自主神经介导的血红素氧合酶-1调控在电针促进心梗后心肌组织修复中的作用研究

Cardiac repair and regeneration has a significant impact on prognosis of surviving patients after myocardial infarction (MI). The effective drugs for prevention and treatment are lack. Our preliminary experiment and recent studies show that application of electroacupuncture (EA) at Neiguan acupoints has a dramatic survival-enhancing effect in mice MI models by ligating the left anterior descending coronary artery, which is likely to be associated with promoting angiogenesis and inhibiting ventricular remodeling. However, the underlying molecular mechanisms remained unclear. Activation of heme oxygenase-1 (HO-1), a heme-degrading enzyme responsive to a wide range of cellular stress, has unique qualities that facilitate tissue regeneration/repair and the formation of new blood vessels during the processes of cardiac repair and regeneration following MI. According to our research results that the regulation of autonomic nervous system is an important mechanism of EA to produce myocardial protection and immunomodulation, and the facts that the autonomic nervous system is involved in HO-1 regulation, we hypothesized that increased vagal tone and/or inhibition of sympathoexcitation induced by EA could upregulate the expression of HO-1, which results in facilitation of myocardial repair and angiogenesis, and improvement of ventricular function and survival rate. In this study, we will use a mice model with ligation of left anterior descending coronary artery and observe the effects of EA on HO-1, angiogenesis, ventricular remodeling, cardiac function and survival of mice following MI. Furthermore, a key role of HO-1 modulated by autonomic nervous system in EA-induced enhancement of cardiac repair and regeneration following MI will determined by application of HO-1 inducer and inhibitor, delivery of HO-1 gene by adeno associated virus, gene knockout mice, and intervention of autonomic nervous function. Elucidation of mechanisms of EA-induced enhancement of cardiac repair and regeneration following MI from a view of amplifying this intrinsic regenerative capacity of the myocardium could provide a scientific basis for clinical application of EA.

心梗后心肌组织修复不良是导致慢性心衰和死亡的主要原因，缺乏有效防治药物。我们的预实验和其他学者的研究显示，电针内关可促进心梗后心肌修复，提高生存率，但机制不明。近年研究显示，血红素氧合酶1（HO-1）在促进心梗后血管新生和心肌再生中具有关键作用。鉴于我们前期研究表明调节自主神经是电针产生心肌保护和神经免疫调节作用的重要机制，且自主神经参与HO-1调控，我们推测：电针可能通过激活迷走和（或）抑制交感神经，上调HO-1，促进血管新生和心肌再生，改善心功能。本项目拟采用小鼠冠脉结扎模型，观察电针对HO-1、血管新生、心室重构和心功能等的影响，并通过HO-1抑制剂和诱导剂、基因病毒转导、基因敲除以及干预自主神经功能，明确自主神经介导的HO-1调控在电针促心肌组织修复中的关键作用。本项目旨在从神经调节心肌内源性再生机制的角度阐释电针作用机制，为促进临床应用电针防治心梗后慢性心衰提供理论依据。

为探讨电针抑制心室重构提高心肌梗死后小鼠心功能的机制，我们建立了小鼠冠脉结扎模型，在心梗后1-3天，3-28，3-6天分别进行电针治疗。观察发现：心梗后3-28天长期电针处理可以改善心梗后心衰小鼠的远期心功能、减少胶原沉积、减轻心肌肥大，对血管新生没有显著影响；心梗后1-3天短期电针处理可以改善心梗后心衰小鼠的远期心功能、改善心室重构，减少早期心肌细胞凋亡；心梗后3-6天短期电针处理不能有效改善心梗后心衰小鼠远期心功能。随后我们在心梗后1-3天电针治疗的小鼠中观察到HO-1在梗死边界区的上调，后采用HO-1抑制剂、AVV干扰病毒、HO-1基因敲除鼠等干预方式削弱HO-1的上调，电针对心梗小鼠新功能的保护作用被削弱。我们还通过单侧颈迷走神经切断的手段，发现心梗后1-3天短期电针处理上调HO-1与迷走神经不相关，切断单侧颈迷走不能改变电针上调心梗边界区HO-1表达的作用。结论：心梗后1-3天短期电针处理通过上调HO-1改善心梗后心衰小鼠的远期心功能，抑制HO-1可以削弱电针改善小鼠远期心功能，心室重构，减少早期心肌凋亡。我们的研究结果为促进电针防治心梗后慢性心衰的临床应用提供理论依据。