Sphingosylphosphorylcholine alleviates pressure overload-induced myocardial remodeling in mice via inhibiting CaM-JNK/p38 signaling pathway  

作　　者：Fang-fang Ren Lin Zhao Xian-yun Jiang Jing-jing Zhang Jia-min Gou Xiao-yu Yu Shu-jin Wu Lei Li 

机构地区：[1]Department of Cardiology,Key Laboratory of Panvascular Diseases of Wenzhou,The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University,Wenzhou 325000,China

出　　处：《Acta Pharmacologica Sinica》2024年第2期312-326,共15页中国药理学报（英文版）

基　　金：supported by Grant No.LZ23H020001 from the Key Natural Science Foundation of Zhejiang Province and Xinmiao Talent Program of Zhejiang Province(Grant No.2023R413084).

摘　　要：Apoptosis plays a critical role in the development of heart failure,and sphingosylphosphorylcholine(SPC)is a bioactive sphingolipid naturally occurring in blood plasma.Some studies have shown that SPC inhibits hypoxia-induced apoptosis in myofibroblasts,the crucial non-muscle cells in the heart.Calmodulin(CaM)is a known SPC receptor.In this study we investigated the role of CaM in cardiomyocyte apoptosis in heart failure and the associated signaling pathways.Pressure overload was induced in mice by trans-aortic constriction(TAC)surgery.TAC mice were administered SPC(10μM·kg^(−1)·d^(−1))for 4 weeks post-surgery.We showed that SPC administration significantly improved survival rate and cardiac hypertrophy,and inhibited cardiac fibrosis in TAC mice.In neonatal mouse cardiomyocytes,treatment with SPC(10μM)significantly inhibited Ang II-induced cardiomyocyte hypertrophy,fibroblast-to-myofibroblast transition and cell apoptosis accompanied by reduced Bax and phosphorylation levels of CaM,JNK and p38,as well as upregulated Bcl-2,a cardiomyocyte-protective protein.Thapsigargin(TG)could enhance CaM functions by increasing Ca^(2+)levels in cytoplasm.TG(3μM)annulled the protective effect of SPC against Ang II-induced cardiomyocyte apoptosis.Furthermore,we demonstrated that SPC-mediated inhibition of cardiomyocyte apoptosis involved the regulation of p38 and JNK phosphorylation,which was downstream of CaM.These results offer new evidence for SPC regulation of cardiomyocyte apoptosis,potentially providing a new therapeutic target for cardiac remodeling following stress overload.

关 键 词：heart failure pressure overload cardiac hypertrophy cardiac fibrosis apoptosis CARDIOMYOCYTE 

分 类 号：R541[医药卫生—心血管疾病]