Irbesartan ameliorates myocardial fibrosis in diabetic cardiomyopathy rats by inhibiting the TGF&beta;1/Smad2/3 pathway

Zong,Min; Zhao,Hua; Li,Qiang; Li,Yanbing; Zhang,Jianjun

doi:10.3892/etm.2020.9245

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

Authors:
- Min Zong
- Hua Zhao
- Qiang Li
- Yanbing Li
- Jianjun Zhang
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Affiliations: Department of Cardiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100043, P.R. China
Published online on: September 18, 2020 https://doi.org/10.3892/etm.2020.9245
Article Number: 117
Copyright: © Zong et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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.

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1	Chen J, Wang J, Zhang X and Zhu H: Inverse relationship between serum bilirubin levels and diabetic foot in Chinese patients with type 2 diabetes mellitus. Med Sci Monit. 23:5916–5923. 2017.PubMed/NCBI View Article : Google Scholar
2	Xu T, Weng Z, Pei C, Yu S, Chen Y, Guo W, Wang X, Luo P and Sun J: The relationship between neutrophil-to-lymphocyte ratio and diabetic peripheral neuropathy in type 2 diabetes mellitus. Medicine (Baltimore). 96(e8289)2017.PubMed/NCBI View Article : Google Scholar
3	Russo I and Frangogiannis NG: Diabetes-associated cardiac fibrosis: Cellular effectors, molecular mechanisms and therapeutic opportunities. J Mol Cell Cardiol. 90:84–93. 2016.PubMed/NCBI View Article : Google Scholar
4	Dillmann WH: Diabetic cardiomyopathy. Circu Res. 124:1160–1162. 2019.PubMed/NCBI View Article : Google Scholar
5	Zhang X, Pan L, Yang K, Fu Y, Liu Y, Chi J, Zhang X, Hong S, Ma X and Yin X: H3 relaxin protects against myocardial injury in experimental diabetic cardiomyopathy by inhibiting myocardial apoptosis, fibrosis and inflammation. Cell Physiol Biochem. 43:1311–1324. 2017.PubMed/NCBI View Article : Google Scholar
6	Zou C, Liu X, Xie R, Bao Y, Jin Q, Jia X, Li L and Liu R: Deferiprone attenuates inflammation and myocardial fibrosis in diabetic cardiomyopathy rats. Biochem Biophys Res Commun. 486:930–936. 2017.PubMed/NCBI View Article : Google Scholar
7	Wang L, Li J and Li D: Losartan reduces myocardial interstitial fibrosis in diabetic cardiomyopathy rats by inhibiting JAK/STAT signaling pathway. Int J Clin Exp Pathol. 8:466–473. 2015.PubMed/NCBI
8	He-He H, Chen DQ, Wang YN, Feng YL, Cao G, Vaziri ND and Zhao YY: New insights into TGF-β/smad signaling in tissue fibrosis. Chem Biol Interact. 2018:76–83. 2018.PubMed/NCBI View Article : Google Scholar
9	Meng XM, Nikolic-Paterson DJ and Lan HY: TGF-β: The master regulator of fibrosis. Nat Rev Nephrol. 12:325–338. 2016.PubMed/NCBI View Article : Google Scholar
10	Xu F, Liu C, Zhou D and Zhang L: TGF-β/SMAD pathway and its regulation in hepatic fibrosis. J Histochem Cytochem. 64:157–167. 2016.PubMed/NCBI View Article : Google Scholar
11	Estato V, Obadia N, Carvalho-Tavares J, Freitas FS, Reis P, Neto HC, Lessa MA and Tibiriçá E: Blockade of the renin-angiotensin system improves cerebral microcirculatory perfusion in diabetic hypertensive rats. Microvasc Res. 87:41–49. 2013.PubMed/NCBI View Article : Google Scholar
