From the Departments of Medicine and Pathology, The Montreal General
Hospital and McGill University (S.C.Y.W., M.F., P.M., A.G.); GenPath
Laboratories (A.G.); and Merck Frosst Laboratories (I.R.), Montreal, Quebec,
Canada.
Correspondence to Dr Adel Giaid, Suite L3–314, The Montreal General Hospital, 1650 Cedar Ave, Montreal, Quebec, Canada H3G 1A4. E-mail mdga{at}musica.mcgill.ca
Abstract
Background—Chronic heart failure is
associated with induction of secondary inflammatory mediators,
including prostanoids. The latter exert diverse functional and
morphological effects on cardiac myocytes. Induction of
cyclooxygenase (COX), the enzyme responsible for
generating prostanoids, requires activation of nuclear factor-
Methods and Results—Myocardial tissue from 27 patients with
end-stage heart failure (various etiologies: ischemic heart
disease, n=16; idiopathic dilated cardiomyopathy,
n=10; and valvular heart disease, n=1), 2 septic patients, and
8 normal control subjects was immunostained with antisera
to COX-2 and NF-
Conclusions—We demonstrate induction of COX-2 and activation of
NF-
Prostanoids
(prostaglandins and thromboxane
A2) are the metabolic products of
the membrane phospholipid arachidonic acid via the COX
pathway. Presently, 2 forms of COX enzyme are recognized: the
constitutive enzyme COX-1, which is normally expressed in most tissues;
and the newly discovered COX-2, which is induced in many cell types in
response to various stimuli, including
cytokines.1 A number of cytokines
have been shown to be expressed in the failing human heart. These
cytokines exert their actions directly on the
myocardium or modulate the expression and release of other
mediators, such as prostanoids. Many inflammatory mediators use NF-
Methods
Subjects
Immunohistochemistry and Western Blotting
In Situ Hybridization
Results
There was a gradient for COX-2 expression in the
myocardium of patients with heart failure secondary to IHD,
with the strongest signal in the subendocardium (infarcted
zone=3.1±0.2, noninfarcted zone=1.8±0.4), the weakest in the
subepicardium (infarcted zone=2.6±0.2, noninfarcted zone=1.9±0.6),
and a midlevel intensity in the midmyocardium (infarcted
zone=2.9±0.1, noninfarcted zone=1.9±0.6) (Figure 1
Discussion
In the present study, we demonstrate for the first time
induction of COX-2 and activation of NF-
Little is known about the expression and regulation of COX-2 in the
myocardium. Previous studies have shown increased release
of thromboxane A2 in myocardial
ischemia and production of arachidonic
metabolites in the ischemic myocardium and in
cardiac myocytes under physiological and stimulated
conditions.7 8 10 In addition, Liu et
al11 have recently shown the presence of both
COX-1 and COX-2 in the normal and lipopolysaccharide-stimulated
rat heart. The latter study supports our findings of induced COX-2
expression in the myocytes and inflammatory cells of patients with
heart failure secondary to sepsis. Beside lipopolysaccharide,
there are several other mediators known to induce COX-2 in other cells
that may contribute to the induction of the enzyme in myocytes of
failing hearts. For example, hypoxia and tumor necrosis
factor-
The current study raises the question of the
pathophysiological significance of COX-2 induction
and NF-
In conclusion, we have demonstrated that induction of COX-2 in failing
human hearts is associated with the presence of myocardial scarring
(inflammation and fibrosis) as well as sepsis. We have also
demonstrated activation of NF-
Selected Abbreviations and Acronyms
Acknowledgments
This study was supported by the Heart and Stroke
Foundations of Canada and Quebec. We thank Dr B. Kennedy for his help
during the study. We also acknowledge the support of the
Endothelium Network of the Fonds de la recherche en santé du
Québec (FRSQ).
Received January 6, 1998;
revision received May 10, 1998;
accepted May 14, 1998.
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© 1998 American Heart Association, Inc.
