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Published on: February 13, 2019
Mitochondria-resident SBK3 confers protection against pressure overload-induced heart failure in mice
Aihua Yang1,2, Yuhang Wang1, Yifeng Zhang1
1Department of Pharmacology, School of Medicine and School of Pharmacy, Nantong University, Nantong 226019, China.
Insights
SBK3, a mitochondrial protein, protects against pathological cardiac hypertrophy and heart failure. Overexpressing SBK3 preserves mitochondrial function and integrity, offering a potential therapeutic target for heart conditions.
Area of Science:
- Cardiovascular Biology
- Mitochondrial Medicine
- Gene Therapy
Background:
- Pathological myocardial hypertrophy, a risk factor for heart failure, is often linked to hypertension.
- The specific role of the SBK3 gene in cardiac function remains largely unknown.
- Mitochondrial dysfunction is implicated in the progression of heart failure.
Purpose of the Study:
- To investigate the role of SBK3 in transverse aortic constriction (TAC)-induced heart failure.
- To determine the therapeutic potential of targeting SBK3 for heart failure treatment.
- To elucidate the mechanisms by which SBK3 influences cardiac health.
Main Methods:
- Subcellular localization of SBK3 in cardiomyocytes using western blot and immunofluorescence.
- Assessment of SBK3 protein expression in pathological hypertrophy.
- In vitro and in vivo overexpression of SBK3 using adenoviral vectors and AAV9.
- Evaluation of cardiac function and hypertrophy markers in response to SBK3 modulation.
- Analysis of mitochondrial ultrastructure, respiratory chain complexes, and dynamics.
Main Results:
- SBK3 is localized to mitochondria in adult rat cardiomyocytes.
- SBK3 protein expression is downregulated during pathological cardiac hypertrophy.
- SBK3 overexpression inhibits hypertrophy markers (ANP, BNP) and improves calcium handling in vitro.
- Cardiac-specific SBK3 overexpression prevents TAC-induced cardiac hypertrophy and heart failure in vivo.
- SBK3 preserves mitochondrial ultrastructure, balances respiratory chain complexes, and modulates mitochondrial dynamics.
Conclusions:
- SBK3 plays a crucial cardioprotective role by maintaining mitochondrial integrity.
- SBK3 mitigates pathological cardiac remodeling and dysfunction.
- SBK3 represents a promising therapeutic target for mitochondrion-targeted heart failure treatment.
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.
