Hydrogen sulfide alleviates heart failure with preserved ejection fraction in mice by targeting mitochondrial abnormalities via PGC-1α.

Increasing evidence has proposed that mitochondrial abnormalities may be an important factor contributing to the development of heart failure with preserved ejection fraction (HFpEF). Hydrogen sulfide (H 2 S) has been suggested to play a pivotal role in regulating mitochondrial function. Therefore, the present study was designed to explore the protective effect of H 2 S on mitochondrial dysfunction in a multifactorial mouse model of HFpEF. Wild type, 8-week-old, male C57BL/6J mice or cardiomyocyte specific- Cse (Cystathionine γ-lyase, a major H 2 S-producing enzyme) knockout mice (CSEcko) were given high-fat diet (HFD) and l -NAME (an inhibitor of constitutive nitric oxide synthases) or standardized chow. After 4 weeks, mice were randomly administered with NaHS (a conventional H 2 S donor), ZLN005 (a potent transcriptional activator of PGC-1α) or vehicle. After additional 4 weeks, echocardiogram and mitochondrial function were evaluated. Expression of PGC-1α, NRF1 and TFAM in cardiomyocytes was assayed by Western blot. Challenging with HFD and l -NAME in mice not only caused HFpEF but also inhibited the production of endogenous H 2 S in a time-dependent manner. Meanwhile the expression of PGC-1α and mitochondrial function in cardiomyocytes were impaired. Supplementation with NaHS not only upregulated the expression of PGC-1α, NRF1 and TFAM in cardiomyocytes but also restored mitochondrial function and ultrastructure, conferring an obvious improvement in cardiac diastolic function. In contrast, cardiac deletion of CSE gene aggravated the inhibition of PGC-1α-NRF1-TFAM pathway, mitochondrial abnormalities and diastolic dysfunction. The deleterious effect observed in CSEcko HFpEF mice was partially counteracted by pre-treatment with ZLN005 or supplementation with NaHS. Our findings have demonstrated that H 2 S ameliorates left ventricular diastolic dysfunction by restoring mitochondrial abnormalities via upregulating PGC-1α and its downstream targets NRF1 and TFAM, suggesting the therapeutic potential of H 2 S supplementation in multifactorial HFpEF. Schematic illustration of the protective effect of H 2 S on mitochondrial dysfunction in HF p EF and the underlying mechanism. [Display omitted] • The production of endogenous H 2 S was insufficient in a mouse model of HFpEF induced by mechanical and metabolic stress. • H 2 S improved mitochondrial function and alleviated HFpEF via upregulating PGC-1α, suggesting a therapeutic potential of H 2 S. • Cardiac deletion of Cse gene exacerbated diastolic dysfunction and mitochondrial abnormalities in HFpEF. [ABSTRACT FROM AUTHOR]