SIRT5 Ameliorates Cardiac Fibrosis via PCK2 Desuccinylation-Mediated Metabolic Reprogramming in Cardiac Fibroblasts.

Abstract (English)

BACKGROUND: SIRT5 (sirtuin 5) is a member of the sirtuin family known to regulate cardiac metabolism, aging, and function. However, its role in cardiac fibroblast (CFB) metabolism, activation, and fibrosis remains elusive. METHODS: Expression changes of SIRT5 in CFBs from cardiac tissue of human and mouse with heart failure were determined. The functional role of SIRT5 in cardiac fibrosis was evaluated through CFB-specific knockout and overexpression of <i>Sirt5</i> in mice. The involvement of succinylation of lysine 489 (Lys489) on PCK2 (phosphoenolpyruvate carboxykinase 2) in SIRT5-mediated regulation of cardiac fibrosis was assessed by introducing the Lys489-to-arginine mutation of PCK2 in <i>Sirt5</i>-deficient CFBs and in CFB-specific <i>Sirt5</i> knockout mice. RESULTS: SIRT5 expression was markedly reduced in CFBs from humans and mice with heart failure and showed a negative correlation with cardiac fibrosis severity. Loss of <i>Sirt5</i> in CFBs exacerbated left ventricular dysfunction, cardiac hypertrophy, and cardiac fibrosis in mice subjected to transverse aortic constriction, whereas overexpression of <i>Sirt5</i> in CFBs significantly attenuated these pathological changes. <i>Sirt5</i> deficiency promoted CFB activation by driving a metabolic shift from oxidative phosphorylation to glycolysis. Mechanistically, <i>Sirt5</i> deficiency increased the succinylation of PCK2 at Lys489, a key enzyme linking glycolysis and the tricarboxylic acid cycle, which consequently inhibited this enzyme activity in CFBs. Importantly, this specific modification at the Lys489 mutation that prevents succinylation effectively reversed both the metabolic reprogramming and the hyperactivation of CFBs induced by <i>Sirt5</i> knockout. <i>In vivo</i>, introducing the <i>Pck2 K489R</i> mutation fully rescued the exacerbated cardiac fibrosis and dysfunction observed in <i>Sirt5</i>-deficient mice after transverse aortic constriction. CONCLUSIONS: By desuccinylating PCK2 at Lys489, SIRT5 prevents the metabolic reprogramming and subsequent activation of CFBs, protecting against cardiac fibrosis.