MicroRNA-221/222 Family Counteracts Myocardial Fibrosis in Pressure Overload–Induced Heart Failure

Abstract

Pressure overload causes cardiac fibroblast activation and transdifferentiation, leading to increased interstitial fibrosis formation and subsequently myocardial stiffness, diastolic and systolic dysfunction, and eventually heart failure. A better understanding of the molecular mechanisms underlying pressure overload-induced cardiac remodeling and fibrosis will have implications for heart failure treatment strategies. The microRNA (miRNA)-221/222 family, consisting of miR-221-3p and miR-222-3p, is differentially regulated in mouse and human cardiac pathology and inversely associated with kidney and liver fibrosis. We investigated the role of this miRNA family during pressure overload-induced cardiac remodeling. In myocardial biopsies of patients with severe fibrosis and dilated cardiomyopathy or aortic stenosis, we found significantly lower miRNA-221/222 levels as compared to matched patients with nonsevere fibrosis. In addition, miRNA-221/222 levels in aortic stenosis patients correlated negatively with the extent of myocardial fibrosis and with left ventricular stiffness. Inhibition of both miRNAs during AngII (angiotensin II)-mediated pressure overload in mice led to increased fibrosis and aggravated left ventricular dilation and dysfunction. In rat cardiac fibroblasts, inhibition of miRNA-221/222 derepressed TGF-β (transforming growth factor-β)-mediated profibrotic SMAD2 (mothers against decapentaplegic homolog 2) signaling and downstream gene expression, whereas overexpression of both miRNAs blunted TGF-β-induced profibrotic signaling. We found that the miRNA-221/222 family may target several genes involved in TGF-β signaling, including JNK1 (c-Jun N-terminal kinase 1), TGF-β receptor 1 and TGF-β receptor 2, and ETS-1 (ETS proto-oncogene 1). Our findings show that heart failure-associated downregulation of the miRNA-221/222 family enables profibrotic signaling in the pressure-overloaded heart.

Human cardiac fibrosis-on-a-chip model recapitulates disease hallmarks and can serve as a platform for drug screening

“…Interestingly, treatment with the anti-fibrotic drug pirfenidone led to a 2.1-fold increase in the miR-221 expression in the HF-chip tissues ( Supplemental Table 1), and an even higher increase in extracellular vesicles (32-fold). This is in line with its recently described role in counteracting myocardial fibrosis in pressure overload-induced heart failure by blunting TGF-β-induced pro-fibrotic signaling (Verjans et al, 2018) and suggests a possible new mechanism of action for the drug. It also demonstrates the potential of the human HF-chip platform to validate animal findings in a human-relevant model.…”

“…It also suggests that the loading of particular miRs into vesicles is a highly specific and regulated process. In support of this, we saw that miR-221, found to target TGF-β-mediated pro-fibrotic SMAD2 (mothers against decapentaplegic homolog 2) signaling and its downstream gene expression (Verjans et al, 2018), was not differentially expressed in control or fibrotic tissues but was significantly downregulated in secreted extracellular vesicles in fibrotic samples. Interestingly, treatment with the anti-fibrotic drug pirfenidone led to a 2.1-fold increase in the miR-221 expression in the HF-chip tissues ( Supplemental Table 1), and an even higher increase in extracellular vesicles (32-fold).…”

MicroRNAs in Cancer Treatment-Induced Cardiotoxicity

“…Reduced myocardial miR-221/222 expression is associated with severe cardiac fibrosis in heart failure patients [95]. miR-221 overexpression has been shown to induce cardiac hyperthropy in vitro [96] and to promote HF [147].…”

“…miR-221 overexpression has been shown to induce cardiac hyperthropy in vitro [96] and to promote HF [147]. Indeed, miR-221/222 are significantly upregulated in patients with hypertrophic cardiomyopathy [95].…”

miR-2954 Inhibits PI3K Signaling and Induces Autophagy and Apoptosis in Myocardium Selenium Deficiency

“…Jeong et al indicate that miR-25 TuD (Tough Decoy) is an effective long-term suppressor of miR-25 and a promising therapeutic candidate to treat heart failure in humans [11]. According to Verjans, heart failure-associated down regulation of the miRNA-221/222 family enables fibrosis signaling in a pressure-overloaded heart in rats [12]. In our previous study, we showed in chickens that regulation of miR-200a-5p and its target gene blocks necroptosis in the heart, which revealed a novel myocardial necrosis regulation model in heart disease [13].…”