Angiotensin Ii-Induced Upregulation of Sbk3 in Mitochondria Via Calcineurin-Nfatc3 Signalling Suppresses Hypertrophy

Abstract

Pathological cardiac hypertrophy is one of the risk factors for heart failure, characterized by elevated levels of renin-angiotensin II (Ang II) and catecholamines. Here, we studied the role of SBK3 in Ang II-induced cardiac hypertrophy to identify a new treatment for cardiac hypertrophy and heart failure by targeting mitochondria. SBK3(SH3 domain binding kinase family member 3), a resident protein in the mitochondria, exhibits relatively high expression selectively in cardiac tissue according to the analysis of RNA abundance in Human Protein Atlas (HPA) database.However, its specific function within the heart has not been reported so far. Our study reveals, for the first time, the mitochondrial localization of SBK3 in rat cardiomyocytes while identifying NFATc3 as a key transcription factor for mitochondrial-resident SBK3 transcription in cardiomyocytes. Overexpression of SBK3 suppressed the cardiac hypertrophy induced by Ang II both in vivo and in vitro, which is driven by inhibiting the phosphorylation of dynamin related protein 1(Drp1) at serine 616 (S616). This maintains the stability of mitochondrial morphology and function, as evidenced by the overexpression of SBK3 improved energy metabolism and rebalanced the level of mitochondrial oxidative stress. Our findings suggest that SBK3 is an adaptive anti-hypertrophic gene that responds to hypertrophic stimuli and is a potential therapeutic target for the treatment of cardiac hypertrophy and heart failure.

Note:
Funding declaration: This work was supported by the National Natural Science Foundation of China (Grant No.81770400) and Postgraduate Research and Practice Innovation Project of Jiangsu Province (Grant No.KYCX20_2625).

Conflict of Interests: No conflict of interest, financial or otherwise, are declared by the authors.

Ethical Approval: All experimental procedures in animal research conformed to the guidelines for laboratory animal care and were approved by the Institutional Animal Care and Use Committee of Nantong University (approval number IACUC20210916-1001).

Keywords: SBK3, Drp1, Hypertrophy, Mitochondria, NFATc3, MFF