Brief Rapid Communication
Induction of Cyclooxygenase-2 and Activation of Nuclear Factor-
B in Myocardium of Patients With Congestive Heart Failure
B
(NF-B). The aim of the present study was to determine the
expression of COX-2 and activation of NF-B in the failing human
heart. B. Western blotting was performed and showed high
anti–COX-2 antibody specificity and the presence of COX-2 protein in
the sample tissues. In situ hybridization and immunohistochemistry
showed little or no expression of COX-2 and NF-B in the control
hearts. In contrast, there was abundant expression of COX-2 mRNA and
protein in myocytes and inflammatory cells in areas of fibrotic scar
compared with regions of normal morphology in all cases of heart
failure, except the cases with sepsis, which showed an abundance of
COX-2 throughout the myocardium. Sites of NF-B
activation were associated with those of COX-2 expression. B in the myocardium of failing human hearts.
Induction of both molecules appears to be associated with the presence
of inflammation and scar formation.
Key Words: heart failure • myocardium • infarction • cardiomyopathyB
as one of their mechanisms of induction and
perpetuation.2 3 Recent studies have shown that
COX-2 is induced by inflammatory cytokines such as tumor
necrosis factor-
, which is produced in heart
failure,4 via the transcription factor
NF-B.2 In addition to cytokines,
hypoxia, an important feature of ischemic
myocardium, induces COX-2 (via NF-B) in cultured
endothelial cells independently of other
stimuli.5 Although there have been several
studies that demonstrated induction of COX-2 and its association with
NF-B activation in various cells,2 3 and
despite the numerous studies describing the production of
prostanoids in myocytes,6 7 whether or not COX-2
is expressed in the human myocardium remains to be
elucidated. Interest in COX-2 expression in the failing heart is
heightened by the diverse inotropic and morphological effects of
prostaglandins on the heart.6 8 We
therefore sought to determine expression of COX-2 and activation of
NF-B in the failing human heart by immunohistochemistry, Western
blotting, and in situ hybridization.
Tissues from failing human hearts were collected at the time of
transplantation from patients with IHD (n=16 males; mean age, 51.6±1.8
years; EF, 18.8±3.0%; LVEDP, 27.7±2.1 mm Hg; LVEDD,
71.0±4.0 mm), DCM (n=10; 8 females; mean age, 44.5±4.0 years;
EF, 14.4±1.8%; LVEDP, 27.6±2.5 mm Hg; LVEDD, 72.5±5.4
mm), and valvular heart disease (one 63-year-old man; EF, 20%;
LVEDD, 75 mm); tissues were also collected at autopsy from 2
patients with sepsis (mean age, 56.0±8.0 years). All patients had
heart failure (NYHA class 3 or 4) and had received treatment with
antiarrhythmic drugs, diuretics, digoxin,
nitroglycerin, ACE inhibitors, ß-receptor
blockers, or Ca2+ channel blockers. Duration of
the disease ranged from 3 months to 9 years. Pretransplant
complications included diabetes, hyperlipidemia,
hypertension, and renal disease. Normal control hearts were collected
at surgery (unused donor hearts, n=5) or autopsy (n=3). Slices of the
left ventricle, from both infarcted and noninfarcted regions, were cut
from the whole heart and placed in either 4%
paraformaldehyde or 10% formalin. The study conformed
to the ethics committee requirements of the Montreal General
Hospital.
Using a previously described method,9 we
immunostained the tissues with polyclonal antisera to human
COX-2 and NF-B (Boehringer Mannheim). Each complete field of
cardiac myocytes was graded in a blinded fashion from 0 to 4 (where
0=no staining, 1=focal staining, 2=diffuse weak staining, 3=diffuse
moderate staining, and 4=diffuse strong
staining).9 In addition to immunohistochemistry,
adjacent left ventricular tissues were
homogenized and analyzed by Western blot with the
Novex Xcell II system (Novex) to confirm the specificity of the COX-2
antiserum.
A nonradioactive technique using the DIG system
(Boehringer Mannheim) was employed. Briefly, cryostat sections
were permeabilized as described
elsewhere10 then hybridized with the labeled
probe at 42°C for 16 hours. This was followed by several washes in
SSC (x4 to 0.1) and RNase A solutions. Sections were incubated with
alkaline phosphatase conjugated sheep anti-digoxigenin Fab fragments.
