Irbesartan ameliorates myocardial fibrosis in diabetic cardiomyopathy rats by inhibiting the TGFβ1/Smad2/3 pathway

Abstract

Myocardial fibrosis (MF) is an important pathological change in diabetic cardiomyopathy. The aim of the present study was to investigate whether irbesartan serves a role in improving MF in a diabetic rat model. Fasting blood glucose (FBG), total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) levels were measured in rats using biochemical methods. Heart weight index (HWI), left ventricular weight index (LVWI), left ventricular systolic pressure (LVSP) and left ventricular end-diastolic pressure (LVEDP) were also measured, whilst type I collagen and hydroxyproline content in myocardial tissue was quantified. Western blotting was used to measure the expression of transforming growth factor β1 (TGFβ1), phosphorylated (p)-Smad2/3 and collagen type I α 1 chain (COL1A1) inmyocardial tissues or rat cardiac fibroblast (RCF) cells. Cell proliferation was measured using EdU staining. Procollagen type III N-terminal peptide (PIIINP) content, FBG, TC, TG and LDL-C levels were found to be significantly higher, whilst HDL-C levels were found to be significantly lower in rats in the diabetic group. Those in the diabetic group also exhibited significantly elevated HWI, LVWI, LVEDP, myocardial tissue type I collagen content and hydroxyproline content values, but significantly reduced LVSP. Changes in the aforementioned indicators were reversed after treatment with irbesartan, where the protein expression levels of TGFβ1 and p-Smad2/3 in myocardial tissue were also significantly reduced. In RCF cells, irbesartan significantly reversed high glucose-induced upregulation of TGFβ1 expression, Smad2/3 phosphorylation and COL1A1 expression, as well as reducing cell proliferation and rat type I PICP and PIIINP levels. Application of pirfenidone produced additive effects on reducing the expression levels of the proteins aforementioned when combined with irbesartan. Therefore, the present results demonstrated that irbesartan reduced the activity of the TGFβ1/Smad2/3 pathway and ameliorated diabetic MF by downregulating the expression of TGFβ1.

Protective effects of swimming exercises and metformin on cardiac and aortic damage caused by a high-fat diet in obese rats with type 2 diabetes, by regulating the Bcl2/Bax signaling pathway

“…EXE and MET were able to reduce the levels of LDL, which carry blood cholesterol, and thus make an important contribution to the prevention of cardiovascular pathologies in terms of lipid regulation. Consistent with these results, Zong et al obtained similar HDL and LDL results in their DM-2 rat model [ 30 ]. Furthermore, Baretti et al showed that obese rat LDL levels decreased by 61% with EXE [ 31 ].…”

Tangshen Formula Improves Diabetes-Associated Myocardial Fibrosis by Inhibiting TGF-β/Smads and Wnt/β-Catenin Pathways

“…Irbesartan ameliorates myocardial fibrosis in diabetic cardiomyopathy ( 15 ). It is an angiotensin domain receptor inhibitor and is considered to be a common medication for improving the structure and function of cardiomyocytes and reducing the risk of death from heart failure ( 16 ).…”

Central role of cardiac fibroblasts in myocardial fibrosis of diabetic cardiomyopathy

“…The specific deletion of Tgfbr1/2 and Smad3 notably reduce cardiac fibrosis resulting from transverse coarctation of aorta, and Smad3 is activated downstream of TGF-b receptor (166,167). In vivo drug research found that inhibiting TGF-b/Smad2/3 pathway can inhibit the proliferation and collagen production of CFs and attenuate the degree of cardiac fibrosis (168). In recent years, there are several researches focus on how TGF-b signaling pathway regulates the phenotypic transformation and function of CFs.…”

“…But it is encouraging that the related research is increasing year by year (188). Previous studies have shown that Irbesartan inhibits CFs proliferation and ameliorates myocardial fibrosis in T2DM rats (168). Inhibition of SGLT1 expression in CFs improves DCM cardiac fibrosis by attenuating myofibroblasts activation (90), and the SGLT1/2 inhibitor sogliflozin (zynquista) has completed phase III clinical trials (189), suggesting a novel therapeutic strategy for the treatment of DCM fibrosis.…”