Department of Pharmacology and Toxicology, School of Medicine, University of Mississippi Medical Center, Jackson, MS 39216, USA.
Int J Mol Sci. 2020 Dec 21;21(24):9744. doi: 10.3390/ijms21249744.
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.
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.
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.
射血分数保留的心力衰竭（HFpEF）的特征是舒张功能障碍，在老年女性中高发。我们的研究表明，内皮细胞沉默信息调节因子 3（SIRT3）的消融会导致雄性小鼠舒张功能障碍。然而，内皮细胞 SIRT3 缺乏对雌性小鼠血压和舒张功能的性别特异性作用仍有待研究。
在这项研究中，我们证明了雌性内皮细胞 SIRT3 的消融会导致其血压升高，与对照组雌性小鼠相比。舒张功能测量也显示，等容松弛时间（IVRT）和心肌做功指数（MPI）显著增加，而内皮细胞特异性 SIRT3 敲除（SIRT3ECKO）雌性小鼠的 E'速度/A'速度（E'/A'）比值降低。为了进一步研究内皮细胞 SIRT3 在代谢应激下对血压和舒张功能障碍的调节作用，SIRT3ECKO 雌性小鼠给予正常饮食和高脂肪饮食（HFD）喂养 20 周。内皮细胞 SIRT3 的敲除导致 HFD 喂养的雌性小鼠血压升高。有趣的是，与对照组雌性小鼠+HFD 相比，SIRT3ECKO 雌性小鼠+HFD 表现出冠状动脉血流储备（CFR）受损和更严重的舒张功能障碍，表现为 IVRT 升高。此外，与雄性 SIRT3ECKO 小鼠相比，雌性 SIRT3ECKO 小鼠的血压和舒张功能障碍更高。此外，与雄性 SIRT3ECKO 小鼠+HFD 相比，雌性 SIRT3ECKO 小鼠+HFD 的 CFR 和舒张功能障碍受损。
这些结果表明内皮细胞 SIRT3 在调节小鼠血压和舒张功能方面具有性别特异性作用。内皮细胞 SIRT3 的缺乏可能是老年女性舒张功能障碍的原因。
