Deficiency of synaptotagmin-1 aggravates pressure overload-induced cardiac hypertrophy and dysfunction via the p38 MAPK signaling pathway in mice.

Abstract

Cardiac hypertrophy is a major risk factor for heart failure and sudden cardiac death, but its molecular mechanisms have not been well clarified. Synaptotagmin-1 (SYT1) is an important regulator of exocytosis and apoptosis and has been found expressed in the myocardium, while its functions in heart diseases have rarely been studied. Here, we investigated the role and mechanism of SYT1 in pressure overload-induced cardiac hypertrophy. Transverse aortic constriction (TAC) surgeries were performed to induce cardiac hypertrophy in global Syt1 knockout (Syt1^+/-) mice and C57BL/6J wild-type (WT) littermates in vivo, with respective sham mice as negative controls. Cardiomyocyte hypertrophy was induced by angiotensin II (Ang II) in H9C2 cells in vitro. The results showed that SYT1 expression was significantly upregulated in WT-TAC mice and in Ang II-treated H9C2 cells. Blocking angiotensin receptor by losartan decreased SYT1 expression in Ang II-treated H9C2 cells. Syt1^+/- mice showed significantly exacerbated cardiac hypertrophy, dysfunction, fibrosis, apoptosis and phosphorylation of myocardial p38 MAPK in response to TAC compared to WT mice. Knocking down SYT1 using siRNA in H9C2 cells aggravated Ang II-induced cell hypertrophy and apoptosis, and also enhanced p38 MAPK phosphorylation. Inhibition of p38 MAPK by SB203580 significantly alleviated the hypertrophy and apoptosis in Ang II-treated H9C2 cells. We conclude that deficiency of SYT1 aggravates pressure overload-induced cardiac hypertrophy via the p38 MAPK signaling pathway. The study elucidates a novel role of SYT1 in cardiac remodeling.