The Effects And Mechanisms Of Uric Acid On Cardiomyocyte Apoptosis

Background: Hyperuricemia is associated with increased risks of multiple cardiovascular diseases,while its impact on cardiovascular disease remains controversial.Calpain is a type of calcium-activated cysteine protease that plays an important role in cardiovascular disease,but the role of calpain in hyperuricemia remains unclear.Aims: The aim of current study was to test the effects of uric acid(UA)on cardiomyocytes survival as well as cardiac function,and to investigate the role of calpain-1 and ER stress in UA-induced effects on the heart and their underlying mechanisms.Methods: In vivo,hyperuricemia were induced by administration of oxonic acid(OA)in Sprague-Dawley rats for 16 weeks,TUNEL staining was used to determine apoptotic cells.Left ventricular(LV)sections were stained with Sirius Red to evaluate interstitial fibrosis.Cardiac catheterization was performed to evaluate the cardiac function.All related gene expressions were analyzed by quantitative real-time PCR(q RT-PCR),and all the protein expressions were analyzed by Western Blot.In vitro,cultured H9c2 cells were incubated with different concentrations of UA.MTT assay and flow cytometry were used to evaluate cell viability and apoptosis.Results: Induction of hyperuricemia in vivo resulted in cellular apoptosis,interstitial fibrosis and diastolic dysfunction in rat heart,as well as increased activation of calpain-1 and ER stress,while treatment with allopurinol mitigated all the above changes.Administration of UA in vitro caused increased apoptosis and decreased viability of H9c2 cells in a dose-dependent manner.Increased activation of calpain-1 and ER stress was also observed in group with high level of UA.Calpain-1 si RNA and calpain inhibitor CI-III alleviated UA induced ER stress and apoptosis,while inhibition of ER stress by TUDCA mitigated UA induced apoptosis without affecting calpain-1 expression or activity.Conclusions: These findings suggest that UA induces apoptosis of cardiomyocytes and diastolic dysfunction through activation of calpain-1 and ER stress.