The Role Of Interleukin-37 In The Development Of Collateral Circulation In Artery Occlusion

Background: With the acceleration of the aging process in China and the shift in a modern social lifestyle,the morbidity and mortality of coronary heart disease(CHD)are increasing.In recent years,with iterative updates in instruments and advances in operating techniques,revascularization strategies,such as percutaneous coronary intervention(PCI)and coronary artery bypass grafting(CABG),can significantly improve the clinical prognosis of CHD patients.However,for patients with chronic total occlusion(CTO),revascularization strategies are extremely difficult,the risks of the procedure are not proportional to the benefits,and the treatment effect is not ideal.Therefore,coronary collateral circulation(CCC)may play a more critical role in the treatment of CTO patients.When an acute coronary occlusion occurs,good coronary collateral circulation(CCC)can play an important role in counteracting myocardial infarction,limiting myocardial infarction size,and prolonging the window of opportunity for reperfusion.In addition,studies have revealed that welldeveloped CCC is strongly associated with improved survival in CTO patients.Interleukin-37(IL-37)is a member of the interleukin 1 family.Previous studies have found that in the myocardial infarction model of mice,IL-37 transgenic mice can significantly reduce infarct size and improve left ventricular function.Meanwhile,IL-37 was demonstrated to be expressed in vascular endothelial cells and to function like vascular endothelial growth factor(VEGF).Thus,we speculate that IL-37 may be involved in the development of CCC.However,the relationship between IL-37 and CCC in CTO patients and the role and possible mechanism of IL-37 in the development of collateral circulation after arterial occlusion are still unclear.Objective1.To investigate the relationship between serum IL-37 levels and CCC in CTO patients.2.To investigate the role of IL-37 in the development of collateral circulation after arterial occlusion.3.To investigate the possible mechanisms of IL-37 in the development of collateral circulation after arterial occlusion.Methods1.A total of 111 CTO patients who met the inclusion and exclusion criteria were included.According to the Rentrop grade,the patients were divided into good CCC and poor CCC groups.Serum samples of patients were collected and measured by ELISA.The relationship between serum IL-37 levels and CCC in CTO patients was analyzed by using statistical software and statistical methods.2.After the successful model construction of lower limb ischemia,12 male C57BL/6 mice aged 8-12 weeks were randomly divided into the IL-37 injection and control groups.Peri Cam PSI,a laser Doppler imager,was used to assess the recovery of lower limb perfusion by acquiring flow images at four different time points(At 1day,3days,7days,and 14 days after operation).At 21 days after the operation,Hematoxylin-eosin(HE)staining and immunohistochemical staining were conducted on gastrocnemius muscles and adductor muscles to observe the angiogenesis in gastrocnemius muscles and the arteriogenesis in adductor muscles respectively.3.Human umbilical vein endothelial cells were extracted and cultured to the third generation for cell intervention.Human recombinant IL-37 protein was given at different concentrations(0ng/ml,0.1ng/ml,1ng/ml,10ng/ml).Cell scratch assay and Transwell assay were used to observe the changes in proliferation and migration ability of vascular endothelial cells after IL-37 intervention.Immunofluorescence staining and Western Blotting assay observed the change in the expression of M1 macrophage and M2 macrophage markers after IL-37 intervention.Results1.In CTO patients,serum IL-37 levels were correlated with welldeveloped CCC.2.IL-37 can promote angiogenesis and arteriogenesis,and significantly improve blood perfusion recovery after arterial occlusion.3.The mechanism by which IL-37 promotes angiogenesis may be related to promoting endothelial cell proliferation and migratory capacity.The mechanism by which IL-37 promotes arteriogenesis may be related to the regulation of macrophage polarization status.ConclusionIn CTO patients,serum IL-37 levels were correlated with welldeveloped CCC.IL-37 can significantly improve blood perfusion recovery after arterial occlusion.The underlying mechanism may be related to the fact that IL-37 mediates angiogenesis and arteriogenesis by promoting endothelial cells’ proliferation and migration ability and regulating the polarization status of macrophages.