Angiotensin II receptor blocker valsartan ameliorates cardiac fibrosis partly by inhibiting miR-21 expression in diabetic nephropathy mice. (5th September 2018)

• Record Type: Journal Article
• Authors: Wang, Jinyang; Duan, Lijun; Gao, Yanbin; Zhou, Shuhong; Liu, Yongming; wei, Suhong; An, Siqin; Liu, Jing; Tian, Liming; Wang, Shaocheng
• Is Part Of: Molecular and cellular endocrinology. Volume 472(2018)
• Page Start: 149
• Page End: 158
• Publication Date: 2018-09-05
• Subjects: Cardiac fibrosis -- miRNAs -- MMP-9 -- Diabetic nephropathy (DN) -- ARB; ARB Angiotensin II receptor blocker -- MMP-9 Matrix metalloprotease-9 -- DN diabetic nephropathy -- ISH In Situ Hybridization -- CVF Collagen volume fraction -- PVCA Perivascular collagen area -- LVMI Left ventricle mass index -- HWI Heart weigh index -- miRNAs, miRs MicroRNAs -- ACR Urinary albumin creatinine ratio -- SBP Systolic blood pressure -- HbA1c glycosylated hemoglobin A1c -- ECM extracellular matrix proteins -- NT-pro-BNP N-terminal pro-brain natriuretic peptide -- T-Cho total cholesterol; Endocrinology -- Periodicals; Molecular biology -- Periodicals; Cytology -- Periodicals; Endocrinology -- Periodicals; Hormones -- Periodicals; Endocrinologie -- Périodiques; Cytology; Endocrinology; Molecular biology; Periodicals; 573.4
• DOI: 10.1016/j.mce.2017.12.005
• Languages: English
• ISSNs: 0303-7207

Abstract

Abstract: Cardiac fibrosis with diabetic nephropathy (DN) is one of major diabetic complications. miR-21 and MMP-9 were closely associated with fibrosis diseases. Angiotensin II receptor blockers (ARB) have cardioprotective effects. However, it remains unclear whether miR-21 was involved in the mechanism of cardiac fibrosis with DN by target MMP-9 and ARB ameliorates cardiac fibrosis partly by inhibiting miR-21 expression. In this study, In Situ Hybridization(ISH), RT-PCR, cell transfection, western blotting and laser confocal telescope were used, respectively. ISH showed that miR-21, concentrated in cytoplasmic foci in the proximity of the nucleus, was mainly localized in cardiac fibroblasts and at relatively low levels in cardiomyocytes within cardiac tissue with DN. RT-PCR showed that miR-21 expression was significantly enhanced in cardiac tissue with DN, accompanied by the increase of col-IV, FN, CVF, PVCA, LVMI, HWI and NT-pro-BNP (p < 0.05). Bioinformatics analysis and Luciferase reporter gene assays showed that MMP-9 was a validated target of miR-21. Furthermore, cell transfection experiments showed that miR-21 overexpression directly decreased MMP-9 expression. Interestingly, miR-21 levels in cardiac tissue was positively correlated with ACR (r = −0.870, P = 0.003), whereas, uncorrelated with SBP, HbA1C and T-Cho (p > 0.05). More importantly, ARB can significantly decrease miR-21 expression in cardiac tissue, cardiac fibroblasts and serum. Overall, our results suggested that miR-21 may contribute to the pathogenesis of cardiac fibrosis with DN by target MMP-9, and that miR-21 may be a new possible therapeutic target for ARB in cardiac fibrosis with DN. Highlights: miR-21 was significantly enhanced in cardiac tissue with DN, accompanied by the increase of NT-pro-BNP. miR-21 overexpression directly decreased MMP-9 expression. miR-21 may be a new possible therapeutic target for ARB in cardiac fibrosis with DN. ARB ameliorated cardiac structure and function by inhibiting miR-21 expression.