基于钙调节的腺苷受体介导针刺预治疗改善缺血性心肌损害的机制研究

Over half of the patients with coronary heart disease are those suffering from non-symptom myocardial ischemia or silent myocardial ischemia, which are the major cause of sudden death leading to a high mortality. The fact calls for the effective therapies in the treatment of the disease. It was shown that ischemia preconditioning can attenuate the myocardial injury induced by ischemic and reperfusion. Adenosine receptor A2b has been proven to be involved in mediating the cardioprotection of ischemia preconditioning. Our previous studies indicate that electroacupuncture pretreatment can mimic myocardial ischemia preconditioning in production of the cardioprotective effects. While in the studies on the acupuncture analgesia it was reported that adenosine receptor was activated by acupuncture stimulation. Based on all above, it is highly likely that adenosine A2b receptor may participate the cardioprotection produced by acupuncture pretreatment. It is well known all the intracellular calcium key regulators, including ryanodine receptor, Ca2+ pump with abbreviation as SEARCA and phospholamban (PLB) on the membrane of sarcoplasmic reticulum, Na-Ca2+ exchanger on cytomembrane and the mitochondrial permeability transition pore (MPTP) , are the downstream signaling components of β1-adrenergic receptor (β1-AR) in cardiomyocytes and all of them are impaired during myocardial ischemia and reperfusion, leading to the intracellular calcium overload, so as to result in a myocardial injury finally. Our previous study showed that activation of myocardial adenosine receptor could effective inhibit the elevated intracellular calcium induced byβ1-AR. Accordingly, it is also possible that adenosine A2b receptor may mediate the acupuncture cardioprotection via influencing the function of the one or several aforementioned calcium regulators. Thus, our proposed study is also aimed to address the possibility above. The completion of the study will not only provide the scientific evidence for the treatment of silent myocardial ischemia by the acupuncture pretreatment, but also exhibit the importance of the famous idea of Chinese medicine, namely, “preventively treating disease”, in solving the knotty medical problem. So far there is no any previous studies addressing the same research topic as we proposed above.

占冠心病1/2以上的无症状性心肌缺血是该病猝死高的重要原因，寻找有效防治方法非常迫切。缺血预处理可减轻缺血性心肌损害，腺苷A2b受体激活被证明参与了缺血预处理的心肌保护作用；针刺预治疗可模仿缺血预处理的心肌保护作用；针刺镇痛的研究证明腺苷受体可被针刺激活。因此， A2b受体极有可能参与针刺的心肌保护作用。心肌细胞肌浆网Ryanodine受体、钙泵SEARCA2α和磷酸受纳蛋白以及细胞膜钠-钙交换器、线粒体的通透转移孔等细胞钙的重要调节因子在心肌缺血时都受到损害，由此介导钙超载引起的心肌损害。腺苷A2b受体有可能通过影响上述钙调因子而介导针刺预治疗改善心肌缺血性损害的作用。围绕上述钙信号调节的关键因子，探讨腺苷受体A2b介导针刺保护缺血性心肌的作用机制，不仅可为针刺预治疗防治隐匿性心肌缺血提供科学证据，还可彰显中医“治未病”思想在解决医学难题中的重要作用。而这方面的工作迄今无人涉足。

占冠心病1/2以上的无症状性心肌缺血是该病猝死高的重要原因，寻找有效防治方法非常迫切。缺血预处理可减轻缺血性心肌损害，腺苷A2b受体激活被证明参与了缺血预处理的心肌保护作用；针刺预治疗可模仿缺血预处理的心肌保护作用；针刺镇痛的研究证明腺苷受体可被针刺激活。因此， A2b受体极有可能参与针刺的心肌保护作用。心肌细胞肌浆网Ryanodine受体、钙泵SEARCA2α和磷酸受纳蛋白以及细胞膜钠-钙交换器、线粒体的通透转移孔等细胞钙的重要调节因子在心肌缺血时都受到损害，由此介导钙超载引起的心肌损害。腺苷A2b受体有可能通过影响上述钙调因子而介导针刺预治疗改善心肌缺血性损害的作用。本项目围绕上述钙信号调节的关键因子，探讨腺苷受体A2b介导针刺保护缺血性心肌的作用机制，实验结果表明：电针预治疗能够有效地减轻心肌缺血再灌注导致的损伤，降低心肌的梗死面积，改善缺血心脏的功能；AR2b的拮抗剂能够阻断针刺预治疗的心肌保护效应，表明AR2b参与了介导电针预治疗对心肌缺血再灌注损伤的保护作用；电针预治疗改善心肌缺血再灌注导致的损伤的作用机制可能是通过促进AR2b的表达，进而影响细胞内钙调关键因子，抑制RyR2、PLB的相对表达量，增加P-PLB(S16)及SERCA2a的表达量，同时减少心肌细胞内钙与肌钙蛋白的结合，减轻心肌细胞缺血再灌注时钙超载的发生。上述研究结果不仅可为针刺预治疗防治隐匿性心肌缺血提供科学证据，还可彰显中医“治未病”思想在解决医学难题中的重要作用。