12	Wong TC, Piehler KM, Kang IA, Kadakkal A, Kellman P, Schwartzman DS, Mulukutla SR, Simon MA, Shroff SG, Kuller LH and Schelbert EB: Myocardial extracellular volume fraction quantified by cardiovascular magnetic resonance is increased in diabetes and associated with mortality and incident heart failure admission. Eur Heart J. 35:657–664. 2014.PubMed/NCBI View Article : Google Scholar
13	Patel BM and Mehta AA: Aldosterone and angiotensin: Role in diabetes and cardiovascular diseases. Eur J Pharmacol. 697:1–12. 2012.PubMed/NCBI View Article : Google Scholar
14	Parving HH, Lehnert H, Bröchner-Mortensen J, Gomis R, Andersen S and Arner P: Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 345:870–878. 2001.PubMed/NCBI View Article : Google Scholar
15	Croom KF, Curran MP, Goa KL and Perry CM: Irbesartan: A review of its use in hypertension and in the management of diabetic nephropathy. Drugs. 64:999–1028. 2004.PubMed/NCBI View Article : Google Scholar
16	Nako H, Kataoka K, Koibuchi N, Dong YF, Toyama K, Yamamoto E, Yasuda O, Ichijo H, Ogawa H and Kim-Mitsuyama S: Novel mechanism of angiotensin II-induced cardiac injury in hypertensive rats: The critical role of ASK1 and VEGF. Hypertens Res. 35:194–200. 2012.PubMed/NCBI View Article : Google Scholar
17	Castoldi G, Di Gioia CR, Bombardi C, Catalucci D, Corradi B, Gualazzi MG, Leopizzi M, Mancini M, Zerbini G, Condorelli G and Stella A: MiR-133a regulates collagen 1A1: Potential role of miR-133a in myocardial fibrosis in angiotensin II-dependent hypertension. J Cell Physiol. 227:850–856. 2012.PubMed/NCBI View Article : Google Scholar
18	Whaley-Connell A, Habibi J, Cooper SA, Demarco VG, Hayden MR, Stump CS, Link D, Ferrario CM and Sowers JR: Effect of renin inhibition and AT1R blockade on myocardial remodeling in the transgenic ren2 rat. Am J Physiol Endocrinol Metab. 295:E103–E109. 2008.PubMed/NCBI View Article : Google Scholar
19	National Research Council (US) Committee for the Update of the Guide for the Care and Use of Laboratory Animals: Guide for the Care and Use of Laboratory Animals. 8th edition. National Academies Press, Washington, DC, 2011. Available from: https://www.ncbi.nlm.nih.gov/books/NBK54050/ doi: 10.17226/12910.
20	Dai H, Zheng M, Tang Rn, Ma Kl, Ni J and Liu BC: Inhibition of integrin-linked kinase by angiotensin II receptor antagonist, irbesartan attenuates podocyte injury in diabetic rats. Chin Med J (Engl). 125:888–893. 2012.PubMed/NCBI
21	Guo Y, Gupte M, Umbarkar P, Singh AP, Sui JY, Force T and Lal H: Entanglement of GSK-3β, β-catenin and TGF-β1 signaling network to regulate myocardial fibrosis. J Mol Cell Cardiol. 110:109–120. 2017.PubMed/NCBI View Article : Google Scholar
22	Yang D, Li L, Qian S and Liu L: Evodiamine ameliorates liver fibrosis in rats via TGF-beta1/smad signaling pathway. J Natl Med. 72:145–154. 2017.PubMed/NCBI View Article : Google Scholar
23	Yang T, Wang J, Pang Y, Dang X, Ren H, Liu Y, Chen M and Shang D: Emodin suppresses silica-induced lung fibrosis by promoting sirt1 signaling via direct contact. Mol Med Rep. 14:4643–4649. 2016.PubMed/NCBI View Article : Google Scholar
