The Role Of High Mobility Group Box-1 In Electroacupuncture-induced Cardioprotection Against Ischemia-reperfusion Injury

Aims: Modulation of the autonomic nerve system(ANS) is implicated in a well-documented cardioprotection of electroacupuncture(EA) against myocardial ischemia-reperfusion(IR) injury. Excessive release of high mobility group box-1(HMGB1) from ischemic cardiomyocytes mediates an inflammatory cascade and enhanced myocardial injury during reperfusion. Since there is a close association between HMGB1 release and the function of ANS both in sepsis and myocardial infarction settings, EA-induced cardioprotection may be achieved by inhibiting HMGB1 release via the ANS. The current study aims to explore the connections among EA, ANS and HMGB1 in the condition of myocardila IR, and uncover the mysterious veil of EA.Methods: After treatment with EA at Neiguan acupoints(PC6), non-acupoints(NA), EA plus recombinant HMGB1(r HMGB1) or EA plus anti-HMGB1 antibody, mice underwent 30 min of left anterior descending coronary artery occlusion followed by reperfusion. Myocardial HMGB1 expression, inflammatory cytokines and markers of myocardial injury were measured. Furthermore, the possible roles of two branches of the ANS(sympathetic and vagal nerve) and the related receptors were evaluated.In vitro, primary cardiomyocytes were exposed to oxygen-glucose deprivation model to mimic the myocardial IR in vivo; Similarly, acetylcholine(ACh), norepinephrine(NE) and their receptor blockers were added to the medium to explore the role on the HMGB1 release under hypoxia condition.Results: EA reduced IR-induced upregulation of HMGB1 expression, upregulation of proinflammatory cytokines, and myocardial damage. Treatment of mice with r HMGB1 attenuated, whereas anti-HMGB1 antibody potentiated the EA-elicited cardioprotection. This action of EA depends on vagal nerve and its nicotinic acetylcholine receptors(n ACh Rs), especially α7n ACh Rs, instead of sympathetic nerve. Further in vitro evidence indicated that acetylcholine, but not noradrenaline, inhibits hypoxia-induced HMGB1 release from isolated neonatal cardiomyocytes through n ACh Rs.Conclusions: EA inhibits HMGB1 release from ischemic cardiomyocytes via vagal nerve and its nicotinic action, resulting in attenuation of proinflammatory response and myocardial injury after reperfusion.