Signals were visualized with 4-nitro-blue-tetrazolium and
5-bromo-4-chloro-3-indolyl phosphate in 10% polyvinyl alcohol–treated
equalization buffer. 
). The most apparent expression of COX-2
was seen in myocytes and inflammatory cells. Expression of COX-2 in
endothelial cells of the endocardium and intramural
coronary arteries ranged from weak focal to strong diffuse
(Figure 1B). There was a very apparent immunoreactivity for NF-B in
the myocytes of patients with IHD in both infarcted and noninfarcted
regions (Figure 2B and 2F). In general,
cells with apparent COX-2 expression showed nuclear staining for
NF-B. Patients with DCM showed unequal signal intensity for COX-2,
ranging from none to a moderate diffuse signal
(subendocardium=2.4±0.3, midmyocardium=2.1±0.4, and
subepicardium=2.2±0.3). Weak to moderate expression of COX-2 in the
myocytes and inflammatory cells in DCM was associated with the presence
of extensive myocardial fibrosis (Figure 1C). No expression of the
enzyme was seen in other cell types. Immunoreactivity for NF-B was
also seen in these cases; however, it was far less evident than in IHD
cases (Figure 2C). Patients with heart failure secondary to sepsis
showed moderate to strong expression of COX-2 in the myocytes,
endocardium, and inflammatory cells (subendocardium=3.5±0.5,
midmyocardium=2.9±0.5, and subepicardium=1.9±0.6) (Figure 1E and 1G). Similarly, there was strong nuclear
immunostaining for NF-B in the myocytes and
inflammatory cells in septic hearts (Figure 2A). The patient with
valvular heart disease showed little expression of COX-2 in the
myocytes and endocardium and no signal in the coronary
arteries. There was only sparse focal immunoreactivity for NF-B
(Figure 2D and 2E). Normal control hearts showed little or no
expression of either factor (Figure 1F). Negative control experiments
did not show any nonspecific signal (Figure 1D and 1H). Western blot
analysis revealed that the COX-2 antiserum showed high
specificity for the activated mouse macrophage lysate
and also detected COX-2 protein in failing hearts of patients with IHD
and DCM. There was no significant correlation between the expression of
these molecules and age, sex, duration of illness, complications, type
of treatment, or cardiac function.
View larger version (115K):
[in a new window]
Figure 1. COX-2 in normal and failing human hearts. A and B,
Localization of COX-2 protein in noninfarcted (A) and infarcted (B)
regions of the myocardium of a patient with IHD. Note the
presence of strong immunostaining for COX-2 in the
endocardium (arrow) and myocytes in the ischemic zone (B). C,
Presence of COX-2 protein in myocytes of a patient with DCM. Note the
strong immunostaining in myocytes surrounded by thick
bands of fibrosis. D, Negative control experiment. E, Strong expression
of COX-2 in myocytes and inflammatory cells in sections from a patient
with heart failure secondary to sepsis. F, Lack of COX-2
immunoreactivity in myocardium of normal control heart. G,
Expression of COX-2 mRNA in cardiomyocytes and inflammatory
cells of a septic heart. H, Absence of hybridization signal in a
negative control section (sense probe) adjacent to that of panel
G.
View larger version (114K):
[in a new window]
Figure 2. Immunolocalization of activated NF- B in
the failing human heart. Nuclear localization of activated
NF-B in the myocardium of patients with sepsis (A), IHD
(B and F), DCM (C), and valvular heart disease (D and E). A to
D, Photomicrographs from routine fluorescent microscope. E and
F, Photomicrographs from confocal microscope.B in the failing human
heart. Our investigations showed abundant expression of COX-2 and
activation of NF-B in myocytes and inflammatory cells in the
infarcted myocardium compared with the noninfarcted
myocardium of patients with heart failure secondary to IHD.
