吡格列酮通过调控Sirt3改善高血压引起的心肌纤维化机制

doi:10.6040/j.issn.1671-7554.0.2016.1378

摘要/Abstract

摘要： 目的探讨吡格列酮对高血压引起的心肌纤维化的作用及可能机制。方法提取新生SD大鼠心肌成纤维细胞,分为空白对照组、单纯刺激组(血管紧张素Ⅱ 1 μmol/L)、单纯药物组(吡格列酮10 μmol/L)、刺激+药物组、沉默信息调节相关因子3(Sirt3)小干扰+刺激组和Sirt3小干扰+刺激+药物组,采用Western blotting法检测平滑肌肌动蛋白(a-SMA)、β-链蛋白(β-catenin)、胶原I(COL I)和Sirt3等蛋白含量;采用RT-PCR法检测a-SMA、Sirt3、β-catenin和COL I等mRNA表达量;采用细胞免疫荧光法检测COL I表达。结果与空白对照组相比,单纯刺激组a-SMA和COL I的mRNA和蛋白表达明显增加,Sirt3表达减少,β-catenin表达增加,COL I绿色荧光增强,心肌纤维化明显(P<0.05);与单纯刺激组相比,刺激+药物组a-SMA和COL I的mRNA和蛋白表达明显减少,Sirt3表达增加,β-catenin表达减少,COL I绿色荧光减弱,心肌纤维化明显改善(P<0.05);与药物+刺激组相比,Sirt3小干扰+药物+刺激组a-SMA、COL I的mRNA和蛋白表达增加,Sirt3表达减少,β-catenin表达增多,COL I绿色荧光增强(P<0.05)。单纯药物组与药物+刺激组相比,a-SMA、COL I、β-catenin和Sirt3的mRNA和蛋白表达无明显变化(P>0.05);Sirt3小干扰+刺激组和Sirt3小干扰+药物+刺激组相比,a-SMA、COL I、β-catenin、Sirt3的mRNA和蛋白表达无明显变化(P>0.05)。结论吡格列酮能改善高血压心肌纤维化,其作用机制可能与Sirt3激活和β-catenin抑制有关。

关键词: β-链蛋白, 吡格列酮, 高血压, 心肌纤维化, 沉默信息调节相关因子3

Abstract: Objective To investigate the effect of pioglitazone on cardiac fibrosis induced by hypertension and the possible mechanism. Methods Cardiac fibroblasts were extracted from newly-born SD rats and divided into 6 groups: negative control group, angiotension II(ANGII 1 μmol/L)group, pioglitazone(Piog 10 μmol/L)group, Piog+ANGII group, Sirt3.siRNA+ANGII group, and Sirt3.siRNA+Piog+ANGII group. The protein expressions of a-SMA, Sirt3, COL I and β-catenin were detected with Western blotting. The mRNA expressions of a-SMA, Sirt3, COL I and β-catenin were detected with quantitative real time PCR. The expression of COL I was evaluated with immuofluorescence staining. Results Compared with the negative control group, the ANGII group showed increased mRNA and protein expressions of a-SMA, COL I and β-catenin, decreased expression of Sirt3, enhanced green fluorescence of COL I, and severer cardiac fibrosis(all P<0.05). Compared with the ANGII group, the Piog+ANGII group 山东大学学报 (医学版)55卷5期 -严芳英,等.吡格列酮通过调控Sirt3改善高血压引起的心肌纤维化机制 \=-showed increased mRNA and protein expressions of Sirt3, decreased expressions of a-SMA, COL I and β-catenin, lower green fluorescence intensity of COL I, and improved cardiac fibrosis(all P<0.05). Compared with the Piog+ANGII group, the Sirt3.siRNA+Piog+ANGII group showed increased mRNA and protein levels of a-SMA, COL I and β-catenin, decreased levels of Sirt3, and higher green fluorescence intensity of COL I(all P<0.05). However, there were no significant differences in the mRNA and protein expressions between Piog and Piog+ANGII groups(P>0.05), and between Sirt3.siRNA+ANGII and Sirt3. siRNA+Piog+ANGII groups(P>0.05). Conclusion Pioglitazone can improve cardiac fibrosis induced by hypertension via activation of Sirt3 and inhibition of β-catenin.

Key words: Pioglitazone, Hypertension, Cardiac fibrosis, β-catenin, Sirtuin3

中图分类号:

R543.1

严芳英,单晓兰,李静媛,张杰,闫雪芳,杨奕,卜培莉. 吡格列酮通过调控Sirt3改善高血压引起的心肌纤维化机制[J]. 山东大学学报（医学版）, 2017, 55(5): 13-18.

YAN Fangying, SHAN Xiaolan, LI Jingyuan, ZHANG Jie, YAN Xuefang, YANG Yi, BU Peili. Pioglitazone ameliorates cardiac fibrosis induced by hypertension via regulating Sirt3[J]. JOURNAL OF SHANDONG UNIVERSITY (HEALTH SCIENCES), 2017, 55(5): 13-18.

