MiRNA-122-5p inhibitor abolishes angiotensin II–mediated loss of autophagy and promotion of apoptosis in rat cardiofibroblasts by modulation of the apelin-AMPK-mTOR signaling

• DOI: 10.1007/s11626-022-00651-4
• Publication Date: 2022-02-08T09:06:40Z
• Authors: Mei Yang; Juan-Juan Song; Xin-Chun Yang; Guang-Zhen Zhong; Jiu-Chang Zhong
• Keywords: 0301 basic medicine; Angiotensin II; TOR Serine-Threonine Kinases; Apoptosis; AMP-Activated Protein Kinases; Rats; 3. Good health; Rats, Sprague-Dawley; MicroRNAs; 03 medical and health sciences; Autophagy; Animals; Apelin; Signal Transduction

MicroRNAs (miRNAs) have emerged as essential regulators that could have pivotal roles in cardiac homeostasis and pathological remodeling of various cardiovascular diseases. We previously demonstrated that miRNA-122-5p overexpression exacerbated the process of vascular hypertrophy, fibrosis, and dysfunction in hypertensive rats and rat aortic adventitial fibroblasts. However, the exact roles and underlying mechanisms of miRNA-122-5p in myocardial fibroblasts remain largely unknown. In this work, neonatal rat cardiofibroblasts (CFs) were isolated and primarily cultured from the hearts of 2- to 3-d-old Sprague-Dawley rats. Stimulation of angiotensin II (Ang II) resulted in marked increases in cellular proliferation and migration and levels of collagen I, collagen III, CTGF, and TGF-β1 in cultured CFs. Furthermore, Ang II led to promoted expression of P62, Bax, and phosphorylated mTOR as well as downregulation of LC3II, beclin-1, and AMPK-phosphorylated levels, thereby contributing to imbalance of autophagy and apoptosis, and cellular injury in CFs, which were significantly ameliorated by treatment with miRNA-122-5p inhibitor. These changes were associated with decreased levels of collagen I, collagen III, CTGF, and TGF-β1. Furthermore, Ang II-induced loss of autophagy and promotion of apoptosis in CFs were prevented by the treatment with Pyr1-apelin-13 or AMPK agonist AICAR or mTOR inhibitor rapamycin, respectively. In contrast, administration of miRNA-122-5p mimics and autophagy inhibitor 3-methylademine reversed beneficial roles of Pyr1-apelin-13. Collectively, these data indicated that miRNA-122-5p is an essential regulator of autophagy and apoptosis in rat CFs via the apelin/AMPK/mTOR signaling pathway, which may be potentially used as a therapeutic target in myocardial fibrosis and related diseases.