Abundant expression of the enzyme was seen in septic hearts. In
contrast, expression of the enzyme in DCM was only seen in areas of
myocardial fibrosis. Activation of NF-B was seen in cells associated
with induction of COX-2. Both molecules were rarely seen in normal
control hearts. These findings demonstrate increased expression of
COX-2 and activation of NF-B in the failing myocardium
and suggest that induction of COX-2 and increased formation of
prostanoids may contribute to the pathophysiology of heart failure. , important features of IHD, have been shown to induce
prostanoid formation in several cell types, including
myocytes.1 5 In part, the pathway of COX-2
induction and the subsequent formation of prostanoids involve
activation of NF-B.2 5 Interestingly, there
are 2 NF-B binding sites in the promoter region of
COX-2.12 In the present study, we demonstrate
induction of COX-2 and translocation of NF-B from the cytoplasm to
the nuclei in cardiomyocytes and inflammatory cells of the
failing human heart. Our data suggest that ischemia and
inflammatory mediators are responsible for activation of NF-B and
induction of COX-2 in this disease condition. B activation in chronic heart failure. It is well known that
prostaglandin formation is increased in patients with
chronic heart failure and that inhibition of the COX
metabolic pathway results in adverse effects on systemic
vascular resistance, cardiac output, renal blood flow,
glomerular filtration, and calf vascular
resistance.13 14 Whether these effects can be
attributed to inhibition of cardiac COX-2 induction remains to be
elucidated. On the other hand, activation of NF-B may be associated
with induction of other mediators known to be present in heart
failure, including NO. Recent reports have demonstrated cytotoxic and
negative inotropic effects of NO on cardiac
myocytes.15 Accordingly, any factor that
modulates NO expression may potentially have deleterious effects on the
heart. B in sites of induced COX-2
expression. We suggest a possible role for NF-B in the
ischemia-mediated induction of COX-2 in myocytes, inflammatory
cells, and endothelial cells of failing human
myocardium. Increased production of prostanoids by
ischemic cells may have important pathological consequences in
IHD and sepsis. The use of specific COX-2 inhibitors in
animal models of heart failure will determine the exact role of the
enzyme in this fatal disease.
COX
=
cyclooxygenase
DCM
=
dilated cardiomyopathy
EF
=
ejection fraction
IHD
=
ischemic heart disease
LVEDD
=
left ventricular end-diastolic diameter
LVEDP
=
left ventricular end-diastolic pressure
NF-
B=
nuclear factor-
B-dependent
induction of cyclo-oxygenase-2 in MC3T3–E1 cells.
J Biol Chem. 1995;270:31315–31320.B: a
pivotal transcription factor in chronic inflammatory diseases.
N Engl J Med. 1997;336:1066–1071. and tumor necrosis
factor receptors in the failing human heart. Circulation. 1996;93:704–711.
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Y. Li, T. Ha, X. Gao, J. Kelley, D. L. Williams, I. W. Browder, R. L. Kao, and C. Li NF-{kappa}B activation is required for the development of cardiac hypertrophy in vivo Am J Physiol Heart Circ Physiol, October 1, 2004; 287(4): H1712 - H1720. [Abstract] [Full Text] [PDF]
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M. C. LaPointe, M. Mendez, A. Leung, Z. Tao, and X.-P. Yang Inhibition of cyclooxygenase-2 improves cardiac function after myocardial infarction in the mouse Am J Physiol Heart Circ Physiol, April 1, 2004; 286(4): H1416 - H1424. [Abstract] [Full Text] [PDF]
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R. M. Delgado III, M. A. Nawar, A. M. Zewail, B. Kar, W. K. Vaughn, K. K. Wu, N. Aleksic, N. Sivasubramanian, K. McKay, D. L. Mann, et al. Cyclooxygenase-2 Inhibitor Treatment Improves Left Ventricular Function and Mortality in a Murine Model of Doxorubicin-Induced Heart Failure Circulation, March 23, 2004; 109(11): 1428 - 1433. [Abstract] [Full Text] [PDF]
