Abstract
Cardiac hypertrophy and ensuing heart failure are among the most common causes of mortality worldwide, yet the triggering mechanisms for progression of hypertrophy to failure are not fully understood. Tissue homeostasis depends on proper relationships between cell proliferation, differentiation, and death and any imbalance between them results in compromised cardiac function. Recently, we developed a transgenic (Tg) mouse model that overexpress myotrophin (a 12-kDa protein that stimulates myocyte growth) in heart resulting in hypertrophy that progresses to heart failure. This provided us an appropriate model to study the disease process at any point from initiation of hypertrophy end-stage heart failure. We studied detailed apoptotic signaling and regenerative pathways and found that the Tg mouse heart undergoes myocyte loss and regeneration, but only at a late stage (during transition to heart failure). Several apoptotic genes were up-regulated in 9-month-old Tg hearts compared with age-matched wild type or 4-week-old Tg hearts. Cardiac cell death during heart failure involved activation of Fas, tumor necrosis factor-alpha, and caspases 9, 8, and 3 and poly(ADP-ribose) polymerase cleavage. Tg mice with hypertrophy associated with compromised function showed significant up-regulation of cyclins,cyclin-dependent kinases (Cdks), and cell regeneration markers in myocytes. Furthermore, in human failing and nonfailing hearts, similar observations were documented including induction of active caspase 3 and Ki-67 proteins in dilated cardiomyopathic myocytes. Taken together, our data suggest that the stress of extensive myocardial damage from longstanding hypertrophy may cause myocytes to reenter the cell cycle. We demonstrate, for the first time in an animal model, that cell death and regeneration occur simultaneously in myocytes during end-stage heart failure, a phenomenon not observed at the onset of the disease process.
Highlights
Cardiac hypertrophy and ensuing heart failure are a major contributor to heart failure
Because we had already shown that apoptosis and cellular regeneration occur during the transition of hypertrophy to heart failure, our goal was to confirm whether cell death and regeneration occurs in cardiac myocytes in the failing heart
Our results clearly show that active caspase 3 protein was found to be significantly up-regulated in failing cardiomyocytes of dilated cardiomyopathic (DCM) heart sections compared with nonfailing sections. 1.2% of Ki-67 positive cardiomyocyte nuclei were observed in DCM heart sections, whereas no Ki-67 positive myocytes was found in nonfailing sections (Fig. 9B)
Summary
Transgenic animals during initiation (about 4 weeks of age) and transition of hypertrophy to heart failure (around 36 weeks of age). A cluster of apoptotic genes, as well as genes involved in cellular regeneration, was found to be significantly up-regulated in 36-week-old Tg mice heart samples but not those from 4-week-old mice [9]. We chose to study the molecular changes for both cardiac cell death and regeneration during initiation of cardiac hypertrophy and during the transition from hypertrophy to heart failure, the later still being an open question. To establish the relevance of our findings in murine model, we studied some key genes in these processes (active caspase 3 for cell death and Ki-67 for cell regeneration) in human dilated cardiomyopathic (DCM) and nonfailing (NF) hearts. Our data showed that both cell death and regeneration occur simultaneously during heart failure that is not evident during onset of this disease
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