Mitochondria-resident SBK3 confers protection against pressure overload-induced heart failure in mice.

Abstract

Pathological myocardial hypertrophy, often caused by hypertension, is a well-established independent risk factor for heart failure. SBK3, a gene selectively expressed at relatively high levels in cardiac tissues, has an unclear functional role in the heart. This study is designed to examine the role of SBK3 in transverse aortic constriction (TAC)-induced heart failure, aiming to identify a novel mitochondrion-targeted therapeutic strategy for heart failure. The subcellular localization of SBK3 in adult rat cardiomyocytes is investigated by western blot analysis and immunofluorescence staining, which reveal that SBK3 is located in the mitochondria. Subsequent western blot analysis shows that SBK3 protein expression is downregulated under pathological hypertrophy. To assess the functional relevance of this observation, SBK3 is overexpressed both in vivo (via cardiac-specific AAV9-cTNT) and in vitro (via adenoviral transduction). In vitro, adenovirus-mediated overexpression of SBK3 significantly inhibits ANP and BNP expression and increases the Ca ²⁺ transient amplitude in angiotensin II (Ang II)-induced hypertrophic cardiomyocytes. In vivo, cardiac-specific SBK3 overexpression using cTNT promoter-containing adeno-associated virus 9 inhibits TAC-induced cardiac hypertrophy and heart failure. Mechanistically, SBK3 exerts its cardioprotective effects by preserving the mitochondrial ultrastructure and regulating the balance of respiratory chain complexes. In addition, SBK3 modulates key regulators of mitochondrial dynamics, including fission and fusion proteins, thereby contributing to mitochondrial integrity and protection against pathological cardiac remodeling.