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Emanueli, M. B. Salis, A. Pinna, T. Stacca, A. F. Milia, A. Spano, J. Chao, L. Chao, L. Sciola, and P. Madeddu Prevention of Diabetes-Induced Microangiopathy by Human Tissue Kallikrein Gene Transfer Circulation, August 20, 2002; 106(8): 993 - 999. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Kuoppala, N. Shiota, J. O. Kokkonen, I. Liesmaa, K. Kostner, M. Mayranpaa, P. T. Kovanen, and K. A. Lindstedt Down-regulation of cardioprotective bradykinin type-2 receptors in the left ventricle of patients with end-stage heart failure J. Am. Coll. Cardiol., July 3, 2002; 40(1): 119 - 125. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Trabold, S. Pons, A. A. Hagege, M. Bloch-Faure, F. Alhenc-Gelas, J.-F. Giudicelli, C. Richer-Giudicelli, and P. Meneton Cardiovascular Phenotypes of Kinin B2 Receptor- and Tissue Kallikrein-Deficient Mice Hypertension, July 1, 2002; 40(1): 90 - 95. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Ozcelik, B. Erdmann, B. Pilz, N. Wettschureck, S. Britsch, N. Hubner, K. R. Chien, C. Birchmeier, and A. N. Garratt Conditional mutation of the ErbB2 (HER2) receptor in cardiomyocytes leads to dilated cardiomyopathy PNAS, June 25, 2002; 99(13): 8880 - 8885. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Fujii, A. Wada, T. Tsutamoto, M. Ohnishi, T. Isono, and M. Kinoshita Bradykinin Improves Left Ventricular Diastolic Function Under Long-Term Angiotensin-Converting Enzyme Inhibition in Heart Failure Hypertension, May 1, 2002; 39(5): 952 - 957. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Stypmann, K. Glaser, W. Roth, D. J. Tobin, I. Petermann, R. Matthias, G. Monnig, W. Haverkamp, G. Breithardt, W. Schmahl, et al. Dilated cardiomyopathy in mice deficient for the lysosomal cysteine peptidase cathepsin L PNAS, April 18, 2002; (2002) 92637699. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Fielitz, A. Dendorfer, R. Pregla, E. Ehler, H. R. Zurbrugg, J. Bartunek, R. Hetzer, and V. Regitz-Zagrosek Neutral Endopeptidase Is Activated in Cardiomyocytes in Human Aortic Valve Stenosis and Heart Failure Circulation, January 22, 2002; 105(3): 286 - 289. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Emanueli, M. Bonaria Salis, T. Stacca, G. Pintus, R. Kirchmair, J. M. Isner, A. Pinna, L. Gaspa, D. Regoli, C. Cayla, et al. Targeting Kinin B1 Receptor for Therapeutic Neovascularization Circulation, January 22, 2002; 105(3): 360 - 366. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Majima, M. Katori, N.-E. Rhaleb, X.-P. Yang, M. Nanba, E. G. Shesely, O. A. Carretero, P. Madeddu, N.-E. Rhaleb, X.-P. Yang, et al. Effect of Chronic Blockade of the Kallikrein-Kinin System on the Development of Hypertension in Rats * Response * Role of Kinins in Blood Pressure Regulation: Reality or Fiction * Response Hypertension, October 1, 2001; 38 (4): e21 - e23. [Full Text] [PDF]
|
|
|
|
|
|
K. T. Weber Cardioreparation in Hypertensive Heart Disease Hypertension, September 1, 2001; 38(3): 588 - 591. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. L. Rouleau, G. Kapuku, S. Pelletier, H. Gosselin, A. Adam, C. Gagnon, C. Lambert, and S. Meloche Cardioprotective Effects of Ramipril and Losartan in Right Ventricular Pressure Overload in the Rabbit: Importance of Kinins and Influence on Angiotensin II Type 1 Receptor Signaling Pathway Circulation, August 21, 2001; 104(8): 939 - 944. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. M. Siragy, M. de Gasparo, M. El-Kersh, and R. M. Carey Angiotensin-Converting Enzyme Inhibition Potentiates Angiotensin II Type 1 Receptor Effects on Renal Bradykinin and cGMP Hypertension, August 1, 2001; 38(2): 183 - 186. