Beneficial effects and mechanisms of long-term voluntary exercise on stroke events in stroke-prone spontaneously hypertensive rats

流行病学研究表明，体育锻炼可以降低心血管疾病的风险，但其机制尚不清楚。本研究旨在探讨长期中等强度运动对易卒中型自发性高血压大鼠（stroke-prone spontaneous hypertensive rats，SHRSP）血管内皮功能障碍引起的卒中事件的影响。高血压前期的SHRSP被允许在一个轮子上自主跑8周（EX）。将安静的大鼠置于不跑动的笼子中（SE），与SE相比，EX大鼠仅轻微降低收缩压，并降低脑卒中的发生率和死亡率。与SE组相比，EX组大鼠Akt磷酸化水平、内皮型一氧化氮合酶（eNOS）水平、eNOS活性和NO生成均升高。而EX的Nox 1和Nox 4、NADPH氧化酶组分的表达、活性和超氧化物产生量均低于SE。EX大鼠表现出较低的血清炎症细胞因子和趋化因子水平。EX组动脉壁增厚程度和胶原含量较SE组明显减轻，动脉壁MAPK、ERK 1/2、JNK和p38 MAPK磷酸化水平以及AP-1和NF-κ B转录激活因子磷酸化水平均较SE组明显降低。与SE相比，EX可减弱脑损伤区巨噬细胞浸润和NF-κ B引发的炎症反应。总之，有益的训练效果与Akt依赖性eNOS激活的增加和氧化应激的减少密切相关，然后减轻与血管中的高血压和脑中的缺血性变化相关的炎症，即使在具有中风风险的遗传性高血压动物中也是如此。

Epidemiological studies have showed that physical exercise reduced the risk of cardiovascular disease, but the mechanisms are not clear. This study planned to examine how a long-term and moderate exercise affected on the stroke events caused by vascular endothelial dysfunction in stroke-prone spontaneously hypertensive rats (SHRSP). SHRSP at pre-hypertensive stave were allowed to run voluntarily in a wheel for 8 wks (EX). Sedentary rats were placed in the cage without running (SE).EX rats decreased only slightly systolic blood pressure compared with SE, and reduced the incidence of stroke and mortality. In aortas of EX, phosphorylated Akt and endothelial nitric oxide synthase (eNOS) levels, eNOS activity and NO production were elevated compared with those SE. Whereas, expression of Nox1 and Nox4, NADPH oxidase components, the activity and superoxide production were lower in aortas of EX than SE. EX rats showed lower serum levels of inflammatory cytokines and chemokines. Furthermore, arterial thickening and collagen contents was attenuated in EX than SE.In aortas of EX, the phosphorylation of MAPKs, ERK1/2, JNK and p38 MAPK, and activating transcription factors of AP-1 and NF-kB were decreased. EX weakened macrophage infiltration and NF-kB-triggered inflammatory responses in cerebral lesion compared with SE. In conclusion, the beneficial training effect is closely related to increase in Akt-dependent eNOS activation and decrease in oxidative stress, and then mitigate the inflammation associated with hypertension in the vessels and ischemic changes in the brain even in genetic hypertensive animals with stroke risk.