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C. Li, T. Ha, J. Kelley, X. Gao, Y. Qiu, R. L Kao, W. Browder, and D. L Williams Modulating Toll-like receptor mediated signaling by (1->3)-{beta}-D-glucan rapidly induces cardioprotection Cardiovasc Res, February 15, 2004; 61(3): 538 - 547. [Abstract] [Full Text] [PDF]
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J.-P. Tessier, B. Thurner, E. Jungling, A. Luckhoff, and Y. Fischer Impairment of glucose metabolism in hearts from rats treated with endotoxin Cardiovasc Res, October 15, 2003; 60(1): 119 - 130. [Abstract] [Full Text] [PDF]
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R. J. O'Brien, I. Loke, J. E. Davies, I. B. Squire, and L. L. Ng Myotrophin in human heart failure J. Am. Coll. Cardiol., August 20, 2003; 42(4): 719 - 725. [Abstract] [Full Text] [PDF]
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N. H. Purcell and J. D. Molkentin Is Nuclear Factor {kappa}B an Attractive Therapeutic Target for Treating Cardiac Hypertrophy? Circulation, August 12, 2003; 108(6): 638 - 640. [Full Text] [PDF]
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M. Qing, K. Schumacher, R. Heise, M. Woltje, J. F. Vazquez-Jimenez, T. Richter, M. Arranda-Carrero, J. Hess, G.o. von Bernuth, and M.-C. Seghaye Intramyocardial synthesis of pro- and anti-inflammatory cytokines in infants with congenital cardiac defects J. Am. Coll. Cardiol., June 18, 2003; 41(12): 2266 - 2274. [Abstract] [Full Text] [PDF]
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C. Arnaud, M. Joyeux-Faure, D. Godin-Ribuot, and C. Ribuot COX-2: an in vivo evidence of its participation in heat stress-induced myocardial preconditioning Cardiovasc Res, June 1, 2003; 58(3): 582 - 588. [Abstract] [Full Text] [PDF]
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R. Rocha, A. E. Rudolph, G. E. Frierdich, D. A. Nachowiak, B. K. Kekec, E. A. G. Blomme, E. G. McMahon, and J. A. Delyani Aldosterone induces a vascular inflammatory phenotype in the rat heart Am J Physiol Heart Circ Physiol, November 1, 2002; 283(5): H1802 - H1810. [Abstract] [Full Text] [PDF]
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R. Bolli, K. Shinmura, X.-L. Tang, E. Kodani, Y.-T. Xuan, Y. Guo, and B. Dawn Discovery of a new function of cyclooxygenase (COX)-2: COX-2 is a cardioprotective protein that alleviates ischemia/reperfusion injury and mediates the late phase of preconditioning Cardiovasc Res, August 15, 2002; 55(3): 506 - 519. [Abstract] [Full Text] [PDF]
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R. Nakamura, K. Egashira, Y. Machida, S. Hayashidani, M. Takeya, H. Utsumi, H. Tsutsui, and A. Takeshita Probucol Attenuates Left Ventricular Dysfunction and Remodeling in Tachycardia-Induced Heart Failure: Roles of Oxidative Stress and Inflammation Circulation, July 16, 2002; 106(3): 362 - 367. [Abstract] [Full Text] [PDF]
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P. Knuefermann, P. Chen, A. Misra, S.-P. Shi, M. Abdellatif, and N. Sivasubramanian Myotrophin/V-1, a Protein Up-regulated in the Failing Human Heart and in Postnatal Cerebellum, Converts NFkappa B p50-p65 Heterodimers to p50-p50 and p65-p65 Homodimers J. Biol. Chem., June 21, 2002; 277(26): 23888 - 23897. [Abstract] [Full Text] [PDF]
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C.-C. Chen, K.-T. Chiu, S.-T. Chan, and J.-W. Chern Conjugated Polyhydroxybenzene Derivatives Block Tumor Necrosis Factor-alpha -Mediated Nuclear Factor-kappa B Activation and Cyclooxygenase-2 Gene Transcription by Targeting Ikappa B Kinase Activity Mol. Pharmacol., December 1, 2001; 60(6): 1439 - 1448. [Abstract] [Full Text] [PDF]
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