Sphingosylphosphorylcholine alleviates hypoxia-caused apoptosis in cardiac myofibroblasts via CaM/p38/STAT3 pathway
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Sphingosylphosphorylcholine alleviates hypoxia‑caused apoptosis in cardiac myofibroblasts via CaM/p38/STAT3 pathway Ying Li1,2,3 · Qi Qi1 · Wan‑cheng Yang1 · Tian‑liang Zhang4 · Chen‑chen Lu1 · Yu‑juan Yao1 · Wei‑hua Kong1 · Jing Zhao1 Accepted: 3 October 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Blockade of hypoxia-caused nonmyocytes apoptosis helps improve survival and mitigate ventricular remodeling and dysfunction during the chronic stage of myocardial infarction. But tools affecting nonmyocyte apoptosis are very rare. Sphingosylphosphorylcholine (SPC), a naturally occurring bioactive sphingolipid in plasma, was proved to protect cardiomyocyte against apoptosis in an ischemic model in our previous study. Here, we showed that SPC also inhibited hypoxia-induced apoptosis in myofibroblasts, an important type of nonmyocytes in the heart. Calmodulin (CaM) is an identified receptor of SPC. We clarified that SPC inhibited myofibroblast apoptosis through CaM as evidenced by decreased cleaved caspase 3, PARP1 and condensed nucleus. Furthermore, the employment of inhibitor and agonist of p38 and STAT3 suggests that SPC inhibits myofibroblast apoptosis by regulating the phosphorylation of p38 and STAT3, and they act as downstream of CaM. The present work may provide new evidence on the regulation of myofibroblasts apoptosis by SPC and a novel target for heart remodeling after hypoxia. Keywords Myofibroblasts · Hypoxia · Calmodulin · Apoptosis · p38 · STAT3
Introduction Ischemic heart disease (IHD) is a leading cause of morbidity and mortality worldwide [1]. Nearly all etiologies of heart diseases involve pathological myocardial remodeling Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10495-020-01639-9) contains supplementary material, which is available to authorized users. * Wei‑hua Kong [email protected] * Jing Zhao [email protected] 1
Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Science, Shandong University, Jinan, China
2
Research Center for Translational Medicine, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
3
Research Center for Translational Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, China
4
Experimental Center for Medical Research, Weifang Medical University, Weifang, China
characterized by excessive deposition of extracellular matrix (ECM) proteins by activated cardiac fibroblasts (CFs), often known as myofibroblasts, which accelerates the progression to heart failure. Numerous signaling pathways have been implicated in the early activation of CFs after initial injury. Modulation of these signals is of intense scientific interest since they represent potentially novel therapeutic targets or strategies. But the role of CFs in the pathophysiological progression of fibrosis and cardiovascular disease remains poorly understood. Recently, several studies have indicated that w
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