24	Li H, Cai H, Deng J, Tu X, Sun Y, Huang Z, Ding Z, Dong L, Chen J, Zang Y and Zhang J: TGF-beta-mediated upregulation of sox9 in fibroblast promotes renal fibrosis. Biochim Biophys Acta Mol Basis Dis. 1864:520–532. 2018.PubMed/NCBI View Article : Google Scholar
25	Kajdaniuk D, Marek B, Borgiel-Marek H and Kos-Kudła B: Transforming growth factor β1 (TGFβ1) in physiology and pathology. Endokrynol Pol. 64:384–396. 2013.PubMed/NCBI View Article : Google Scholar
26	Chen G, Grotendorst G, Eichholtz T and Khalil N: GM-CSF increases airway smooth muscle cell connective tissue expression by inducing TGF-β receptors. Am J Physiol Lung Cell Mol Physiol. 284:L548–L556. 2003.PubMed/NCBI View Article : Google Scholar
27	Loboda A, Sobczak M, Jozkowicz A and Dulak J: TGF-beta1/smads and miR-21 in renal fibrosis and inflammation. Med Inflamm. 2016(8319283)2016.PubMed/NCBI View Article : Google Scholar
28	Li Y, Yang Y, Yu D and Liang Q: The effect of tanshinone IIA upon the TGF-beta1/smads signaling pathway in hypertrophic myocardium of hypertensive rats. J HuazhongUnivSciTechnolog Med Sci. 29:476–480. 2009.PubMed/NCBI View Article : Google Scholar
29	Yuan X, Gong Z, Wang B, Guo X, Yang L, Li D and Zhang Y: Astragaloside inhibits hepatic fibrosis by modulation of TGF-beta1/smad signaling pathway. evidence-based complementary and alternative medicine. Evid Based Complement Alternat Med. 2018(3231647)2018.PubMed/NCBI View Article : Google Scholar
30	Wang S, Zhao X, Yan S, Chen B and Shi J: Knockdown of NLRC5 inhibits renal fibroblast activation via modulating TGF-beta1/smad signaling pathway. Eur J Pharmacol. 829:38–43. 2018.PubMed/NCBI View Article : Google Scholar
31	Yu B, Li W, Al F and Chen Z: MicroRNA-33a deficiency inhibits proliferation and fibrosis through inactivation of TGF-beta/smad pathway in human cardiac fibroblasts. Pharmazie. 72:456–460. 2017.PubMed/NCBI View Article : Google Scholar
32	Zhang Y, Shao L, Ma A, Guan G, Wang J, Wang Y and Tian G: Telmisartan delays myocardial fibrosis in rats with hypertensive left ventricular hypertrophy by TGF-beta1/smad signal pathway. Hypertens Res. 37:43–49. 2014.PubMed/NCBI View Article : Google Scholar
33	Zhang ZZ, Cheng YW, Jin HY, Chang Q, Shang QH, Xu YL, Chen LX, Xu R, Song B and Zhong JC: The sirtuin 6 prevents angiotensin II-mediated myocardial fibrosis and injury by targeting AMPK-ACE2 signaling. Oncotarget. 8:72302–72314. 2017.PubMed/NCBI View Article : Google Scholar
34	Roth L, Schrijvers DM, Martinet W and De Meyer GR: Angiotensin II increases coronary fibrosis, cardiac hypertrophy and the incidence of myocardial infarctions in ApoE^-/- Fbn1^C1039G+/- mice. Acta Cardiol. 71:483–488. 2016.PubMed/NCBI View Article : Google Scholar
35	Chen Q, Pang L, Huang S, Lei W and Huang D: Effects of emodin and irbesartan on ventricular fibrosis in goldblatt hypertensive rats. Pharmazie. 69:374–378. 2014.PubMed/NCBI
36	Ritchie RH, Zerenturk EJ, Prakoso D and Calkin AC: Lipid metabolism and its implications for type 1 diabetes-associated cardiomyopathy. J Mol Endocrinol. 58:R225–R240. 2017.PubMed/NCBI View Article : Google Scholar
37	Shen N, Li X, Zhou T, Bilal MU, Du N, Hu Y, Qin W, Xie Y, Wang H, Wu J, et al: Shensong Yangxin capsule prevents diabetic myocardial fibrosis by inhibiting TGF-beta1/smad signaling. J Ethnopharmacol. 157:161–170. 2014.PubMed/NCBI View Article : Google Scholar
