Abstract 13046: Lysophosphatidic Acid Activates Spinal TRPV1 Signaling and Contributes to Myocardial Ischemia/Reperfusion Injury

Introduction: Lysophosphatidic acid (LPA) has been shown to directly activate transient receptor potential vanilloid 1 (TRPV1) on primary nociceptors via the binding site of K710 to produce acute pain. However, it is unclear whether LPA participates in myocardial ischemia/reperfusion (I/R) injury by activating TRPV1 receptors.

Hypothesis: We hypothesize that LPA contributes to myocardial I/R injury by acting on TRPV1 receptors in the spinal cord, and that blocking the interaction between LPA and TRPV1 could exert cardioprotective effects.

Methods: Wild type male C57BL/6 mice underwent myocardial I/R injury, and LPA levels in cerebrospinal fluid (CSF) were measured. LPA synthesis inhibitor HA-130 or exogenous LPA were intrathecally administrated during myocardial ischemia. Additionally, CRISPR/Cas-9 edited TRPV1K710N knock-in mice and a peptide V1-Cal targeting the K710 region were utilized to block the interaction of LPA with TRPV1.

Results: The levels of LPA in CSF of the I/R group were found to be 1.5-fold higher than those of the sham group (Fig.1B, p=0.0001). Intrathecal administration of HA130 reduced infarct size (Fig.1C, p=0.0021) and CSF LPA levels (Fig.1D, p=0.0018). The CSF LPA levels were positively correlated with infarct size (Fig.1E, p<0.0001). Intrathecal administration of LPA caused a 1.4-fold rise in infarct size relative to I/R group in wild type mice (Fig.1F, p<0.0001), but not in TRPV1K710N mice (Fig.1F, p>0.9999). LPA treatment enhanced the activation of spinal TRPV1 receptors following I/R injury in wild type mice, but not in TRPV1K710N mice (Fig.1 G-I). Further, the V1-Cal peptide reduced myocardial I/R injury, as well as the protein levels of TRPV1 and pTRPV1 in spinal cord (Fig.1 J-M).

Conclusions: Our results suggest that LPA activates spinal TRPV1 signaling and contributes to myocardial I/R injury. Blockade of the interaction between LPA and TRPV1 in spinal cord may be a promising therapeutic approach for myocardial ischemic injury.