孤束核Ang II/AT1/自噬通路参与硫化氢调控肾血管性高血压大鼠子代血压的机制研究

The incidence of chronic hypertension during pregnancy is increasing, which is associated with an increased risk of cardiovascular disease in the fetus’ adulthood. Epigenetics is involved in fetal-programmed hypertension. The genetic predisposition of secondary hypertension is not clear. Recent studies have reported that hydrogen sulfide (H2S) can be used as epigenetic drug to intervene fetal-programmed disease. Preliminary studies have found that the offspring of renovascular hypertensive dams exhibited increased blood pressure and prenatal treatment with H2S decreased blood pressure in the offspring. Based on the crucial finding, this project is designed to collect blood samples of fetus labored from hypertensive and normotensive pregnant women, and examine the relationship between Ang II and H2S. Then maternal renovascular hypertensive rats treated with GYY4137 (H2S sustained-release agent) to observe the effect of H2S on offspring. We focuse on investigating the neural and molecular mechanism of baroreflex impaired and revealing the protective effect of H2S on offspring of renovascular hypertensive dams at integrative, molecular and gene expression levels in vitro and in vivo. We further investigate the epigenetic mechanism of Ang II/AT1/ autophagy pathway in nucleus tractus solitarius, which participates in baroreflex impaired and hypertension in offspring of renovascular hypertensive dams. From the perspective of epigenetic, the above study will provide a new strategy for the prevention and treatment of hypertension.

妊娠合并慢性高血压的发病率逐年升高，其胎儿在成年期更易患心血管疾病。表观遗传学参与胚胎编码高血压的发病，继发性高血压遗传倾向不明确。有报道硫化氢（H2S）可用于围产期干预胎儿编码疾病。预实验发现肾血管性高血压大鼠子代的血压升高，围产期给予亲代H2S可降低子代大鼠的血压，基于上述发现，进一步探讨其相关机制。首先收集高血压和正常血压孕妇同月龄新生儿的血样，检测血管紧张素II(Ang II)和H2S的相关性。以肾血管性高血压大鼠为模型，围产期给予亲代高血压大鼠GYY4137（H2S缓释剂），观察其对子代大鼠血压的作用及机制。在整体、离体脑片、分子和基因水平，探讨肾血管性高血压大鼠子代压力感受性反射钝化的神经机制和分子机制，特别是孤束核Ang II/AT1/自噬通路在高血压子代压力感受性反射钝化和血压升高的表观机制。从分子和基因水平揭示H2S的作用机制。以表观遗传学角度为高血压防治提供新策略。

妊娠合并慢性高血压的发病率在逐年增加，并且与成年后代患心血管疾病风险增加有关。最近的研究，硫化氢（H2S）已被证明是胎盘血管的一种强有力血管扩张剂，可以改善胎盘血管的阻力，改善子宫内生长受限。然而，有关围产期硫化氢干预对胚胎编码高血压的中枢作用还少有研究。本项目应用两肾一夹制备肾血管性高血压模型，观察子代大鼠的血压以及自主神经功能相关参数。同时围产期给予H2S处理，观察其对子代大鼠自主神经功能的影响机制。探讨肾血管性高血压子代大鼠是否存在压力感受性反射钝化、交感激活等自主神经功能紊乱，探讨AngII/AT1通路是否参与以及H2S的保护机制，探讨肾血管性高血压子代大鼠交感系统的传出活动是否对血管紧张素II（Ang II）的敏感性增加，探讨肾血管性高血压子代大鼠心功能的异常表现。我们发现肾血管性高血压子代大鼠基础血压升高，压力感受性反射钝化，交感的紧张性增高，并且侧脑室微量注射AngII，肾血管性高血压子代大鼠交感的反应性比正常血压子代大鼠增加。分子生物学实验发现肾血管性高血压子代大鼠血浆AngII水平升高，延髓腹外侧头端以及孤束核内源性H2S生成酶水平降低，AT1R以及下游炎症氧化应激相关蛋白表达增加，孤束核ATRAP水平下降。围产期给予H2S处理可以改善上述指标。我们还发现与正常血压子代大鼠相比，肾血管性高血压雌性子代大鼠心功能降低，左心室收缩压，左心室舒张压均增高。HE染色显示心肌炎症浸润。以上结果提示肾血管性高血压子代大鼠血压升高，自主神经功能紊乱，可能与AngII\AT1R\炎症通路激活，硫化氢水平降低有关。母体环境在维持出生后正常的生理功能中起着重要的作用。因此，围产期采取预防措施来防治心血管疾病很有必要。本研究为预防和治疗胚胎编码高血压提供了一种新的策略，为进一步研究H2S对亲代高血压后代的保护作用，提供了一条很有意义的途径，为高血压的防治提供新思路。