Vagal modulation of high mobility group box-1 protein mediates electroacupuncture-induced cardioprotection in ischemia-reperfusion injury

Abstract

Excessive release of high mobility group box-1 (HMGB1) protein from ischemic cardiomyocytes activates inflammatory cascades and enhances myocardial injury after reperfusion. Here we report evidence that electroacupuncture of mice at Neiguan acupoints can inhibit the up-regulation of cardiac HMGB1 following myocardial ischemia and attenuate the associated inflammatory responses and myocardial injury during reperfusion. These benefits of electroacupuncture were partially reversed by administering recombinant HMGB1 to the mice, and further potentiated by administering anti-HMGB1 antibody. Electroacupuncture-induced inhibition of HMGB1 release was markedly reduced by unilateral vagotomy or administration of nicotinic receptor antagonist, but not by chemical sympathectomy. The cholinesterase inhibitor neostigmine mimicked the effects of electroacupuncture on HMGB1 release and myocardial ischemia reperfusion injury. Culture experiments with isolated neonatal cardiomyocytes showed that acetylcholine, but not noradrenaline, inhibited hypoxia-induced release of HMGB1 via a α7nAchR-dependent pathway. These results suggest that electroacupuncture acts via the vagal nerve and its nicotinic receptor-mediated signaling to inhibit HMGB1 release from ischemic cardiomyocytes. This helps attenuate pro-inflammatory responses and myocardial injury during reperfusion.

The nuclear melatonin receptor RORα is a novel endogenous defender against myocardial ischemia/reperfusion injury

“…At 24 hr after MI/R injury, myocardial infarct size was measured by Evans blue‐TTC double staining . In brief, the suture beneath the left coronary artery was re‐tied, and perfusion of Evans blue dye was achieved by injecting 0.2 mL 2% Evans blue into the left ventricular cavity, with the dye uniformly distributed except in the ischemic area (area at risk, AAR).…”

Effects of Perioperative Transcutaneous Electrical Acupoint Stimulation on Monocytic HLA-DR Expression in Patients undergoing Coronary Artery Bypass Grafting with Cardiopulmonary Bypass: Study Protocol for a Double-blind Randomized Controlled Trial

“…HMGB1, originally described as a DNA-binding protein and passively released by necrotic cells and actively released by macrophages/monocytes, was discovered to be an essential cytokine that mediates the response to infection, injury, and inflammation [51] . Our previous animal study has shown that EA can inhibit excessive release of HMGB1 following myocardial ischemia and attenuate the associated inflammatory responses and myocardial injury during reperfusion [52] . Recently, HMGB1 was found to directly enhance immune inhibitory functions of Treg and limit the number and activity of conventional T cells [53,54] .…”

Revisiting the Cardioprotective Effects of Acetylcholine Receptor Activation against Myocardial Ischemia/Reperfusion Injury

“…Disruption of parasympathetic activity is a common hallmark of a variety of cardiovascular diseases including AMI [ 5 ]. The results from preclinical studies have shown that increased vagal activity exerts cardioprotective effects against myocardial I/R injury [ 6 , 7 , 8 , 9 , 10 ]. At cellular level, ACh, a neurotransmitter of the cardiac vagus nerve, is the chemical released which acts as a stimulus for the modulation of the parasympathetic activity involved in both electrical and mechanical functions of the heart [ 11 , 12 , 41 ].…”

“…The beneficial effects of GTS21 were blocked when co-administered with MLA, suggesting that GTS21 treatment decreased the infarct size and improved cardiac contractile function through the activation of α7nAChR [ 55 ]. In addition, Zhang et al have also demonstrated that the infarct size in mice hearts pretreated with electroacupuncture at the Neiguan acupoint (PC6) was significantly reduced compared with the control [ 8 ]. Additionally, the serum cardiac troponin I was significantly decreased after electroacupuncture.…”

“…Disruption of cardiac parasympathetic (vagal) activity is a common hallmark of a variety of cardiovascular diseases including AMI [ 5 ]. Indeed, several experimental studies have shown that increased cardiac vagal activity exerts cardioprotective effects against myocardial I/R injury [ 6 , 7 , 8 , 9 , 10 ]. Specifically, increased vagal activity by electrical stimulation can improve cardiac function in both small and large animal models in the setting of myocardial I/R injury, suggesting that activation of the cholinergic pathway may provide therapeutic benefits [ 11 , 12 ].…”