Mechanism Of Mechanical Stretch-induced Apoptosis In Neonatal Rat Cardiomyocytes

Mechanical force functions as an important biological signal to cardiac cells to maintain their physiological role. Mechanical overload triggers cardiac remodeling, which was associated with a number of heart diseases such as hypertension, myocardial infarction and heart failure. Cardiac remodeling is characterized by the loss of contractile tissue, compensatory hypertrophy of cardiomyocytes and increase in fibrous tissue. Apoptosis in cardiomyocytes has been recently recognized as a major mechanism for heart remodeling and the development of a number of cardiovascular diseases, diseases afflicting millions of people in the world. The loss of functional cardiomyocytes by apoptosis caused the loss of contracting power, which eventually leads to heart failure. Manipulation of apoptosis of heart cells might provide the possibility to prevent the development of heart diseases. To further understand the mechanism of how mechanical stretch induces apoptosis in cardiomyocytes, we employ an in vitro system and an in vivo abdominal-aorta-constricted (AAC) hypertension rat model, to delineate the signaling pathways of stretch-induced apoptosis in cardiomyocytes.1. We established an in vitro cellular stretch system and found that stretch-induced mitochondria-dependent apoptosis in neonatal rat cardiomyocytes. Cardiomyocyte apoptosis was determined by Annexin V flowcytometry and DAPI staining assay. Cardiomyocytes, but not cardiac fibroblasts, underwent caspases activation and apoptosis as early as 1 hr after stretch. We found that mechanical stretch induced cytochrome c (cyto c) release from mitochondria into cytosol and mitochondria membrane potential reduction in these cardiomyocytes. These mitochondrial apoptotic events were blocked by Cyclosporin A (CsA), an inhibitor of mitochondrial permeability transition pore (PTP). Following stretch, there were increased expression of pro-apoptotic proteins of Bax and Bad, and Bax appeared to accumulate in mitochondria following stretch, suggesting that Bcl-2 family...