Authors: Qile M et al.
Source: Anesthesia & Analgesia. January 14, 2026. DOI: 10.1213/ANE.0000000000007907
Summary:
Perioperative myocardial ischemia/reperfusion (I/R) injury remains a significant contributor to morbidity and mortality in both cardiac and noncardiac surgery. In this translational mechanistic study, Qile and colleagues investigated the role of lysophosphatidic acid (LPA), a bioactive phospholipid, in mediating myocardial I/R injury through direct interaction with the transient receptor potential vanilloid 1 (TRPV1) channel.
Using a CRISPR/Cas9-generated knock-in mouse model harboring a point mutation at the known LPA-binding site on TRPV1 (K710N), the investigators demonstrated that disruption of the LPA–TRPV1 interaction confers marked cardioprotection. Isolated Langendorff-perfused hearts from TRPV1K710N mice exhibited significantly reduced infarct size, lower lactate dehydrogenase release, and preserved mitochondrial structure and function compared with wild-type hearts following global I/R injury. Administration of exogenous LPA dramatically worsened myocardial injury in wild-type hearts but had no effect in TRPV1K710N hearts, confirming the specificity of this signaling pathway.
Mechanistic in vitro studies using H9c2 cardiomyocytes reinforced these findings. LPA exposure increased mitochondrial calcium influx and reduced cell viability in cells expressing wild-type TRPV1, whereas cells expressing TRPV1-K710N were protected. Importantly, pharmacologic blockade using the V1-Cal peptide targeting the TRPV1 K710 region attenuated LPA-induced myocardial injury ex vivo and mitigated mitochondrial calcium overload in vitro.
Collectively, these results identify LPA–TRPV1 signaling as a previously underappreciated driver of myocardial I/R injury, acting through mitochondrial calcium dysregulation and structural damage. The study provides strong proof-of-concept that targeted disruption of this interaction may represent a novel therapeutic avenue for perioperative myocardial protection.
What You Should Know:
• LPA is a potent endogenous mediator that exacerbates myocardial I/R injury through direct activation of TRPV1.
• The TRPV1 K710 residue is critical for LPA binding and downstream myocardial and mitochondrial injury.
• Genetic or peptide-based blockade of this site markedly reduces infarct size and preserves mitochondrial function.
• Mitochondrial calcium overload appears to be a central mechanism linking LPA–TRPV1 activation to cardiomyocyte death.
Key Points:
• TRPV1K710N mutation confers resistance to myocardial I/R injury.
• LPA worsens infarct size and mitochondrial damage in wild-type but not mutant hearts.
• TRPV1-mediated mitochondrial calcium influx is a key injury pathway.
• Targeting LPA–TRPV1 signaling may offer a novel strategy for perioperative myocardial protection.
Thank you to Anesthesia & Analgesia for publishing this rigorous mechanistic study that advances our understanding of perioperative myocardial ischemia–reperfusion injury and identifies a promising new cardioprotective target.