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Wnt信号通路抑制参与运动训练对自发性高血压大鼠心脏的保护作用

郭继峰¹, 李梦薇², 石炳烨², 张翼^2,3, 李娜², 王红杰^1,2,4,*

¹河北大学临床医学院，保定 071000；²河北大学基础医学院，保定 071000；³河北医科大学生理学教研室，石家庄 050017；⁴河北省慢性肾脏病骨骼代谢生理学重点实验室，保定 071000

摘要

本文旨在探讨低中强度运动训练对自发性高血压大鼠(spontaneously hypertensive rat, SHR)心脏的保护作用，以及Wnt信号通路在其中所起的作用。SHR和正常血压WKY (Wistar-Kyoto)大鼠随机分为高血压对照组(SHR-S)、高血压运动组(SHR-E)、正常血压对照组(WKY-S)、正常血压运动组(WKY-E)和高血压运动+Wnt激动剂组(SHR-E-Wnt)。运动组大鼠进行16周低中强度游泳运动，SHR-E-Wnt组大鼠在游泳结束前4周尾静脉注射Wnt通路激动剂Wnt agonist 1，每周测定大鼠动脉血压。运动结束后，超声心动图测定左心室壁厚度和射血功能、HE染色和Masson染色观察心肌结构和胶原纤维变化，实时荧光定量聚合酶链反应和Western blot分别检测左心室心肌β-连环蛋白(β-catenin)和DVL-1 (Dishevelled-1) mRNA和蛋白表达。结果显示：与WKY-S大鼠相比较，SHR-S大鼠体重下降(P < 0.05)，动脉血压明显升高(P < 0.01)，心脏重量和室壁厚度明显增加(P < 0.01)、左室射血功能明显减弱(P < 0.05)，心肌结构受损和胶原纤维明显增多，左室β-catenin和DVL-1的mRNA和蛋白表达明显上调(P < 0.01)。与SHR-S大鼠相比较，SHR-E大鼠体重未见明显改变，而动脉血压明显下降(P < 0.01)，心脏重量和室壁厚度明显减小、射血功能明显增强(P < 0.01)，心肌结构损伤明显改善、胶原纤维明显减少，左室β-catenin和DVL-1的mRNA和蛋白表达明显下调(P < 0.01)。此外，运动训练对SHR的降压和心脏保护作用可被Wnt信号通路激动剂所消除。上述结果表明，低中强度运动训练对SHR心脏具有保护作用，此作用可能通过抑制Wnt信号通路实现。

关键词： 运动训练; Wnt信号通路; 心室重构; 左心室功能; 自发性高血压大鼠

Inhibition of the Wnt signaling pathway contributes to the cardiac protection of exercise training in spontaneously hypertensive rats  

GUO Ji-Feng¹, LI Meng-Wei², SHI Bing-Ye², ZHANG Yi^2,3, LI Na², WANG Hong-Jie^1,2,4,*

¹College of Clinical Medicine, Hebei University, Baoding 071000, China；²College of Basic Medical Sciences, Hebei University, Baoding 071000, China；³Department of Physiology, Hebei Medical University, Shijiazhuang 050017, China；⁴Hebei Provincial Key Laboratory of Skeletal Metabolic Physiology of Chronic Kidney Disease, Baoding 071000, China

Abstract

The objective of this study was to investigate the cardiac protective effect of low-to-moderate intensity exercise training and the role of the Wnt signaling pathway in spontaneously hypertensive rats (SHR). SHR and Wistar-Kyoto (WKY) rats were randomly divided into 5 groups, namely hypertensive control (SHR-S), hypertensive plus exercise training (SHR-E), normal blood pressure control (WKY-S), normal blood pressure plus exercise training (WKY-E) and SHR-E plus Wnt agonist (SHR-E-Wnt). The rats in SHR-E and WKY-E groups underwent low-to-moderate intensity swimming for 16 weeks, and the rats in SHR-E-Wnt group were injected with Wnt agonist 1 through tail vein 4 weeks before the end of swimming. The blood pressure of rats was measured every week. After exercise training, the left ventricular wall thickness and ejection function were measured by ultrasound cardiogram, myocardial structure and collagen fiber changes were observed by HE staining and Masson staining, and the expression levels of β-catenin and Dishevelled-1 (DVL-1) mRNA and protein in left ventricular myocardium were detected by real-time fluorescence quantitative PCR and Western blot, respectively. The results showed that the body weight was decreased (P < 0.05), blood pressure was increased (P < 0.01), heart weight and ventricular wall thickness were increased (P < 0.01), and the left ventricular ejection function was decreased (P < 0.05) in SHR-S group compared with those in WKY-S group. In addition, the heart structure was damaged, collagen fibers were significantly increased, and the mRNA and protein expressions of β-catenin and DVL-1 in the left ventricle were significantly up-regulated in SHR-S group compared with those in WKY-S group (P < 0.01). Compared with those in SHR-S group, the body weight of SHR-E group did not change significantly (P > 0.05), but the blood pressure was decreased (P < 0.01), heart weight and ventricular wall thickness were diminished, ejection function was increased (P < 0.01), myocardial structure injury was significantly improved, collagen fibers were significantly reduced, and mRNA and protein expression levels of β-catenin and DVL-1 in the left ventricle were significantly down-regulated (P < 0.01) in SHR-E group. Importantly, exercise-induced antihypertensive and cardioprotective effects in SHR were blunted by Wnt agonist. These results suggest that low-to-moderate intensity exercise training exerts cardioprotective effects in SHR, possibly through inhibiting the Wnt signaling pathway.

Key words: exercise training; Wnt signaling pathway; ventricular remodeling; left ventricular function; spontaneously hypertensive rats

收稿日期：　　录用日期：

通讯作者：王红杰　　E-mail: hongjiew68@163.com

DOI: 10.13294/j.aps.2022.0032

引用本文：

郭继峰, 李梦薇, 石炳烨, 张翼, 李娜, 王红杰. Wnt信号通路抑制参与运动训练对自发性高血压大鼠心脏的保护作用[J]. 生理学报 2022; 74 (5): 773-782.

GUO Ji-Feng, LI Meng-Wei, SHI Bing-Ye, ZHANG Yi, LI Na, WANG Hong-Jie. Inhibition of the Wnt signaling pathway contributes to the cardiac protection of exercise training in spontaneously hypertensive rats  . Acta Physiol Sin 2022; 74 (5): 773-782 (in Chinese with English abstract).