Akt-Kv4.3-CaMKⅡ在有氧运动抑制压力负荷小鼠心肌肥厚中的作用及其机制

目的 探讨丝氨酸/苏氨酸激酶（Akt）-离子通道Kv4.3（Kv4.3）-钙调素依赖性蛋白激酶Ⅱ（CaMKⅡ）信号通路在有氧运动抑制压力负荷小鼠心肌肥厚中的作用及其机制。方法 60只实验小鼠均分为5组：假手术（SHAM）组、主动脉缩窄手术（TAC）组、假手术+有氧运动（SHAM+E）组、主动脉缩窄术+有氧运动（TAC+E）组，主动脉缩窄术+有氧运动+ Akt抑制剂Perifosine（TAC+E+Peri）组。高分辨率小动物超声系统评价小鼠心功能及肥厚程度，麦胚凝集素（WGA）染色检测心肌细胞横截面积；荧光定量PCR（RT-qPCR）检测ANP表达，Western blot检测蛋白心房钠尿肽（ANP）、p-Akt、Kv4.3、p-CaMKⅡ表达水平。结果 与SHAM组相比，TAC促进心肌肥厚，恶化心功能（P＜0.01）。给予有氧运动训练后，TAC+E组较TAC组小鼠心功能改善，心肌肥厚程度减轻（P＜0.01）。同时Western blot检测显示，TAC组较SHAM组p-Akt、Kv4.3表达降低，p-CaMKⅡ上调（P＜0.01）；TAC+E组p-Akt和Kv4.3表达较TAC小鼠增加，p-CaMKⅡ下调（P＜0.01）。而给予Akt抑制剂Perifosine后，相比于TAC+E组，TAC+E+Peri组心功能恶化、心肌肥厚程度和ANP表达增加，心肌细胞横截面积增大，同时伴随Kv4.3表达降低、p-CaMKⅡ增高（P＜0.01）。结论 有氧运动训练能够通过调节Akt-Kv4.3-CaMKⅡ信号通路抑制压力负荷心肌肥厚。

The role and mechanism of Akt-Kv4.3-CaMKII in aerobic exercise inhibited pressureoverload-induced cardiac hypertrophy

Objective To investigate the role and mechanism of serine / threonine kinase (Akt) - ion channel Kv4.3(Kv4.3) - calmodulin-dependent protein kinase Ⅱ (CaMK Ⅱ) signaling pathway in aerobic exercise inhibited pressureoverload-induced cardiac hypertrophy. Methods Sixty mice were divided into five groups: Sham group, transverse aorticconstriction (TAC) group, SHAM+ aerobic exercise (E) group, TAC + E group and TAC+ E + AKt inhibitor perifosine (Peri)group. Transthoracic echocardiography was used to assess the cardiac function and extent of myocardial hypertrophy. Thecross-sectional area of myocardial cells was measured by WGA staining. The mRNA expression of ANP was detected by RTqPCR. The protein expression levels of ANP, p-AKt, Kv4.3 and p-CaMKⅡ were detected by Western-blot assay. ResultsCompared with Sham group, the cardiac function of mice was deteriorated in TAC group (P＜0.01), and the extent of cardiachypertrophy was increased (P＜0.01). After aerobic exercise training, the cardiac function was improved in TAC + E group,and the level of myocardial hypertrophy was alleviated compared with TAC group (P＜0.01). Western-blot assay showed thatthe expressions of p-AKT and Kv4.3 were down-regulated, p-CaMKⅡ was up-regulated in TAC group than those in Sham group (P＜0.01). However, the expressions of p-AKT and Kv4.3 were higher, p-CaMKⅡ was lower in TAC+E group thanthose in TAC mice (P＜0.01). Furthermore, pretreatment with the AKT inhibitor perifosine, deteriorated cardiac function,augmented myocardial hypertrophy and ANP, increased cross-sectional area were observed in TAC+E+Peri group comparedwith those of TAC+E group (P＜0.01). Meanwhile, the downregulation of p-AKT、Kv4.3 and upregulation p-CaMKⅡ weredetected in the TAC+E+Peri group compared with the TAC+E group. Conclusion Aerobic exercise training can inhibitpressure overload-induced cardiac hypertrophy by regulating Akt-Kv4.3-CaMKⅡ.