Abstract 1283: Autophagy in Cardiomyocyte is Essential for Maintenance of Cardiac Function and Response to External Stress
Autophagy is an intracellular bulk degeneration system through which a portion of the cytoplasm is delivered to lysosomes to be degraded. The primary role of autophagy in various organisms is supposed to be an adaptation to starvation. In the heart, it has been reported that the number of autophagosomes increases in some types of cardiomyopathy, while it decreases in the progression of cardiac hypertrophy induced by pressure overload or isoproterenol. However, little is known about the precise role of autophagy in the pathogenesis of cardiac remodeling. To elucidate roles of autophagy in the heart, we generated temporally controlled cardiac-specific Atg5 (autophagy related 5) deficient mice, which is essential for autophago-some formation. Mice bearing an Atg5flox allele were crossed with alpha-myosin heavy chain promoter-driven tamoxifen-inducible Cre recombinase transgenic mice (Ic). The Atg5flox/ flox;Ic(+) (f/f:Ic(+)) mice showed no cardiac dysfunction compared to age-matched control littermates bearing Atg5flox/flox (f/f:Ic(-)). Upon subcutaneous injection of tamoxifen, the f/f:Ic(+) mice exhibited reduced level of Atg5 expression only in the heart, and the level of autophagy assessed by immunoblot analysis using antibodies against LC3 or p62 was significantly reduced. Tamoxifen-injected f/f:Ic(+) mice developed cardiac hypertrophy, left ventricular dilatation and contractile dysfunction that are accompanied with increased levels of ubiquiti-nation, endoplasmic reticulum stress and apoptosis. On the other hand, when the floxed mice was crossed with myosin light chain IIv promoter-driven Cre recombinase mice (MLCCre), the f/f:MLCCre(+) mice showed normal cardiac function at baseline, but developed a severe cardiac dysfunction 1 week after pressure overload by means of thoracic transverse aortic constriction. Taken together, autophagy in the heart may be involved in the mechanism of maintenance of cardiomyocytes and cardiac function at basal conditions as well as in response to stress. The control of autophagy will be a valid target for the development of novel therapy for cardiac hypertrophy and heart failure.