State Key Laboratory of Cardiovascular Disease (J.P., L.C., C.X., S.P., X.C., Z.Z.), Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
National Health Commission Key Laboratory of Cardiovascular Regenerative Medicine, Fuwai Central-China Hospital, Central-China Branch of National Center for Cardiovascular Diseases, Zhengzhou, China (J.P., Z.Z.).
Circ Res. 2022 Aug 19;131(5):388-403. doi: 10.1161/CIRCRESAHA.122.321036. Epub 2022 Aug 3.
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.
To study the unknown role of LPA and its receptors in heart during MI.
In this study, we found that mice also had elevated LPA level in peripheral blood, as well as increased cardiac expression of its receptor LPA in the early stages after MI. With adult and neonate MI models in global knockout (-KO) mice, we found 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 -KO mice. Furthermore, -KO also attenuated blood flow recovery after femoral artery ligation with decreased vascular density in gastrocnemius. Our study revealed that was mainly expressed and altered in cardiac endothelial cells during MI, and use of endothelial-specific knockout mice phenocopied the global knockout mice. Additionally, adenovirus- and pharmacologically activated LPA 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-LPA signaling could promote endothelial cell proliferation through PI3K-Akt/PLC-Raf1-Erk pathway and enhanced endothelial cell tube formation via PKD1-CD36 signaling.
Our results indicate that endothelial LPA-LPA signaling promotes angiogenesis and maintains vascular homeostasis, which is vital for restoring blood flow and repairing tissue function in ischemic injuries. Targeting LPA-LPA signal might have clinical therapeutic potential to protect the heart from ischemic injury.
心肌梗死（MI）是最危险的心血管不良事件之一。我们之前的研究发现，溶血磷脂酸（LPA）在 MI 后会在人体外周血中增加，并且 LPA 对各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 中的作用还不太清楚。
研究 LPA 及其受体在 MI 心脏中的未知作用。
在这项研究中，我们发现小鼠在 MI 后早期外周血中的 LPA 水平也升高，其受体 LPA 在心脏中的表达也增加。通过在成年和新生 MI 模型中使用全局敲除（-KO）小鼠，我们发现 LPA1 缺乏会导致血管渗漏增加，从而破坏其体内平衡，导致心脏功能受损和早期死亡率增加。组织学检查显示 -KO 小鼠的心脏疤痕面积更大、纤维化增加、血管密度降低。此外，-KO 还通过降低腓肠肌中的血管密度，减弱了股动脉结扎后的血流恢复。我们的研究表明，在 MI 期间，LPA1 主要在心脏内皮细胞中表达和改变，并且使用内皮细胞特异性 -KO 小鼠模拟了全局敲除小鼠。此外，腺病毒和药理学激活的 LPA 通过保护血管免受渗漏，显著改善心脏功能、减少疤痕面积、增加血管形成，并减轻早期死亡率，从而维持血管内稳态。机制研究表明，LPA-LPA 信号通过 PI3K-Akt/PLC-Raf1-Erk 途径促进内皮细胞增殖，并通过 PKD1-CD36 信号增强内皮细胞管形成。
我们的结果表明，内皮细胞 LPA-LPA 信号促进血管生成并维持血管内稳态，这对于恢复缺血损伤中的血流和修复组织功能至关重要。靶向 LPA-LPA 信号可能具有保护心脏免受缺血损伤的临床治疗潜力。