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. G. Nebigil, P. Hickel, N. Messaddeq, J.-L. Vonesch, M. P. Douchet, L. Monassier, K. Gyorgy, R. Matz, R. Andriantsitohaina, P. Manivet, et al. Ablation of Serotonin 5-HT2B Receptors in Mice Leads to Abnormal Cardiac Structure and Function Circulation, June 19, 2001; 103(24): 2973 - 2979. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Meneton, M. Bloch-Faure, A. A. Hagege, H. Ruetten, W. Huang, S. Bergaya, D. Ceiler, D. Gehring, I. Martins, G. Salmon, et al. Cardiovascular abnormalities with normal blood pressure in tissue kallikrein-deficient mice PNAS, February 15, 2001; (2001) 51619598. [Abstract] [Full Text]
|
|
|
|
|
|
C. Emanueli, A. Minasi, A. Zacheo, J. Chao, L. Chao, M. B. Salis, S. Straino, M. G. Tozzi, R. Smith, L. Gaspa, et al. Local Delivery of Human Tissue Kallikrein Gene Accelerates Spontaneous Angiogenesis in Mouse Model of Hindlimb Ischemia Circulation, January 2, 2001; 103(1): 125 - 132. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Blais Jr., D. Fortin, J.-L. Rouleau, G. Molinaro, and A. Adam Protective Effect of Omapatrilat, a Vasopeptidase Inhibitor, on the Metabolism of Bradykinin in Normal and Failing Human Hearts J. Pharmacol. Exp. Ther., November 1, 2000; 295(2): 621 - 626. [Abstract] [Full Text]
|
|
|
|
 |
|
 C. Emanueli, A. Zacheo, A. Minasi, J. Chao, L. Chao, M. B. Salis, T. Stacca, S. Straino, M. C. Capogrossi, and P. Madeddu Adenovirus-Mediated Human Tissue Kallikrein Gene Delivery Induces Angiogenesis in Normoperfused Skeletal Muscle Arterioscler. Thromb. Vasc. Biol., November 1, 2000; 20(11): 2379 - 2385. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. T. Weber Targeting Pathological Remodeling : Concepts of Cardioprotection and Reparation Circulation, September 19, 2000; 102(12): 1342 - 1345. [Full Text] [PDF]
|
|
|
|
 |
|
 F. C. Luft STOPPING at the CAPPP of good HOPE Nephrol. Dial. Transplant., April 1, 2000; 15(4): 451 - 452. [Full Text] [PDF]
|
|
|
|
|
|
M. Schachter ACE inhibitors, angiotensin receptor antagonists and bradykinin Journal of Renin-Angiotensin-Aldosterone System, March 1, 2000; 1(1): 27 - 29. [PDF]
|
|
|
|
|
|
L. J. Dell’Italia and S. Oparil Bradykinin in the Heart : Friend Or Foe? Circulation, December 7, 1999; 100(23): 2305 - 2307. [Full Text] [PDF]
|
|
|
|
|
|
P. Meneton, M. Bloch-Faure, A. A. Hagege, H. Ruetten, W. Huang, S. Bergaya, D. Ceiler, D. Gehring, I. Martins, G. Salmon, et al. Cardiovascular abnormalities with normal blood pressure in tissue kallikrein-deficient mice PNAS, February 27, 2001; 98(5): 2634 - 2639. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Stypmann, K. Glaser, W. Roth, D. J. Tobin, I. Petermann, R. Matthias, G. Monnig, W. Haverkamp, G. Breithardt, W. Schmahl, et al. Dilated cardiomyopathy in mice deficient for the lysosomal cysteine peptidase cathepsin L PNAS, April 30, 2002; 99(9): 6234 - 6239. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X.-P. Yang, Y.-H. Liu, D. Mehta, M. A. Cavasin, E. Shesely, J. Xu, F. Liu, and O. A. Carretero Diminished Cardioprotective Response to Inhibition of Angiotensin-Converting Enzyme and Angiotensin II Type 1 Receptor in B2 Kinin Receptor Gene Knockout Mice Circ. Res., May 25, 2001; 88(10): 1072 - 1079. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. C. FRANCIS, M. K. RAIZADA, A. A. MANGI, L. G. MELO, V. J. DZAU, P. R. VALE, J. M. ISNER, D. W. LOSORDO, J. CHAO, M. J. KATOVICH, et al. Genetic targeting for cardiovascular therapeutics: are we near the summit or just beginning the climb? Physiol Genomics, December 21, 2001; 7(2): 79 - 94. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||