MicroRNA-26a Protects the Heart Against Hypertension-Induced Ventricular Remodeling

Background: Hypertensive ventricular remodeling can lead to heart failure with preserved ejection fraction. Therefore, seeking new therapeutic targets for hypertensive ventricular remodeling at the molecular level has become important. Methods: We examined the expression patterns of circulating and myocardial microRNA-26a (miR-26a) in hypertensive patients, Spontaneously Hypertensive Rats (SHRs) and miR-26a+/− mice. For mechanistic studies, we used recombinant adeno-associated virus (rAAV)-miR-26a to upregulate the expression of miR-26a in SHRs, and we used miR-26a mimic or inhibitor to intervene in angiotensin II-induced cardiofibroblasts. Findings: We found the downregulation of miR-26a in the plasma of both in SHRs and patients with hypertensive left ventricular hypertrophy; myocardial miR26a level was significantly decreased in SHRs as compared with normal control rats. More importantly, miR-26a-deficient mice showed cardiac hypertrophy and fibrosis, whereas overexpression of miR-26a significantly prevented elevated blood pressure and inhibited myocardial fibrosis in vivo and angiotensin II-induced fibrogenesis in cardiofibroblasts by directly targeting connective tissue growth factor and Smad4. miR-26a inhibited cardiofibroblast proliferation and promoted apoptosis by the enhancer of zeste homolog 2/p21 pathway, thereby reducing cardiac hypertrophy. Interpretation: Our study identified a novel role for miR-26a in blood pressure control and hypertensive ventricular remodeling and provides a possible treatment strategy for miR-26a to alleviate and reverse hypertensive ventricular remodeling. Funding Statement: National Natural Science Foundation of China (81570382, 81872563). Declaration of Interests: The authors declared no conflict of interest. Ethics Approval Statement: The study was explained, and informed consent obtained. All procedures were performed in compliance with protocols approved by the Ethics Committee for Human Studies at the Second Affiliated Hospital of Xian Jiaotong University.