DGKζ deficiency promotes maladaptive cardiac hypertrophy through modulating autophagy via mTOR/TFEB signaling pathway

Abstract

Abstract The activation of diacylglycerol (DAG) signaling by Gq protein-coupled receptor (GPCR) is a crucial factor contributing to maladaptive cardiac hypertrophy. Previous studies showed that diacylglycerol kinase zeta (DGKζ) suppressed cardiac hypertrophy by attenuating DAG signaling. However, the mechanisms involved remain to be elucidated. In present study, we showed that DGKζ ameliorated adverse cardiac hypertrophy induced by DAG signaling through negatively regulating autophagy. We demonstrated that sustained activation of DAG signaling by transverse aortic constriction (TAC) in mice or by endothelin (ET)-1 in cardiomyocytes triggered progressive cardiac hypertrophy, cardiac dysfunction and ultimately heart failure. In response to prohypertrophic challenge, autophagy activity was markedly upregulated. Importantly, we found that the persistent upregulation of autophagy flux by rapamycin aggravated the long-term adverse cardiac hypertrophy and dysfunction. While all of which could be ameliorated by inhibition of autophagy by CQ or 3-MA. Furthermore, we observed that expression of DGKζ was significantly downregulated both in TAC mice heart and in ET-1-treated cardiomyocytes. Specific gene deletion of DGKζ augmented autophagy flux by disrupting the activation of AKT/mTOR signaling, the association between mTOR and TFEB, and favoring the nuclear translocation of TFEB from cytoplasm and the nuclear accumulation of TFEB. Of note, knockdown of TFEB blunted the effects of DGKζ deletion on cardiac autophagy and cardiac hypertrophy. Taken together, these results suggested that regulating autophagy via mTOR/TFEB signaling pathway might be a novel mechanism for DGKζ to ameliorate pathological cardiac hypertrophy.