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Lysophosphatidic acid contributes to myocardial ischemia/reperfusion injury by activating TRPV1 in spinal cord

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Abstract

Lysophosphatidic acid (LPA) is a bioactive phospholipid that plays a crucial role in cardiovascular diseases. Here, we question whether LPA contributes to myocardial ischemia/reperfusion (I/R) injury by acting on transient receptor potential vanilloid 1 (TRPV1) in spinal cord. By ligating the left coronary artery to establish an in vivo I/R mouse model, we observed a 1.57-fold increase in LPA level in the cerebrospinal fluid (CSF). The I/R-elevated CSF LPA levels were reduced by HA130, an LPA synthesis inhibitor, compared to vehicle treatment (4.74 ± 0.34 vs. 6.46 ± 0.94 μg/mL, p = 0.0014). Myocardial infarct size was reduced by HA130 treatment compared to the vehicle group (26 ± 8% vs. 46 ± 8%, p = 0.0001). To block the interaction of LPA with TRPV1 at the K710 site, we generated a K710N knock-in mouse model. The TRPV1K710N mice were resistant to LPA-induced myocardial injury, showing a smaller infarct size relative to TRPV1WT mice (28 ± 4% vs. 60 ± 7%, p < 0.0001). Additionally, a sequence-specific TRPV1 peptide targeting the K710 region produced similar protective effects against LPA-induced myocardial injury. Blocking the K710 region through K710N mutation or TRPV1 peptide resulted in reduced neuropeptides release and decreased activity of cardiac sensory neurons, leading to a decrease in cardiac norepinephrine concentration and the restoration of intramyocardial pro-survival signaling, namely protein kinase B/extracellular regulated kinase/glycogen synthase kinase-3β pathway. These findings suggest that the elevation of CSF LPA is strongly associated with myocardial I/R injury. Moreover, inhibiting the interaction of LPA with TRPV1 by blocking the K710 region uncovers a novel strategy for preventing myocardial ischemic injury.

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Data availability

The data that support the findings of this study are available from the corresponding authors upon reasonable request.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (32271194 to SH, 81970231to YZ), Anhui Provincial Natural Science Foundation (2208085MH218 to SH), Key Program of Natural Science Foundation of Higher Education Institutions of Anhui Province (KJ2020A0212 to SH), Program for Excellent Research and Innovation Team of Higher Education Institutions of Anhui Province (2023AH010081 to YZ) and the National Institutes of Health (GM119522 to ERG). The authors thank the Center for Scientific Research of the Second Affiliated Hospital of Anhui Medical University for valuable help in experiments.

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  1. Chao Wu, Meiyan Sun and Muge Qile contributed equally to this work.

Authors and Affiliations

  1. Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital of Anhui Medical University, 678 Furong Road, Hefei, 230601, Anhui Province, China

    Chao Wu, Meiyan Sun, Muge Qile, Yu Zhang, Liu Liu, Xueying Cheng, Xiaoxiao Dai, Ye Zhang & Shufang He

  2. Key Laboratory of Anesthesiology and Perioperative Medicine of Anhui Higher Education Institutes, Anhui Medical University, Hefei, China

    Chao Wu, Meiyan Sun, Muge Qile, Yu Zhang, Liu Liu, Xueying Cheng, Xiaoxiao Dai, Ye Zhang & Shufang He

  3. Department of Anesthesiology, Perioperative and Pain Medicine, School of Medicine, Stanford University, Stanford, CA, USA

    Eric R. Gross

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Contributions

YZ, SFH and ERG conceived and designed the experiments. CW, MYS, MGQL, YZ, LL, XYC, and XXD performed the experiments and analyzed the data. SFH and CW wrote the manuscript, which was revised by ERG and YZ.

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Correspondence to Ye Zhang or Shufang He.

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All animal experiments have been approved by the Institutional Animal Care and Use Committee of Anhui Medical University.

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Wu, C., Sun, M., Qile, M. et al. Lysophosphatidic acid contributes to myocardial ischemia/reperfusion injury by activating TRPV1 in spinal cord. Basic Res Cardiol 119, 329–348 (2024). https://doi.org/10.1007/s00395-023-01031-z

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  • DOI: https://doi.org/10.1007/s00395-023-01031-z

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