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

Acta Pharmacologica Sinica volume 45, pages 312–326 (2024)Cite this article

Abstract

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 (10 μM·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 (10 μM) 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 Ca2+ levels in cytoplasm. TG (3 μM) 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.

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Fig. 1: SPC improves survival and cardiac hypertrophy in mice induced by pressure overload.
Fig. 2: SPC reduces fibrosis in pressure overload mice.
Fig. 3: SPC reduces AngII-induced hypertrophy in vitro.
Fig. 4: SPC inhibits fibroblast differentiation into myofibroblasts.
Fig. 5: SPC protects CMs from AngII-induced cell apoptosis.
Fig. 6: SPC alleviates AngII-induced cardiac hypertrophy by inhibiting CaM.
Fig. 7: Activation of CaM inhibited the anti-apoptotic effect of SPC on CMs.
Fig. 8: SPC alleviates AngII-induced cardiomyocyte apoptosis by inhibiting CaM.
Fig. 9: P38/JNK is involved in CaM-mediated apoptosis under AngII stimulation.
Fig. 10: SPC reduces apoptosis in mice under pressure overload.

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Acknowledgements

The study was supported by Grant No. LZ23H020001 from the Key Natural Science Foundation of Zhejiang Province and Xinmiao Talent Program of Zhejiang Province (Grant No. 2023R413084).

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  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

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

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Contributions

FFR carried out the study and wrote the paper; FFR, LZ, and XYJ carried out the animal model, RT-qPCR, Western blotting experiments; JJZ and JMG carried out the cell culture and echocardiographic analysis; XYY and SJW analyzed the data. LL conceived and supervised the study.

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Correspondence to Lei Li.

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Ren, Ff., Zhao, L., Jiang, Xy. et al. Sphingosylphosphorylcholine alleviates pressure overload-induced myocardial remodeling in mice via inhibiting CaM-JNK/p38 signaling pathway. Acta Pharmacol Sin 45, 312–326 (2024). https://doi.org/10.1038/s41401-023-01168-6

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