RalGDS-Dependent Cardiomyocyte Autophagy Is Necessary for Load-Induced Ventricular Hypertrophy
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Recent work has demonstrated that autophagy, a phylogenetically conserved, lysosome-mediated pathway of protein degradation, is a key participant in pathological cardiac remodeling. One common feature of cell growth and autophagy is membrane biogenesis and processing. The exocyst, an octomeric protein complex involved in vesicle trafficking, is implicated in numerous cellular processes, yet its role in cardiomyocyte plasticity is unknown. Here, I set out to explore the role of small G protein-dependent membrane trafficking in stress-induced cardiomyocyte remodeling and autophagy. To explore underlying mechanisms, I tested in cultured neonatal cardiomyocytes two isoforms of Ral that are downstream of RalGDS (RalA, RalB) and whose actions are mediated by the exocyst. In these experiments, mTOR inhibition was maintained in response to starvation and Torin 1 despite RalA or RalB knockdown; however, autophagy was diminished only in NRCM's with RalB knockdown, implicating RalB as required for cardiomyocyte autophagy. Hearts from mice lacking RalGDS (Ralgds-/-), a guanine exchange factor (GEF) for the Ral family of small GTPases, were similar to wild-type (WT) littermates in terms of ventricular structure, contractile performance, and gene expression. However, Ralgds-/- hearts manifested a blunted growth response (p<0.05) to TAC-mediated pressure-overload stress as determined by heart weight to body weight ratios Ventricular chamber size and contractile performance were preserved in response to TAC in Ralgds-/- mice. Interestingly, TAC-induced activation of the fetal gene program was similar in both genotypes despite the relative lack of hypertrophic growth in mutant hearts. Ralgds-/- mice also exhibited diminished load-induced cardiomyocyte autophagy. Consistent with the TAC findings, Ralgds-/- mice manifested a blunted autophagic response to 24-hour fasting, suggesting a generalized defect in autophagy. Together, these data implicate RalGDS-mediated induction of autophagy as a critical feature of load-induced cardiac hypertrophy.