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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
1Shandong Provincial Key Laboratory of Animal Cells and Developmental Biology, School of Life Science, Shandong University, Jinan, China.
Insights
Sphingosylphosphorylcholine (SPC) prevents heart cell death in nonmyocytes, crucial for mitigating damage after myocardial infarction. This study reveals SPC’s protective role via Calmodulin (CaM), offering a new therapeutic target for heart remodeling.
Area of Science:
- Cardiovascular Biology
- Cellular Signaling
- Molecular Medicine
Background:
- Hypoxia-induced nonmyocyte apoptosis exacerbates myocardial infarction.
- Effective interventions targeting nonmyocyte apoptosis are limited.
- Sphingosylphosphorylcholine (SPC) previously protected cardiomyocytes from ischemic injury.
Purpose of the Study:
- To investigate SPC's effect on hypoxia-induced myofibroblast apoptosis.
- To elucidate the molecular mechanisms underlying SPC's protective action.
- To identify potential therapeutic targets for post-myocardial infarction heart remodeling.
Main Methods:
- Exposure of cardiac myofibroblasts to hypoxia.
- Treatment with SPC and assessment of apoptosis markers (cleaved caspase 3, PARP1, nuclear condensation).
- Utilizing Calmodulin (CaM) inhibitors/agonists and examining p38/STAT3 phosphorylation pathways.
Main Results:
- SPC significantly inhibited hypoxia-induced apoptosis in cardiac myofibroblasts.
- SPC's effect was mediated through its receptor Calmodulin (CaM).
- SPC regulated the phosphorylation of p38 and STAT3, downstream of CaM, to inhibit apoptosis.
Conclusions:
- SPC demonstrates a novel protective role against myofibroblast apoptosis under hypoxic conditions.
- The SPC-CaM-p38/STAT3 signaling axis represents a potential therapeutic strategy for heart remodeling.
- Targeting myofibroblast apoptosis with SPC may improve outcomes in myocardial infarction.
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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