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 TRPV1^K710N mice were resistant to LPA-induced myocardial injury, showing a smaller infarct size relative to TRPV1^WT 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.

溶血磷脂酸（LPA）是一种生物活性磷脂，在心血管疾病中发挥着至关重要的作用。在这里，我们质疑LPA是否通过作用于脊髓中的瞬时受体电位香草酸1（TRPV1）而导致心肌缺血/再灌注（I/R）损伤。通过结扎左冠状动脉建立体内 I/R 小鼠模型，我们观察到脑脊液 (CSF) 中 LPA 水平增加了 1.57 倍。与媒介物治疗相比，HA130（一种 LPA 合成抑制剂）降低了 I/R 升高的 CSF LPA 水平（4.74 ± 0.34 vs. 6.46 ± 0.94 μg/mL，p  = 0.0014）。与赋形剂组相比，HA130 治疗后心肌梗塞面积减少（26 ± 8% vs. 46 ± 8%，p  = 0.0001）。为了阻断 LPA 与 TRPV1 在 K710 位点的相互作用，我们生成了 K710N 敲入小鼠模型。 TRPV1 ^{K710N小鼠对 LPA 诱导的心肌损伤具有抵抗力，与 TRPV1 WT}小鼠相比，显示出更小的梗塞面积（28 ± 4% vs. 60 ± 7%，p  < 0.0001）。此外，针对 K710 区域的序列特异性 TRPV1 肽对 LPA 诱导的心肌损伤产生了类似的保护作用。通过K710N突变或TRPV1肽阻断K710区域，导致神经肽释放减少和心脏感觉神经元活性降低，导致心脏去甲肾上腺素浓度降低和心肌内促生存信号恢复，即蛋白激酶B/细胞外调节激酶/糖原合酶激酶-3β途径。这些发现表明脑脊液 LPA 升高与心肌 I/R 损伤密切相关。此外，通过阻断 K710 区域来抑制 LPA 与 TRPV1 的相互作用，揭示了预防心肌缺血性损伤的新策略。