Chaperone-Mediated Autophagy Regulates Hypoxic Pathology in Cardiomyocytes.

Tight regulation of protein degradation pathways is essential for maintaining cardiac homeostasis. The goal of this work was to define the role of chaperone-mediated autophagy (CMA), in cardiomyocytes. CMA acts as a selective degradation pathway of proteins using a cytosolic and lysosomal co-chaperone, HSPA8/HSC70, and the CMA-specific LAMP2A (lysosomal-associated membrane protein 2A) receptor. LAMP2A protein levels are known to be necessary for CMA function. While CMA was shown to exert protection against neurodegenerative disorders and cancer, the role of CMA during cardiac pathology was not known. It was hypothesized that enhancing CMA could mitigate hypoxic pathology in cardiomyocytes. Thus, a genetic gain- and loss-of-CMA-function approach was employed using a Lamp2a-overexpressing adenovirus and a Lamp2a-silencing siRNA, respectively, in primary cardiomyocytes treated with CoCl₂ (a hypoxia-mimetic agent) or vehicle control. The experiments performed clearly showed that Lamp2a-overexpression leads to CMA activation that is sufficient to attenuate hypoxia-induced cardiomyocyte death and toxicity.