Rationale:Myocardial infarction (MI) is one of the most dangerous adverse cardiovascular events. Our previous study found that lysophosphatidic acid (LPA) is increased in human peripheral blood after MI, and LPA has a protective effect on the survival and proliferation of various cell types. However, the role of LPA and its receptors in MI is less understood.Objectives:To study the unknown role of LPA and its receptors in heart during MI.Methods and Results:In this study, we found that mice also had elevated LPA level in peripheral blood, as well as increased cardiac expression of its receptor LPA₂ in the early stages after MI. With adult and neonate MI models in global Lpar2 knockout (Lpar2-KO) mice, we found Lpar2 deficiency increased vascular leak leading to disruption of its homeostasis, so as to impaired heart function and increased early mortality. Histological examination revealed larger scar size, increased fibrosis, and reduced vascular density in the heart of Lpar2-KO mice. Furthermore, Lpar2-KO also attenuated blood flow recovery after femoral artery ligation with decreased vascular density in gastrocnemius. Our study revealed that Lpar2 was mainly expressed and altered in cardiac endothelial cells during MI, and use of endothelial-specific Lpar2 knockout mice phenocopied the global knockout mice. Additionally, adenovirus-Lpar2 and pharmacologically activated LPA₂ significantly improved heart function, reduced scar size, increased vascular formation, and alleviated early mortality by maintaining vascular homeostasis owing to protecting vessels from leakage. Mechanistic studies demonstrated that LPA-LPA₂ signaling could promote endothelial cell proliferation through PI3K-Akt/PLC-Raf1-Erk pathway and enhanced endothelial cell tube formation via PKD1-CD36 signaling.Conclusions:Our results indicate that endothelial LPA-LPA₂ signaling promotes angiogenesis and maintains vascular homeostasis, which is vital for restoring blood flow and repairing tissue function in ischemic injuries. Targeting LPA-LPA₂ signal might have clinical therapeutic potential to protect the heart from ischemic injury.

中文翻译：

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LPA2 有助于心肌梗死后的血管内皮稳态和心脏重塑

理由：心肌梗塞 (MI) 是最危险的不良心血管事件之一。我们前期研究发现，心肌梗死后人外周血中溶血磷脂酸（LPA）升高，LPA对多种细胞类型的存活和增殖具有保护作用。然而，LPA 及其受体在 MI 中的作用知之甚少。目的：研究 MI 期间 LPA 及其受体在心脏中的未知作用。方法和结果：在本研究中，我们发现小鼠 LPA 水平也升高外周血，以及心肌梗死后早期其受体 LPA _{2的心脏表达增加。}在全球Lpar2敲除 ( Lpar2 -KO) 小鼠的成人和新生儿 MI 模型中，我们发现了 Lpar2缺乏会增加血管渗漏，导致其稳态破坏，从而损害心脏功能并增加早期死亡率。组织学检查显示Lpar2 -KO 小鼠心脏的疤痕较大、纤维化增加和血管密度降低。此外，Lpar2- KO 还减弱了股动脉结扎后腓肠肌血管密度降低的血流恢复。我们的研究表明，Lpar2在 MI 期间主要在心脏内皮细胞中表达和改变，并且使用内皮特异性Lpar2基因敲除小鼠复制了全局基因敲除小鼠。此外，腺病毒-Lpar2和药理学激活的 LPA ₂显着改善心脏功能，减少疤痕大小，增加血管形成，并通过保护血管免于渗漏维持血管稳态来降低早期死亡率。机制研究表明，LPA-LPA ₂信号通路可通过 PI3K-Akt/PLC-Raf1-Erk 通路促进内皮细胞增殖，并通过 PKD1-CD36 信号通路促进内皮细胞管形成。结论：我们的结果表明，内皮 LPA-LPA ₂信号通路促进内皮细胞增殖血管生成并维持血管稳态，这对于在缺血性损伤中恢复血流和修复组织功能至关重要。靶向 LPA-LPA ₂信号可能具有保护心脏免受缺血性损伤的临床治疗潜力。