Lysophosphatidic acid contributes to myocardial ischemia/reperfusion injury by activating TRPV1 in spinal cord
© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:119 |
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| Enthalten in: |
Basic research in cardiology - 119(2024), 2 vom: 18. Apr., Seite 329-348 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wu, Chao [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 12.04.2024 Date Revised 12.04.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1007/s00395-023-01031-z |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM367268167 |
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| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Cerebrospinal fluid | |
| 650 | 4 | |a Lysophosphatidic acid | |
| 650 | 4 | |a Myocardial ischemia/reperfusion | |
| 650 | 4 | |a Sequence-specific peptide | |
| 650 | 4 | |a Transient receptor potential vanilloid 1 | |
| 650 | 7 | |a lysophosphatidic acid |2 NLM | |
| 650 | 7 | |a PG6M3969SG |2 NLM | |
| 650 | 7 | |a TRPV Cation Channels |2 NLM | |
| 650 | 7 | |a Peptides |2 NLM | |
| 650 | 7 | |a TRPV1 protein, mouse |2 NLM | |
| 650 | 7 | |a Lysophospholipids |2 NLM | |
| 700 | 1 | |a Sun, Meiyan |e verfasserin |4 aut | |
| 700 | 1 | |a Qile, Muge |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Yu |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Liu |e verfasserin |4 aut | |
| 700 | 1 | |a Cheng, Xueying |e verfasserin |4 aut | |
| 700 | 1 | |a Dai, Xiaoxiao |e verfasserin |4 aut | |
| 700 | 1 | |a Gross, Eric R |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Ye |e verfasserin |4 aut | |
| 700 | 1 | |a He, Shufang |e verfasserin |4 aut | |
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