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      Progression From Compensated Hypertrophy to Failure in the Pressure-Overloaded Human Heart : Structural Deterioration and Compensatory Mechanisms

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          Most cited references15

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          Induction of cardiac fibrosis by transforming growth factor-beta(1).

          The role of transforming growth factor-beta(1) (TGF-beta(1)) in the production and deposition of collagens and in the induction of gene expression in the myocardium in relation to the development of myocardial fibrosis will be discussed. Very low expression of TGF-beta(1) and collagen type I and III mRNA is seen in the normal rat heart. Both expressions are markedly increased in the infarcted heart and the levels of TGF-beta(1) mRNA precedes increases in mRNA levels for extracellular matrix (ECM) proteins, suggesting a possible role of TGF-beta(1) in remodeling processes in the myocardium. The TGF-beta(1) expression is normally only transient since continuous TGF-beta(1) overexpression seems to promote nonadaptive cardiac hypertrophy and myocardial fibrosis. In vitro, TGF-beta(1) induces an increase in collagen production and secretion and enhances the abundance of mRNA levels for collagen type I and III in rat cardiac fibroblasts in culture. TGF-beta(1) also stimulates in vivo the expression of ECM proteins and in vivo gene transfer of TGF-beta(1) can induce myocardial fibrosis. Increased myocardial TGF-beta(1) and ECM protein mRNA are found in myocardial fibrosis induced by angiotensin II infusion, by noradrenaline treatment, by isoprenaline infusion, and by long-term blockade of NO synthesis. In vivo antagonism of TGF-beta(1) by neutralizing anti-TGF-beta(1) antibodies or by proteoglycans prevents the increase in gene expression of ECM proteins and inhibits myocardial fibrosis, suggesting that the increases in matrix protein production and fibrosis are mediated by TGF-beta(1). Copyright 2000 Academic Press.
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            Apoptosis in heart failure: release of cytochrome c from mitochondria and activation of caspase-3 in human cardiomyopathy.

            Apoptosis has been shown to contribute to loss of cardiomyocytes in cardiomyopathy, progressive decline in left ventricular function, and congestive heart failure. Because the molecular mechanisms involved in apoptosis of cardiocytes are not completely understood, we studied the biochemical and ultrastructural characteristics of upstream regulators of apoptosis in hearts explanted from patients undergoing transplantation. Sixteen explanted hearts from patients undergoing heart transplantation were studied by electron microscopy or immunoblotting to detect release of mitochondrial cytochrome c and activation of caspase-3. The hearts explanted from five victims of motor vehicle accidents or myocardial ventricular tissues from three donor hearts were used as controls. Evidence of apoptosis was observed only in endstage cardiomyopathy. There was significant accumulation of cytochrome c in the cytosol, over myofibrils, and near intercalated discs of cardiomyocytes in failing hearts. The release of mitochondrial cytochrome c was associated with activation of caspase-3 and cleavage of its substrate protein kinase C delta but not poly(ADP-ribose) polymerase. By contrast, there was no apparent accumulation of cytosolic cytochrome c or caspase-3 activation in the hearts used as controls. The present study provides in vivo evidence of cytochrome c-dependent activation of cysteine proteases in human cardiomyopathy. Activation of proteases supports the phenomenon of apoptosis in myopathic process. Because loss of myocytes contributes to myocardial dysfunction and is a predictor of adverse outcomes in the patients with congestive heart failure, the present demonstration of an activated apoptotic cascade in cardiomyopathy could provide the basis for novel interventional strategies.
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              TGF-β1 mediates the hypertrophic cardiomyocyte growth induced by angiotensin II

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                Author and article information

                Journal
                Circulation
                Circulation
                Ovid Technologies (Wolters Kluwer Health)
                0009-7322
                1524-4539
                February 25 2003
                February 25 2003
                : 107
                : 7
                : 984-991
                Affiliations
                [1 ]From Kerckhoff-Clinic (S.H., M.S., E.P.B., W.-P.K.) and Max-Planck-Institute (E.A., S.K., V.P., J.S.), Bad Nauheim, Germany, and the Department of Cardiology (A.E.), Albert-Ludwigs-University, Freiburg, Germany.
                Article
                10.1161/01.CIR.0000051865.66123.B7
                f3e3c28f-36a7-4268-a1ac-7f9021d58824
                © 2003
                History

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