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 Ca2+ 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.

1. Introduction

Cardiac hypertrophy is a common pathological feature of various cardiovascular diseases, including hypertension, and frequently precedes the development of heart failure, a condition of increasing public health significance [1–3]. Among the different forms of hypertrophy, pressure overload–induced myocardial hypertrophy, such as that caused by aortic stenosis, is recognized as an independent risk factor for heart failure [4]. Despite significant advances in clinical management, the morbidity and mortality associated with heart failure remain high and continue to rise worldwide [5,6].

In the context of cardiovascular diseases, mitochondria serve not only as a source of cellular damage but also as a target for therapeutic intervention [7]. Changes in mitochondrial function are closely associated with cardiac hypertrophy and heart failure [8]. Evidence suggests that mitochondrial homeostasis in the myocardium is integral to cardiac health and is implicated in the progression of a broad spectrum of cardiac disorders. This includes disruption of the mitochondrial structure, dynamics, mitophagy, and energy metabolism [9–11]. Interestingly, compensatory cardiac hypertrophy—a temporary adaptive response to increased workload—is often associated with the preservation of mitochondrial function [8,12,13]. Therefore, targeting mitochondrial function to prolong the physiological compensatory phase or reverse pathological hypertrophy may serve as a promising therapeutic strategy for hypertrophic heart failure.

SH3 domain binding kinase family member 3 (SBK3), also known as SGK110, is encoded on human chromosome 19 [14]. A genome-wide association study (GWAS) revealed that the SBK3 protein is predominantly enriched in heart tissues and is strongly associated with cardiovascular function [14]. SBK3 is closely related to SBK2, with the two genes located only a few kilobases apart. In 2022, van Gorp and colleagues [15] identified SBK2 as a gene enriched in both atrial and ventricular tissues, where it contributes to sarcomere integrity. SBK3 has a spatial distribution similar to that of SBK2. According to RNA abundance data from the Human Protein Atlas (HPA; https://www.proteinatlas.org), SBK3 is predominantly expressed in the heart and localized to mitochondria. However, its role in cardiac function remains poorly understood.