Abstract
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.
Highlights
It has been reported that the apoptotic machinery is turned on during transition of cardiac hypertrophy to heart failure.[3]
On the basis of the leads obtained from a comparative proteome profiling between hypertrophy and myocardial infarction (MI) performed by us, the levels of voltage-dependent anion channel-1 (VDAC1) and 78 kDa glucose-regulated protein (GRP78) were estimated in our experimental animal groups by western blot analysis
In agreement with the proteomics data, VDAC1 expression showed significant increase (3.08±0.06-fold) exclusively during hypertrophy, whereas significant upregulation of GRP78 expression was observed during MI in isoproterenol-treated (3.4±0.08-fold) or ligated MI (LAD)-ligated rats (3.72± 0.17-fold) compared with either control or hypertrophy (Figures 1a and b)
Summary
It has been reported that the apoptotic machinery is turned on during transition of cardiac hypertrophy to heart failure.[3]. Involvement of p53 and its interaction with nuclear factor k-light-chain enhancer of activated B cells (NF-kB) by p300 was shown recently to be a major regulator of apoptosis in hypertrophic cardiomyocytes.[3]. Analysis of downstream signaling pathways revealed that CRYAB has a crucial role in regulating cardiomyocyte apoptosis during hypertrophy and MI. This is the first report identifying novel molecular mechanisms for cardiomyocyte apoptosis, with precise role of CRYAB as a chief regulator for differential modes of myocyte apoptosis in two cardiac disease forms
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