Cardiac hypertrophy and myocardial infarction (MI) are two major causes of heart failure with different etiologies. However, the molecular mechanisms associated with these two diseases are not yet fully understood. So, this study was designed to decipher the process of cardiomyocyte apoptosis during cardiac hypertrophy and MI in vivo. Our study revealed that mitochondrial outer membrane channel protein voltage-dependent anion channel-1 (VDAC1) was upregulated exclusively during cardiac hypertrophy, whereas 78 kDa glucose-regulated protein (GRP78) was exclusively upregulated during MI, which is an important upstream regulator of the endoplasmic reticulum (ER) stress pathway. Further downstream analysis revealed that mitochondrial pathway of apoptosis is instrumental in case of hypertrophy, whereas ER stress-induced apoptosis is predominant during MI, which was confirmed by treatment with either siRNA against VDAC1 or ER stress inhibitor tauroursodeoxycholic acid (TUDCA). Very interestingly, our data also showed that the expression and interaction of small heat-shock protein α-crystallin B (CRYAB) with VDAC1 was much more pronounced during MI compared with either hypertrophy or control. The study demonstrated for the first time that two different organelles—mitochondria and ER have predominant roles in mediating cardiomyocyte death signaling during hypertrophy and MI, respectively, and activation of CRYAB acts as a molecular switch in bypassing mitochondrial pathway of apoptosis during MI.

Signal transducer and activator of transcription 3 (STAT-3)-mediated signaling in relation to upregulated collagen expression in fibroblasts during cardiac hypertrophy is well defined. Our recent findings have identified heat shock protein 90 (Hsp90) to be a critical modulator of fibrotic signaling in cardiac fibroblasts in this disease milieu. The present study was therefore intended to analyze the role of Hsp90 in the STAT-3-mediated collagen upregulation process. Our data revealed a significant difference between in vivo and in vitro results, pointing to a possible involvement of myocyte-fibroblast cross talk in this process. Cardiomyocyte-targeted knockdown of Hsp90 in rats (Rattus norvegicus) in which the renal artery was ligated showed downregulated collagen synthesis. Furthermore, the results obtained with cardiac fibroblasts conditioned with Hsp90-inhibited hypertrophied myocyte supernatant pointed toward cardiomyocytes' role in the regulation of collagen expression in fibroblasts during hypertrophy. Our study also revealed a novel signaling mechanism where myocyte-derived Hsp90 orchestrates not only p65-mediated interleukin-6 (IL-6) synthesis but also its release in exosomal vesicles. Such myocyte-derived exosomes and myocyte-secreted IL-6 are responsible in unison for the biphasic activation of STAT-3 signaling in cardiac fibroblasts that culminates in excess collagen synthesis, leading to severely compromised cardiac function during cardiac hypertrophy.KEYWORDS cardiac hypertrophy, collagen, Hsp90, myocyte-fibroblast cross talk, STAT-3 M yocardial fibrosis is a hallmark of cardiac hypertrophy and a proposed substrate for heart failure (1, 2). The extracellular space is frequently the site for such abnormal accumulation of fibrillar collagen, accounting for myocardial stiffness and ventricular dysfunction during cardiac hypertrophy (3). The cardiac fibroblast is the principal cell type in the myocardium and synthesizes and secretes collagen in response to pressure-overload hypertrophy (4). A close relationship between angiotensin II (AngII) and profibrotic cytokines has been suggested, and several molecular signaling networks have been implicated in the progression of cardiac fibrosis (5, 6). A few reports have also shown that the role of myocytes in myocardial collagen production is mediated by myocyte-derived paracrine factors (7,8). However, the precise mechanisms involving the role of different signaling intermediates in the regulation of collagen gene expression during cardiac hypertrophy have remained unsolved.In an earlier report, we described the mechanism of interleukin-6 (IL-6)-mediated activation of the signal transducer and activator of transcription 3 (STAT-3) and consequent collagen synthesis in the hypertrophied rat heart (9). STAT-3 activation has also

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