MiR-22 may Suppress Fibrogenesis by Targeting TGFβR I in Cardiac Fibroblasts

Abstract

Background/Aims: Cardiac fibrosis after myocardial infarction (MI) has been identified as a key factor in the development of heart failure, but the mechanisms undelying cardiac fibrosis remained unknown. microRNAs (miRNAs) are novel mechanisms leading to fibrotic diseases, including cardiac fibrosis. Previous studies revealed that miR-22 might be a potential target. However, the roles and mechanisms of miR-22 in cardiac fibrosis remained ill defined. The present study thus addressed the impact of miR-22 in cardiac fibrosis. Methods: After seven days following coronary artery occlusion in mice, tissues used for histology were collected and processed for Masson's Trichrome staining. In addition, cardiac fibroblasts were transfected with mimics and inhibitors of miR-22 using Lipofectamin 2000, and luciferase activity was measured in cell lysates using a luciferase assay kit. Western blotting was used to detect the expression of collagen1, α-SMA and TGFβRI proteins levels, and real time-PCR was employed to measure the Col1α1, Col3α1, miR-22 and TGFβRI mRNA levels. Results: In this study, we found that miR-22 was dynamically downregulated following MI induced by permanent ligation of the left anterior descending coronary artery for 7 days, an effect paralleled by significant collagen deposition. Inhibition of miR-22 with AMO-22 resulted in increased expression of Col1α1, Col3α1 and fibrogenesis in cultured cardiac fibroblasts. Conversely, overexpression of miR-22 in cultured cardiac fibroblasts significantly abrogated angiotensin II-induced collagen formation and fibrogenesis. Furthermore, we found that TGFβRI is a direct target for miR-22, and downregulation of TGFβR may have mediated the antifibrotic effect of miR-22. Conclusion: Our data clearly demonstrate that miR-22 acts as a novel negative regulator of angiotensin II-induced cardiac fibrosis by suppressing the expression of TGFβRI in the heart and may represent a new potential therapeutic target for treating cardiac fibrosis.

Novel heart failure biomarkers: why do we fail to exploit their potential?

“…Only later, a link between activation of the fetal gene program, miRNAs, and HF development was suggested [160][161][162]. For some solitary miRNAs, a role in pathological cardiac remodeling in animal models was found [160,[163][164][165][166]. Also, in humans, the relationship between miRNAs and cardiac remodeling has been investigated.…”

Effects of the Calcium-Activated Chloride Channel Inhibitors T16Ainh-A01 and CaCCinh-A01 on Cardiac Fibroblast Function

“…The precise mechanisms responsible for the actions of these inhibitors require further investigation. Further, we evaluated the effects of T16Ainh-A01 and CaCCinh-A01 on the expression of α-SMA, a typical marker of myofibroblasts, which are closely associated with cardiac fibrosis [30,31], and demonstrated that both inhibitors reduced α-SMA expression at the mRNA and protein level. The synthesis and secretion of collagen are the main functions of CFs, which play a pivotal role in the myocardial repair process [32].…”

Two Liters a Day Keep the Doctor Away? Considerations on the Pathophysiology of Suboptimal Fluid Intake in the Common Population

“…Excessive SGK1 expression was observed in lung fibrosis, diabetic nephropathy, glomerulonephritis, experimental nephrotic syndrome, obstructive nephropathy, liver cirrhosis, fibrosing pancreatitis, peritoneal fibrosis, Crohn´s disease and coeliac disease [7, 43, 91, 92]. SGK1 expression is up-regulated by TGFβ [43], a key stimulator of fibrosis [88, 93-98]. TGFß is in part effective through transcription factors Smad2/3 [7], which are degraded by the ubiquitin ligase Nedd4L [7].…”