Abstract
Background: Heart failure with preserved ejection fraction (HFpEF) is characterized by a diastolic dysfunction and is highly prevalent in aged women. Our study showed that ablation of endothelial Sirtuin 3 (SIRT3) led to diastolic dysfunction in male mice. However, the sex-specific role of endothelial SIRT3 deficiency on blood pressure and diastolic function in female mice remains to be investigated. Methods and Results: In this study, we demonstrate that the ablation of endothelial SIRT3 in females elevated blood pressure as compared with control female mice. Diastolic function measurement also showed that the isovolumic relaxation time (IVRT) and myocardial performance index (MPI) were significantly increased, whereas the E’ velocity/A’ velocity (E’/A’) ratio was reduced in the endothelial-specific SIRT3 knockout (SIRT3 ECKO) female mice. To further investigate the regulatory role of endothelial SIRT3 on blood pressure and diastolic dysfunction in metabolic stress, SIRT3 ECKO female mice were fed a normal diet and high-fat diet (HFD) for 20 weeks. The knockout of endothelial SIRT3 resulted in an increased blood pressure in female mice fed with an HFD. Intriguingly, SIRT3 ECKO female mice + HFD exhibited impaired coronary flow reserve (CFR) and more severe diastolic dysfunction as evidenced by an elevated IVRT as compared with control female mice + HFD. In addition, female SIRT3 ECKO mice had higher blood pressure and diastolic dysfunction as compared to male SIRT3 ECKO mice. Moreover, female SIRT3 ECKO mice + HFD had an impaired CFR and diastolic dysfunction as compared to male SIRT3 ECKO mice + HFD. Conclusions: These results implicate a sex-specific role of endothelial SIRT3 in regulating blood pressure and diastolic function in mice. Deficiency of endothelial SIRT3 may be responsible for a diastolic dysfunction in aged female.
Highlights
Heart failure (HF) is a highly prevalent disease, driven by aging, hypertension, diabetes mellitus, obesity, and ischemic heart disease [1]
Our previous study demonstrates that ablation of endothelial Sirtuin 3 (SIRT3) led to the altered endothelial cell (EC) metabolism and diastolic dysfunction in male mice [6], suggesting a cell-specific effect of SIRT3 on EC glycolytic metabolism, and coronary microvascular and diastolic dysfunction
Female SIRT3 ECKO mice exhibited a significant increase in the mean arterial pressure (MAP) and systolic blood pressure (SBP) when compared to the control mice (Figure 1A,B)
Summary
Heart failure (HF) is a highly prevalent disease, driven by aging, hypertension, diabetes mellitus, obesity, and ischemic heart disease [1]. The sex-specific role of endothelial SIRT3 deficiency on blood pressure and diastolic function in female, especially obese mice, has not been investigated. We utilized the unique endothelial-specific SIRT3 knockout (SIRT3 ECKO) male and female mice to investigate the sex-specific role of endothelial SIRT3 on blood pressure and diastolic function in females. We found that the female SIRT3 ECKO mice had impaired diastolic function, along with increased blood pressure, as compared with their female control mice. Female SIRT3 ECKO mice fed an HFD showed impaired diastolic function as compared to their male littermates. These results implicate a sex-specific role of endothelial SIRT3 in regulating blood pressure and diastolic function in mice
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