胆碱能抗炎通路介导电针延缓高血压心肌重构进程的机制研究

Chronic hypertension further evokes abnormal cardiac plasticity, the effective prevent and treatment of which have great clinical significance. It has been shown that imbalanced function of autonomic nervous system (ANS) induced by chronic hypertension, including hyper-excitation of sympathetic nerves and suppression of parasympathetic (vagal) nerves, activates immune cells-mediated inflammatory responses, which play critical roles in the progression from chronic hypertension to cardiac hypertrophy as well as diastolic and systolic malfunction. Besides the negative inotropic outcomes, excitation of vagal nerves also has anti-inflammatory effect which is mediated by inhibiting the synthesis and release of pro-inflammatory factors via activation of α7nAchR by Ach (cholinergic anti-inflammatory pathway, CAP). Previous studies showed that electro-acupuncture (EA) could increase vagal activity and exhibit anti-hypertensive effect by regulating ANS’s function. Taken together, the possible role of CAP in the EA’s effect on alleviating the abnormal cardiac plasticity under chronic hypertension condition still need to be further explored..The present study aims to investigate the effects of EA on the abnormal cardiac plasticity of SHR and reveal the potential contribution of CAP, so as to provide scientific evidence and clinical relevance regarding EA’s therapeutic effects for this pathological progression.

慢性高血压病可诱发病理性心肌重构，是引起进行性死亡的主导原因，寻找阻滞该病理进程的有效防治手段具有重大临床意义。研究表明，高血压状态可引起自主神经功能失衡，即交感活动增强，副交感（迷走）活动受到抑制，进而激活由免疫细胞介导的炎性反应，而后者在慢性高血压-病理性心肌重构进程中发挥关键作用。激活迷走神经除可发挥负性心力作用外，还具有胆碱能抗炎作用。相关研究显示，电针可兴奋迷走神经，且可通过影响自主神经功能而发挥降压效应；本实验室前期工作亦提示：电针可延缓高血压性心肌肥厚的发展进程。而胆碱能抗炎通路在介导电针缓解慢性高血压心肌重构病理进程中的作用犹未可知，值得深入探究。.本课题以自发性高血压大鼠（SHR）为研究对象，观察电针对SHR病理性心肌重构的作用，并揭示与迷走神经活动相关的胆碱能抗炎通路在该电针效应中可能的角色，为电针延缓高血压心肌重构进程提供科学依据和临床借鉴。

本课题以自发性高血压大鼠（Spontaneously Hypertensive Rat，SHR）为研究对象，通过无创血压记录、超声心动图检测、形态学及病理组织学检测等技术，对血压和与心肌重构相关的指标进行检测，观察电针内关穴对SHR病理性心肌重构进程的疗效；在此基础上，采用心电图监测、电生理记录、荧光免疫组织化学及分子生物学检测等技术手段，并结合相应的拮抗剂等，探讨了与迷走神经活动相关的胆碱能抗炎通路各信号分子在参与介导电针延滞高血压心肌重构进程中的作用。实验结果表明：SHR除表现为血压升高外，其HW/BW、LVWI显著增加，左心室壁厚度，collagen I、collagen III的浓度异常增高，说明出现心肌肥厚为主要特征的心肌重构。电针内关穴可以显著地抑制SHR上述指标的异常增加，提示电针改善SHR心肌重构发展进程疗效明确，而电针前阻断ɑ7nAchR能显著减轻电针的抗压作用及对心肌重构的延缓作用。另一方面，电针内关穴可以明显上调SHR组HF的异常降低，增加颈迷走神经放电频率。下调心肌组织中炎症信号转录因子NF-κB p65的异常表达，降低SHR血清及心肌组织中促炎因子TNF-α、IL-1β、IL-6含量的异常升高；而阻断ɑ7nAchR后，电针的抗炎效应受到抑制，进一步表明电针对SHR的抗炎效应可能与激活胆碱能抗炎通路有关。