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Sphingosylphosphorylcholine alleviates hypoxia-caused apoptosis in cardiac myofibroblasts via CaM/p38/STAT3 pathway

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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.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Nos. 31671180, 81700217, and 81170087), the Provincial Natural Science Foundation of Shandong (Nos. ZR2018MH003 and ZR2016HB57) and the clinical medical science and technology innovation Program of Jinan (201805004, 201805059) and China Postdoctoral Science Foundation (2019M662370).

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  1. Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Science, Shandong University, Jinan, China

    Ying Li, Qi Qi, Wan-cheng Yang, Chen-chen Lu, Yu-juan Yao, Wei-hua Kong & Jing Zhao

  2. Research Center for Translational Medicine, Jinan Central Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China

    Ying Li

  3. Research Center for Translational Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, China

    Ying Li

  4. Experimental Center for Medical Research, Weifang Medical University, Weifang, China

    Tian-liang Zhang

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JZ and WK designed the research and finally approved of the version to be published. YL analyzed the data and wrote the paper. QQ, WY, YY performed the research. CL analyzed the data. TZ revised the article.

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10495_2020_1639_MOESM1_ESM.tif

Supplementary Fig. S1 Hypoxia induces apoptosis of neonatal mouse-derived cardiac myofibroblasts. (a) Cell morphology was observed by inverted phase contrast microscope after hypoxia exposure for 2, 4, 6, and 8 h, respectively. (b) Cell viability determined by SRB assay. (c) Levels of cleaved caspase 3 (c-caspase 3) and (d) cleaved PARP1 (c-PARP1) were determined by Western blotting after hypoxia stimulation for 0, 2, 4, 6, and 8 h, respectively. *P < 0.05,**P < 0.01,***P < 0.001, ****P < 0.0001. n=3. Supplementary file1 (TIF 2485 kb)

10495_2020_1639_MOESM2_ESM.tif

Supplementary Fig. S2 SPC inhibits the hypoxia-induced apoptosis of neonatal mouse-derived cardiac myofibroblasts. (a) Effects of SPC pretreatment on cell morphology exposed to hypoxia for 4 h. (b) Cell viability determined by SRB assay. (c) Relative protein level of c-caspase 3 was determined in neonatal mouse-derived cardiac myofibroblasts pretreated with SPC and followed by hypoxia treatment. ***P < 0.001, ****P < 0.0001. n =3. Supplementary file2 (TIF 2169 kb)

10495_2020_1639_MOESM3_ESM.tif

Supplementary Fig. S3 Pretreatment with the specific inhibitor of p38 or STAT3 inhibits the hypoxia-induced apoptosis of neonatal mouse-derived cardiac myofibroblasts. Effects of p38 inhibitor pretreatment on the relative protein levels of cleaved PARP1 (a-c). Effects of STAT3 inhibitor pretreatment on the relative protein levels of cleaved Caspase 3 (d-f). The group of ctr, DMSO, and SPC5 was subject to ethanol, DMSO, or SPC at 5 μM, respectively. *P < 0.05, ***P < 0.001. n =3. Supplementary file3 (TIF 118 kb)

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Li, Y., Qi, Q., Yang, Wc. et al. Sphingosylphosphorylcholine alleviates hypoxia-caused apoptosis in cardiac myofibroblasts via CaM/p38/STAT3 pathway. Apoptosis 25, 853–863 (2020). https://doi.org/10.1007/s10495-020-01639-9

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