Right Superior Cervical Sympathetic Ganglion Resection Improves Myocardial Ischemia-reperfusion Injury In Diabetic Mice Through A7nAchR/JAK2/STAT3 Pathway

BackgroundAcute myocardial infarction is a common health problem worldwide and can seriously impair cardiac function.The morbidity and mortality of type 2 diabetes mellitus are increasing year by year,and the mortality of type 2 diabetes mellitus combined with cardiovascular disease is the highest.Population epidemiological studies showed that the prevalence of cardiac autonomic neuropathy was 61.6%and 62.6%in Chinese patients with type Ⅰ diabetes and type Ⅱ diabetes,respectively.Diabetic patients with myocardial ischemia-reperfusion injury have lower long-term survival rate and higher mortality.It may be associated with cardiac autonomic neuropathy in type 2 diabetic patients,but the exact mechanism is still unclear.Our previous studies have demonstrated that bilateral upper cervical sympathectomy can effectively relieve myocardial ischemia-reperfusion injury in mice,and the activation of STAT3 signal plays a crucial role.It is necessary to further explore whether superior cervical sympathetic ganglion resection has the same protective effect on myocardial ischemia-reperfusion injury in diabetic mice?What are the mechanisms?ObjectivesIn this study,Myocardial ischemia reperfusion injury(MI/R)model was used in diabetic mice.To investigate whether the Right superior cervical sympathetic ganglion resection(RSCG)protects myocardial ischaemic reperfusion injury by reducing sympathetic excitability and activating parasympathetic resection.And to explore whether it plays a role through a7nAchR/JAK2/STAT3 pathway,so as to find new therapeutic approaches and targets for MI/R exacerbation of cardiac autonomic neuropathy in diabetic patients.Methods1.Electrocardiogram(ECG)was collected in diabetic mice(DM)and non-diabetic(N-DM)mice to analyze their heart rate variability and verify whether there was any difference in sympathetic excitability between the two mice.MI/R model was constructed to detect cardiac ultrasound function and degree of inflammation after MI/R,and to verify whether abnormal sympathetic excitability of diabetic cardiac autonomic neuropathy aggravated myocardial ischemia reperfusion injury.2.The MI/R model of diabetic mice was established and pretreated with RSCG.Cardiac echocardiography and myocardial Evan’s Blue/TTC staining were detected after MI/R,and the degree of myocardial tissue injury was observed.At the same time,the levels of CKMB,LDH,inflammatory factors in serum and TUNEL in myocardial tissue were detected to observe the degree of inflammation and apoptosis of cardiomyocytes.3.The MI/R model of diabetic mice was established and pretreated with RSCG.The expression levels of a7nAchR,JAK2 and STAT3 in myocardial tissue were detected to verify whether RSCG pretreatment attenuates myocardial ischemia-reperfusion injury through the a7nAchR/JAK2/STAT3 pathway.Results1.Compared with the non-diabetic group,left ventricular Ejection Fraction(EF)and left ventricular short axis Shortening(Fractional Shortening,FS)after MI/R were lower in the diabetic group(P--0.0026 and P=0.004,respectively).Evan’s Blue/TTC staining showed greater infarct size in the diabetic group compared to the non-diabetic group(P=0.0437)when the risk area was roughly the same.2.Compared with MI/R group,EF and FS in RSCG pretreatment group were decreased(P<0.05).The expressions of CKMB and LDH in serum were decreased(P<0.05),the expressions of pro-inflammatory factors(IL-1β,TNF-α,IL-6)in myocardial tissue were decreased,the expression of anti-inflammatory factor IL-10 was increased,and the apoptosis of myocardial cells was decreased.3.After MI/R pretreatment with RSCG,the expression of myocardial Tyrosine hydroxylase(TH)decreased,the expression of a7nAchR receptor increased,and the ratio of LF/HF decreased.Inflammatory response and apoptosis induced by MI/R were effectively alleviated by activating JAK2/STAT3 pathway.Compared with MI/R group,the expressions of a7nAchR,PJAK2 and PSTAT3 in myocardial tissue of RSCG preconditioning group were increased.ConclusionMyocardial ischemia-reperfusion injury is aggravated by abnormal sympathetic excitability in diabetic cardiac autonomic neuropathy.RSCG preconditioning can effectively reduce myocardial inflammation and apoptosis by activating a7nAchR/JAK2/Stat3-mediated signaling cascade,and alleviate myocardial ischemia-reperfusion injury in diabetic mice.