有氧运动对自发性高血压大鼠心肌纤维化的影响及机制

摘要：目的 观察长期有氧运动对自发性高血压大鼠（SHR）心肌纤维化的影响，并探讨调控胶原代谢的信号分 子——转化生长因子-β（1 TGF-β1）、结缔组织生长因子（CTGF）、基质金属蛋白酶2（MMP-2）和组织金属蛋白酶抑制 物-2（TIMP-2）在其中的作用机制。方法 30只雄性SHR随机分为安静对照（SHR-RC）组和有氧运动（SHR-AT） 组，同时将15只Wistar-Kyoto大鼠作为正常血压对照（NC）组。NC组和SHR-RC组动物在鼠笼安静饲养，SHR-AT组 进行24周跑台训练。实验结束后利用无创血压仪测定尾动脉血压，超声心动术检测心脏结构与功能，Masson染色获 取心脏胶原容积分数（CVF），实时荧光定量 PCR 检测心钠素（ANP）、脑钠素（BNP）和 β-肌球蛋白重链（β-MHC） mRNA表达量，Western blotting检测TGF-β1、CTGF、MMP-2［包括总MMP-2（72 ku）和活化型MMP-2（64 ku）］、TIMP- 2和α-平滑肌肌动蛋白（α-SMA）蛋白表达量。结果 与NC组比较，SHR-RC组大鼠心腔扩张同时室壁变薄，心脏 CVF 增加，心功能下降，ANP、BNP 和 β-MHC mRNA 以及 TGF-β1、CTGF、TIMP-2 和 α-SMA 蛋白表达量上调（P＜ 0.05），活化型MMP-2蛋白表达量以及活化型MMP-2/TIMP-2比值下降（P＜0.05）；与SHR-RC组比较，SHR-AT组心 脏扩张减轻，心脏CVF下降，心功能增强，ANP、BNP和β-MHC mRNA以及α-SMA蛋白表达量下调，活化型MMP-2 蛋白表达量以及活化型 MMP-2/TIMP-2 比值增加（P＜0.05），而 TGF-β1、CTGF 和 TIMP-2 蛋白表达量无明显变化 （P＞0.05）。结论 长期规律有氧运动能够改善SHR心肌纤维化，并延缓心脏重塑和心力衰竭进程，其机制与胶原 降解增加（但对胶原合成无影响）以及抑制成纤维细胞向成肌纤维细胞分化有关

The effect and mechanism of aerobic training on cardiac fibrosis in spontaneously hypertensive rats

Abstract: Objective To observe the effects of long-term aerobic training on cardiac fibrosis in spontaneously hypertensive rats (SHR) and to investigate the role and mechanism of collagen metabolism regulators such as transforming growth factor - β1 (TGF - β1), connective tissue growth factor (CTGF), matrix metalloproteinase-2 (MMP-2) and tissue inhibitors of metalloproteinase-2 (TIMP-2). Methods Thirty male SHRs were randomly separated to rest control (SHRRC) or aerobic training (SHR-AT) groups, and 15 Wistar-Kyoto rats were used as normotensive control (NC) group. Animals in NC and SHR-RC groups were kept silent at cage while those in SHR-AT group undertook treadmill exercise for 24 weeks. At the end of experiment, a series of measurements were determined for caudal artery pressure by non-invasive blood pressure tester, cardiac structure and function were detected by echocardiogram, cardiac collagen volumetric fraction (CVF) was determined by Masson dyeing, mRNA expression levels of atrial natriuretic factor (ANP), brain natriuretic peptide (BNP) and β-myosin heavy chain (β-MHC) were detected by real-time Q-PCR, and protein expressions of TGF-β1, CTGF, MMP- 2 (including 64 ku and 72 ku isoforms), TIMP-2 and alpha-smooth muscle actin (α-SMA) were detected by Western blot assay. Results Compared with NC group, the dilated cardiac chamber with thinner ventricular wall was found in rats of SHR-RC group, and the cardiac CVF increased (P＜0.05), cardiac function decreased (P＜0.05), and ANP, BNP and β- MHC mRNA as well as TGF-β1, CTGF, TIMP-2 and α-SMA proteins upregulated (P＜0.05). Also 64 ku MMP-2 and 64 ku MMP-2 / TIMP-2 ratio reduced (P＜0.05). Compared with SHR-RC group, animals in SHR-AT group showed alleviated cardiac chamber dilation, reduced cardiac CVF (P＜0.05), enhanced cardiac function (P＜0.05), downregulated ANP, BNP and β-MHC mRNA and α-SMA protein (P＜0.05), increased 64 ku MMP-2 and 64 ku MMP-2/TIMP-2 ratio (P＜0.05). There were no significant changes in TGF-β1, CTGF and TIMP-2 protein expressions (P＞0.05). Conclusion Long-term regular aerobic training can improve cardiac fibrosis and delay cardiac remodeling and heart failure progression in SHR, and the mechanism is related with the augment of collagen degradation (however, no effect on collagen synthesis) and inhibition of differentiation from fibroblasts into myofibroblasts