MiR-375-3p Promotes Cardiac Fibrosis by Regulating the Ferroptosis Mediated by GPX4

Abstract

Although coronary artery recanalization after myocardial infarction improves patient outcomes, inadequate ventricular remodeling following ischemia-reperfusion (IR) injury and secondary cardiac fibrosis (CF) are common and can lead to heart failure. MicroRNAs (miRNAs) play an important role in cardiovascular disorders. However, the underlying molecular mechanism of miRNAs in the occurrence and progression of CF has not been fully elucidated. Herein, through the construction of an I/R rat model and an angiotensin II-induced CF cell model, we evaluated the role of miR-375-3p in the progression of CF. In the I/R rat model and CF cell model, miR-375-3p promoted fibrosis by accelerating the ferroptosis of cardiomyocytes through mediating glutathione peroxidase 4 (GPX4). Furthermore, we treated the rats or cell model with miR-375-3p antagomir (or inhibitor) and ferroptosis inhibitor Ferrostatin-1 (Fer-1). The results showed that miR-375-3p antagomir (or inhibitor) and Fer-1 promoted the antioxidant capacity of cardiac fibroblasts, reduced GPX4-mediated ferroptosis process and alleviated I/R-induced CF. In conclusion, this study revealed that miR-375-3p directly targeted GPX4—an inhibitor of the ferroptosis pathway. Meanwhile, miR-375-3p can be a new potential biomarker for the prevention and treatment of CF.

Coinfection of Dermal Fibroblasts by Human Cytomegalovirus and Human Herpesvirus 6 Can Boost the Expression of Fibrosis-Associated MicroRNAs

“…Specifically, the pro-fibrotic miR-1, miR-19b; miR-122, miR-129, miR-150, miR-155, miR-192, miR-200b, miR-215, miR-216a, miR-32, miR-328, miR-375, miR-449b, miR-491, miR-661, and miR-7 were all more induced than in single-infected cells, showing values suggesting true synergism between the viruses rather than a mere additional effect. The pro-fibrotic action of the up-regulated miRNAs was well documented in several reports; miR-1 was reported as involved in increased fibrosis of the cartilage in acetabular dysplasia [ 43 ] and in liver fibrosis [ 44 ]; miR-19b-3p was associated with hypertrophic and fibrosis indexes in acute heart failure [ 45 ]; miR-122 has been related with fibrosis-induced cardiovascular remodeling [ 46 ] and, in this regard, it is intriguing that both HCMV and HHV-6A have been associated with cardiovascular diseases [ 25 , 47 , 48 , 49 ]; miR-150 was correlated with renal fibrosis and miR-150 antagonists can ameliorate the pro-fibrotic pathway in a mouse model [ 50 ]; miR-155 is essential in fibrosis and it is consistently up-regulated in fibrotic disorders [ 51 ]; miR-192 can promote fibrosis by transforming growth factor beta (TGF-β) activation, which is recognized as a major mediator of fibrosis [ 52 ], and its circulating levels are increased in patients with hypertrophic cardiomyopathy and diffuse myocardial fibrosis [ 53 ]; miR-200b was found to be up-regulated in fibrotic liver samples compared to non-fibrotic ones [ 54 ]; miR-216a accelerates fibrogenesis in cardiac fibroblasts [ 55 ]; miR-32 has been reported to mediate the glucose-induced hepatic fibrosis [ 56 ]); miR-328 was found to be up-regulated in cardiac fibrosis and shown to directly stimulate TGF-β1 signaling, promoting collagen production in cultured fibroblasts [ 57 ], although its pro-fibrotic role it is not so clear, since it has been also reported to prevent renal fibrogenesis [ 58 ]; miR-375 was recognized to promote cardiac fibrogenesis by accelerating the ferroptosis of cardiomyocytes through mediating glutathione peroxidase 4 (GPX4) [ 59 ]; the miR-449 family was detected to be up-regulated in cystic fibrosis [ 60 ] and in bleomycin-induced lung fibrosis [ 61 ] and able to activate TGF-β1 in nasopharyngeal carcinoma [ 62 ]; miR-491 is induced by TGF-β1 during renal fibrosis [ 63 ]; miR-661 has been recently shown to accelerate fibrosis by increasing fibroblast growth factor 2 (FGF2) [ 64 ]; miR-...…”

miR−122−5p Regulates Renal Fibrosis In Vivo

“…The other five miRNAs (miR−511−3p, −375−3p, −127−3p, 504−3p, and −363−3p) we identified might also be interesting targets for future research. In particular, miR−375−3p was reported to be associated with liver fibrosis and cardiac fibrosis [ 37 , 38 ]. In addition, miR−127−3p might be involved in tissue repair in ischemic kidney models [ 39 ].…”

From Iron Metabolism to Ferroptosis: Pathologic Changes in Coronary Heart Disease

“…In myocardial I/R injury mouse models, miR-375-3p was found to promote MF development by downregulating GPX4 expression. However, both miR-375-3p inhibitors and Fer-1 significantly attenuated MF in these mice and enhanced the antioxidant capacity of cardiac fibroblasts in vitro [ 71 ]. In another study, dexmedetomidine activated the SLC7A11/GPX4 signaling pathway, inhibited CM ferroptosis after myocardial I/R in mice, and significantly reduced the area of MF.…”