S100A9 deficiency mitigates cardiac oxidative stress and improves function via SIRT3 in HFpEF mice

Heart failure with preserved ejection fraction (HFpEF) is the predominant manifestation of heart failure, yet effective treatment options remain limited, and its underlying mechanisms are not well understood. In the present study, the hearts of HFpEF mice were collected for proteomics analyses, and differentially expressed proteins were screened. Then, the effects of S100A9 on HFpEF were investigated using S100A9-knockout (KO) mice. The results revealed elevated levels of S100A8 and S100A9 mRNA and protein in the hearts of HFpEF mice, primarily driven by high-fat diet (HFD) exposure. S100A9 deficiency resulted in lowered systolic blood pressure, reduced cardiac oxidative stress, enhanced mitochondrial bioenergetics, mitigated myocardial hypertrophy and fibrosis, ultimately improving cardiac diastolic dysfunction and alleviating pulmonary congestion in HFpEF mice. Moreover, S100A9 deficiency increased the NAD + /NADH ratio, restored SIRT3 levels, decreased NOX2 expression, and suppressed the hyperacetylation of SOD2 at its K68 site in HFpEF hearts. Inhibiting SIRT3 diminished the protective effects of S100A9 deficiency on cardiac diastolic dysfunction in vivo . In vitro , palmitic acid (PA) significantly elevated S100A8 and S100A9 expression in cardiomyocytes via oxidative stress-related mechanisms. Recombinant mouse S100A9 protein decreased SIRT3 expression, leading to oxidative stress and mitochondrial dysfunction. S100A9 knockdown mitigated PA-induced oxidative stress and mitochondrial dysfunction by preserving SIRT3 expression. In conclusion, our study suggests that S100A9 deficiency improves cardiac function by reducing oxidative stress and alleviating mitochondrial dysfunction through increasing SIRT3 levels in HFpEF mice.