38	Lv J, Wang Z and Wang Y, Sun W, Zhou J, Wang M, Liu WJ and Wang Y: Renoprotective effect of the shen-yan-fang-shuai formula by inhibiting TNF-alpha/NF-kappaB signaling pathway in diabetic rats. J Diabetes Res. 2017(4319057)2017.PubMed/NCBI View Article : Google Scholar
39	Tunçdemir M and Oztürk M: The effects of angiotensin-II receptor blockers on podocyte damage and glomerular apoptosis in a rat model of experimental streptozotocin-induced diabetic nephropathy. Acta Histochem. 113:826–832. 2011.PubMed/NCBI View Article : Google Scholar
40	Chen C, Liang Z, Chen Q and Li ZG: Irbesartan and emodin on myocardial remodeling in Goldblatt hypertensive rats. J Cardiovasc Pharm. 60:375–380. 2012.PubMed/NCBI View Article : Google Scholar
41	Kataoka N, Nishida K, Kinoshita K, Sakamoto T, Nakatani Y, Tsujino Y, Mizumaki K, Inoue H and Kinugawa K: Effect of irbesartan on development of atrial fibrosis and atrial fibrillation in a canine atrial tachycardia model with left ventricular dysfunction, association with p53. Heart Vessels. 31:2053–2060. 2016.PubMed/NCBI View Article : Google Scholar
42	Tanaka J, Tajima S, Asakawa K, Sakagami T, Moriyama H, Takada T, Suzuki E and Narita I: Preventive effect of irbesartan on bleomycin-induced lung injury in mice. Respir Investig. 51:76–83. 2013.PubMed/NCBI View Article : Google Scholar
43	Zhao G, Zhao H, Tu L, Xu X, Zheng C, Jiang M, Wang P and Wang D: Effects and mechanism of irbesartan on tubulointerstitial fibrosis in 5/6 nephrectomized rats. J Huazhong Univ Sci Technol Med Sci. 30:48–54. 2010.PubMed/NCBI View Article : Google Scholar
44	Kim MY, Baik SK, Park DH, Jang YO, Suk KT, Yea CJ, Lee IY, Kim JW, Kim HS, Kwon SO, et al: Angiotensin receptor blockers are superior to angiotensin-converting enzyme inhibitors in the suppression of hepatic fibrosis in a bile duct-ligated rat model. J Gastroenterol. 43:889–896. 2008.PubMed/NCBI View Article : Google Scholar
45	Pellman J, Zhang J and Sheikh F: Myocyte-Fibroblast communication in cardiac fibrosis and arrhythmias: Mechanisms and model systems. J Mol Cell Cardiol. 94:22–31. 2016.PubMed/NCBI View Article : Google Scholar
46	Ivey MJ and Tallquist MD: Defining the cardiac fibroblast. Circ J. 80:2269–2276. 2016.PubMed/NCBI View Article : Google Scholar
47	Jin-Cheng L, Zhou L, Wang F, Cheng ZQ and Rong C: Osthole decreases collagen Ⅰ/III contents and their ratio in TGF-β1-overexpressed mouse cardiac fibroblasts through regulating the TGF-β/smad signaling pathway. Chin J Nat Med. 16:321–329. 2018.PubMed/NCBI View Article : Google Scholar
48	Eriksen HA, Satta J, Risteli J, Veijola M, Väre P and Soini Y: Type I and type III collagen synthesis and composition in the valve matrix in aortic valve stenosis. Atherosclerosis. 189:91–98. 2006.PubMed/NCBI View Article : Google Scholar
49	Liu X, Xu Q, Wang X, Zhao Z, Zhang L, Zhong L, Li L, Kang W, Zhang Y and Ge Z: Irbesartan ameliorates diabetic cardiomyopathy by regulating protein kinase D and ER stress activation in a type 2 diabetes rat model. Pharmacol Res. 93:43–51. 2015.PubMed/NCBI View Article : Google Scholar