Potassium dehydroandrographolide succinate regulates the MyD88/CDH13 signaling pathway to enhance vascular injuryinduced pathological vascular remodeling

Pathological vascular remodeling is a hallmark of various vascular diseases.Previous research has established the significance of andrographolide in maintaining gastric vascular homeostasis and its pivotal role in modulating endothelial barrier dysfunction,which leads to pathological vascular remodeling.Potassium dehydroandrographolide succinate(PDA),a derivative of andrographolide,has been clinically utilized in the treatment of inflammatory diseases precipitated by viral infections.This study investigates the potential of PDA in regulating pathological vascular remodeling.The effect of PDA on vascular remodeling was assessed through the complete ligation of the carotid artery in C57BL/6 mice.Experimental approaches,including rat aortic primary smooth muscle cell culture,flow cytometry,bromodeoxyuridine(BrdU)incorporation assay,Boyden chamber cell migration assay,spheroid sprouting assay,and Matrigel-based tube formation assay,were employed to evaluate the influence of PDA on the proliferation and motility of smooth muscle cells(SMCs).Molecular docking simulations and co-immunoprecipitation assays were conducted to examine protein interactions.The results revealed that PDA exacerbates vascular injury-induced pathological remodeling,as evidenced by enhanced neointima formation.PDA treatment significantly increased the proliferation and migration of SMCs.Further mechanistic studies disclosed that PDA upregulated myeloid differentiation factor 88(MyD88)expression in SMCs and interacted with T-cadherin(CDH13).This interaction augmented proliferation,migration,and extracellular matrix deposition,culminating in pathological vascular remodeling.Our findings underscore the critical role of PDA in the regulation of pathological vascular remodeling,mediated through the MyD88/CDH13 signaling pathway.

Aerobic interval training preconditioning protocols inhibit isoproterenol-induced pathological cardiac remodeling in rats:Implications on oxidative balance,autophagy,and apoptosis

This study aimed to investigate the potential cardioprotective effects of moderate and high-intensity aerobic interval training(MIIT and HIIT)preconditioning.The focus was on histological changes,pro-oxidant-antioxidant balance,autophagy initiation,and apoptosis in myocardial tissue incited by isoproterenol-induced pathological cardiac remodeling(ISO-induced PCR).Male Wistar rats were randomly divided into control(n=6),ISO(n=8),MIIT(n=4),HIIT(n=4),MIIT+ISO(n=8),and HIIT+ISO(n=8)groups.The MIIT and HIIT protocols were administered for 10 weeks,followed by the induction of cardiac remodeling using subcutaneous injection of ISO(100 mg/kg for two consecutive days).Alterations in heart rate(HR),mean arterial pressure(MAP),rate pressure product(RPP),myocardial oxygen consumption(MVO_(2)),cardiac hypertrophy,histopathological changes,prooxidant-antioxidant balance,autophagy biomarkers(Beclin-1,Atg7,p62,LC3Ⅰ/Ⅱ),and apoptotic cell distribution were measured.The findings revealed that the MIIT+ISO and HIIT+ISO groups demonstrated diminished myocardial damage,hemorrhage,immune cell infiltration,edema,necrosis,and apoptosis compared to ISO induced rats.MIIT and HIIT preconditioning mitigated HR,enhanced MAP,and preserved MVO_(2)and RPP.The pro-oxidant-antioxidant balance was sustained in both MIIT+ISO and HIIT+ISO groups,with MIIT primarily inhibiting pro-apoptotic autophagy progression through maintaining pro-oxidant-antioxidant balance,and HIIT promoting pro-survival autophagy.The results demonstrated the beneficial effects of both MIIT and HIIT as AITs preconditioning in ameliorating ISO-induced PCR by improving exercise capacity,hemodynamic parameters,and histopathological changes.Some of these protective effects can be attributed to the modulation of cardiac apoptosis,autophagy,and oxidative stress.