Heart failure with preserved ejection fraction (HFpEF) is characterized by diastolic dysfunction and is commonly observed in elderly, diabetic, hypertensive, and obese patients. Accumulating evidence suggests a close relationship between sirtuins and myocardial damage in HFpEF. This study aimed to explore whether sirtuin 3 (Sirt3) is involved in HFpEF. Wistar-Kyoto (WKY) rats served as the controls, while spontaneously hypertensive rats (SHRs) were randomly divided into three groups: the SHR group, HFpEF group, and HFpEF + 3-TYP group. Except for rats in the WKY and SHR groups, rats in the other groups were subjected to a high-fat diet (45%) and an intraperitoneal (i.p.) injection of streptozotocin (35 mg/kg) to establish the HFpEF model. Moreover, Sirt3 was inhibited using 3-TYP to further explore the regulatory mechanism of key molecules in this process. Cardiac function was evaluated by echocardiography, histological changes were examined by microscopy, and the morphology of the ER and mitochondria was observed through transmission electron microscopy. Western blotting was used to measure the levels of endoplasmic reticulum stress (ERS) and mitophagy-related proteins. Following high-fat feeding and i.p. injection of streptozotocin, SHRs presented markedly impaired diastolic function, decreased exercise tolerance, increased cardiac hypertrophy and fibrosis, and increased Sirt3 protein expression. Treatment with 3-TYP led to a significant reversal of these changes. When Sirt3 expression increased, endoplasmic reticulum stress and mitochondrial autophagy increased. Sirt3 silencing markedly reduced the excessive ERS and mitophagy levels induced by metabolic stress. 3-TYP can mitigate cardiac hypertrophy and improve function in HFpEF patients by inhibiting Sirt3, thereby protecting against metabolic disorders and excessive endoplasmic reticulum stress. These findings suggest that 3-TYP may be a promising therapeutic candidate for patients with metabolic syndrome-related HFpEF.
