Myocardial Cell Death and Regeneration during Progression of Cardiac Hypertrophy to Heart Failure

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-␣, and caspases 9, 8, and 3 and poly(ADP-ribose) polymerase cleavage. Tg mice with hypertrophy associated with compromised functionshowedsignificantup-regulationofcyclins,cyclindependent 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.

Ubiquitination and Degradation of the Anti-apoptotic Protein ARC by MDM2

“…load is known to activate signaling cascades, including oxidative stress, which in turn predisposes to cardiomyocyte apoptosis (22), and the latter is seen during the transition from hypertrophy to dilated cardiomyopathy (23). In wild-type mice 12 weeks after transverse aortic banding we found a ϳ1.8-fold decrease in ARC levels on Western blot compared with sham-operated mice, and this decrease in ARC protein levels was associated with a marked increase in MDM2 expression (Fig.…”

Effect of Apoptosis-Inducing Antitumor Agents on Endocardial Endothelial Cells

“…Additionally, our results suggest that endocardial endothelial cell resistance to apoptosis is possibly linked to the ability of these cells to regulate programmed cell death at very early stages of apoptotic process, the loss of mitochondrial transmembrane potential (MMP). Previous studies have reported the importance of both caspase-dependent and caspaseindependent cell death in cardiovascular dysfunction [26][27][28][29][30][31]. Since endocardial endothelial cells appear to have resistance to transmembrane potential loss, both caspasedependent and independent death signaling are likely to be inhibited in these cells.…”

Significance of Fas receptor protein expression in epithelial ovarian cancer

“…Both FasR and FasL have been identified in lymphoid [23] and epithelial cells. Expression FasR has been demonstrated in renal tubules [24], skeletal muscle [25], smooth and cardiac muscle [26,27], pituitary gland [28], parathyroid gland [29], pancreatic islets [30], hepatocytes [31], testicular germ cells [32], prostatic glands [33], neurons [34], epithelium of fallopian tube [29,35], endometrial glands [29,35], trophoblasts [29,35], bronchial epithelial [29,35] and gastrointestinal-type cells [29,35], chondrocytes [36], thyroid cells [37], and skin [38].…”