Improvement of vascular insulin sensitivity by downregulation of GRK2 mediates exercise-induced alleviation of hypertension in spontaneously hypertensive rats
Improvement of vascular insulin sensitivity by downregulation of GRK2 mediates exercise-induced alleviation of hypertension in spontaneously hypertensive rats
复制标题
通过下调 GRK2 改善血管胰岛素敏感性介导自发性高血压大鼠运动诱发的高血压缓解
DOI：
10.1152/ajpheart.00290.2013
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发表时间：
2013-10-01
影响因子：
4.8
通讯作者：
Gao, Feng
中科院分区：
文献类型：
--
作者：
Xing, Wenjuan;Li, Youyou;Gao, Feng
运动训练降低血压，是高血压患者推荐的一种非药物策略和有用的辅助治疗。研究表明，体育活动可以减缓高血压的进展。然而，潜在的机制仍然难以捉摸。血管胰岛素抵抗和内皮功能障碍在高血压的发展中起着至关重要的作用。本研究探讨高血压前期开始的长期体育锻炼是否通过改善血管胰岛素敏感性来预防高血压的发展。研究对象为年轻（4周龄）高血压前期自发性高血压大鼠（SHRs）及其正常Wistar-Kyoto （WKY）对照大鼠，进行为期10周的无负荷游泳训练（60分钟/天，5天/周）。测定血压、肠系膜小动脉血管松弛、G蛋白偶联受体激酶-2 （GRK2）表达和活性、胰岛素刺激Akt/内皮型一氧化氮合酶（eNOS）活性。与WKY大鼠相比，SHRs有更高的收缩压、全身胰岛素抵抗和抵抗血管中胰岛素的血管舒张作用受损。运动后SHRs的收缩压明显低于久坐大鼠。运动训练后，肠系膜动脉血管胰岛素敏感性得到改善，血管扩张剂对胰岛素的反应增加。此外，运动下调血管GRK2的表达和活性，进一步增加胰岛素刺激的血管Akt/eNOS在运动SHRs中的激活。内皮细胞中GRK2特异性小干扰RNA的下调模拟了运动增强血管胰岛素敏感性的效果。同样，通过战车介导的递送上调GRK2与运动诱导的血管胰岛素增敏相反。综上所述，我们的研究结果表明，从高血压前期开始的长期运动可以通过下调血管GRK2来改善血管胰岛素敏感性，这可能有助于限制高血压的进展。
Exercise training lowers blood pressure and is a recommended nonpharmacological strategy and useful adjunctive therapy for hypertensive patients. Studies demonstrate that physical activity attenuates progression of hypertension. However, underlying mechanisms remain elusive. Vascular insulin resistance and endothelial dysfunction plays a critical role in the development of hypertension. The present study investigated whether long-term physical exercise starting during the prehypertensive period prevents the development of hypertension via improving vascular insulin sensitivity. Young (4 wk old) prehypertensive spontaneously hypertensive rats (SHRs) and their normotensive Wistar-Kyoto (WKY) control rats were subjected to a 10-wk free-of-loading swim training session (60 min/day, 5 days/wk). Blood pressure, mesenteric arteriolar vasorelaxation, G protein-coupled receptor kinase-2 (GRK2) expression and activity, and insulin-stimulated Akt/endothelial nitric oxide synthase (eNOS) activation were determined. SHRs had higher systolic blood pressure, systemic insulin resistance, and impaired vasodilator actions of insulin in resistance vessels when compared with WKY rats. Systolic blood pressure in SHRs postexercise was significantly lower than that in sedentary rats. Vascular insulin sensitivity in mesenteric arteries was improved after exercise training as evidenced by an increased vasodilator response to insulin. In addition, exercise downregulated vascular GRK2 expression and activity, which further increased insulin-stimulated vascular Akt/eNOS activation in exercised SHRs. Specific small interfering RNA knockdown of GRK2 in endothelium mimicked the effect of exercise-enhanced vascular insulin sensitivity. Likewise, upregulation of GRK2 by Chariot-mediated delivery opposed exercise-induced vascular insulin sensitization. Taken together, our results suggest that long-term exercise beginning at the prehypertensive stage improves vascular insulin sensitivity via downregulation of vascular GRK2 that may help to limit the progression of hypertension.