参考文献

[1] Xu T, Liu J, Zhu G, et al. Prevalence of prehypertension and associated risk factors among Chinese adults from a large-scale multi-ethnic population survey[J]. BMC Public Health, 2016, 16(1): 775.
[2] Burchfield JS, Xie M, Hill JA. Pathological ventricular remodeling: mechanisms: part 1 of 2[J]. Circulation, 2013, 128(4): 388-400.
[3] Braunwald E. Heart failure[J]. JACC Heart Fail, 2013, 1(1): 1-20.
[4] Semple RK, Chatterjee VK, ORahilys. PPAR gamma and human metabolic disease[J]. J Clin Invest, 2006, 116(3): 581-589.
[5] Panchapakesan U, Sumual S, Pollock CA, et al. PPARgamma agonists exert antifibrotic effects in renal tubular cells exposed to high glucose[J]. Am J Physiol Renal Physiol, 2005, 289(5): 1153-1158.
[6] Chen T, Li J, Liu J, et al. Activation of SIRT3 by resveratrol ameliorates cardiac fibrosis and improves cardiac function via the TGF-β/Smad3 pathway[J]. Am J Physiol Heart Circ Physiol, 2015, 308(5): 424-434.
[7] Rosenkranz S. TGF-beta1 and angiotensin networking in cardiac remodeling[J]. Cardiovasc Res, 2004, 63(3): 423-432.
[8] 赵红梅, 吴铿. 吡格列酮在抗动脉粥样硬化中的作用[J]. 中国全科医学, 2010, 13(5): 555-557.
[9] Kularni AA, Woeller CF, Thatcher TH, et al. Emerging PPARγ-Independent role of PPARγ ligands in Lung Diseases[J]. PPAR Res, 2012, 705352. doi:10.1155/2012/705352.
[10] Wei WY, Ma ZG, Xu SC, et al. Pioglitazone protected against cardiac hypertrophy via inhibiting AKT/GSK3βand MAPK signaling pathways[J]. PPAR Res, 2016, 9174190. doi: 10.1155/2016/9174190.
[11] Zhao SM, Li HW, Guo CY, et al. Cardiac fibrosis in diabetic rats: regulation and mechanism of activation of PPARamma signal pathway[J]. Chin J Physiol, 2010, 53(4): 262-267.
[12] Nakamura T, Yamamoto E, Kataoka K, et al. Beneficial effects of pioglitazone on hypertensive cardiovascular injury are enhanced by combination with candesartan[J]. Hypertension, 2008, 51(2): 296-301.
[13] Yang Y, Cimen H, Han MJ, et al. NAD+-dependent deacetylase SIRT3 regulates mitochondrial protein synthesis by deacetylation of ribosomal protein MRPL10[J]. J Biol Chen, 2010, 285(10): 7417-7429.
[14] Kim SH, Lu HF, Alano CC. Neuronal SIRT3 protects against exicitotoxic injury in mouse cortical neuron culture[J]. PLoS One, 2011, 6(3): 14731.
[15] Onyango P, Celic I, McCaffery JD, et al. SIRT3, a human SIR2 homologue, is an NAD-dependent deacetylase localizes to mitochondria[J]. Proc Natl AcadSci USA, 2002, 99(21): 13653-13658.
[16] Bellizzi D, Rose G, Cavalcante P, et al. Anovel VNTR enhancedr within the SIRT3 gene, a human homologue of SIR2, is associated with survival at oldest ages[J]. Genomics, 2005, 85(2): 258-263.
[17] Rose G, Data S, Altomare K, et al. Variability of SIRT3 gene, human silent information regulator Sir2 homologue, and survivorship in the elderly[J]. Exp Gerontol, 2003, 38(10): 1065-1070.
[18] Hafner AV, Dai J, Gomes AP, et al. Regulation of the mPTP by SIRT3-mediated deacetylation of CypD at lysine166 suppresses age-related cardiac hypertrophy[J]. Aging(Albany NY), 2010, 2(12): 914-923.
[19] Pronobis MI, Peifer M. Wnt signaling: The many interfaces of β-catenin[J]. Curr Biol, 2012, 22(4): 137-139.
[20] Villar J, Cabrera NE, Valadares F, et al. Activation of the Wnt/β-catenin signaling pathway by mechanical ventilation is associated with ventilator-induced pulmonary fibrosis in healthy lungs[J]. PLoS One, 2011, 6(9): 23914.
[21] Cuevas CA, Gonzalez AA, Intestrosa NC, et al. Angiotensin II increases fibronectin and collagen I through the β-catenin-dependent signaling in mouse collecting duct cells[J]. Am J Physiol Renal Physiol, 2015, 308(4): 358-365.
[22] Sundaresan NR, Bindu S, Pillai VB, et al. SIRT3 blocks aging-associated tissue fibrosis in mice by deacetylating and activating glycogen synthase kinase 3β[J]. Mol Cell Biol, 2015, 36(5): 678-692.

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