PVAT旁分泌H2S调节平滑肌细胞KCNQ通道在运动干预肥胖高血压中的作用和机制

Obesity and the accumulation of fat especially excess visceral fat is the pivotal and independent factor that induces hypertension. There are beneficial effects of exercise on controlling blood pressure and reversing vascular structure and function in obesity. Perivascular adipose tissue (PVAT) is categorized as visceral fat, and paracrine dysfunction of PVAT plays a central role on high systemic arterial pressure in obesity hypertension. H2S is the main gaseous substance that secreted by PVAT and functions on KCNQ channel of vascular smooth muscle cell (VSMC). Our pretest study found that exercise could up-regulate circulating H2S in obese adolescence, and we also observed long-term exercise increased expression of CSE, the key enzyme that synthesize H2S, in mesenteric PVAT of rats. Therefore, we hypothesize that: (1) Regular exercise could modulate the function of PVAT paracrine and improve arterial relaxation in obesity hypertension; (2) Endogenous H2S secreted by PVAT plays a key role on exercise-induced vascular adaptation in obesity hypertension; (3) Altered activity or remodeling of KCNQ channels on VSMCs are influenced by H2S during exercise intervention in obese hypertensive arteries. This study would increase our understanding of the molecular mechanisms underlying exercise on KCNQ channel regulation and contribute to develop therapeutic targets for treatment of obesity related vascular diseases.

肥胖特别是内脏脂肪的增加是高血压的独立且首要危险因素，运动对于控制血压和逆转肥胖所诱发的血管病变有积极作用。血管周围脂肪组织（PVAT）被归为内脏脂肪，在肥胖诱发高血压中PVAT旁分泌紊乱导致小动脉张力改变在系统性动脉高压中具有关键影响。H2S是PVAT分泌并作用于小动脉血管平滑肌细胞（VSMC）的主要成分，且PVAT的舒血管效应依赖于H2S作用于VSMC上KCNQ通道。我们前期工作发现运动可以上调肥胖青少年循环血液中H2S水平，长期运动使大鼠肠系膜PVAT中催化合成H2S的关键酶CSE表达增多。故本项目推测：(1)规律运动可以调节肥胖机体PVAT旁分泌功能并影响小动脉血管舒张；(2)运动后肥胖小动脉舒张功能的改善依赖于PVAT旁分泌H2S的增加；(3)运动调节PVAT旁分泌H2S主要作用于小动脉平滑肌KCNQ通道的活化或重塑。该研究可能为肥胖诱发高血压提供治疗的新靶点或策略。

肥胖可诱发高血压，而运动可以有效控制血压。血管周围脂肪（PVAT）以旁分泌的形式将脂肪与血管的相互作用连接在一起，成为研究肥胖诱发心血管病理反应的关键点。本项目从脂肪-血管耦连入手，研究运动调节肥胖小动脉舒张的作用和机理；H2S是PVAT分泌的重要的舒血管气体调节物质，并且内源性H2S主要由脂肪组织分泌；而阻断平滑肌KCNQ通道将使PVAT丧失大部分的舒张血管功能。研究通过不同干预（运动和/或阻断剂）的大鼠肠系膜PVAT制备组织浴液，对小动脉舒张功能和VSMC通道蛋白进行检测，排除了在体多种因素对血管的影响。本项目确定了运动对肥胖诱发高血压小动脉舒张活性的调节作用与PVAT旁分泌的关系，证实了运动经PVAT旁分泌H2S调节小动脉VSMC上的KCNQ通道活性，并且明确运动经PVAT旁分泌H2S对VSMC上的KCNQ4通道亚基具有重塑作用。本研究结果为运动有效干预肥胖诱发高血压的原理提供新思路，也为在肥胖机体PVAT功能紊乱的病理条件下提供一种重要的抗高血压治疗的新靶点或策略。