LPA ₂ Contributes to Vascular Endothelium Homeostasis and Cardiac Remodeling After Myocardial Infarction

Abstract

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 LPA 2 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 LPA 2 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 2 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-LPA 2 signaling promotes angiogenesis and maintains vascular homeostasis, which is vital for restoring blood flow and repairing tissue function in ischemic injuries. Targeting LPA-LPA 2 signal might have clinical therapeutic potential to protect the heart from ischemic injury.

Lysophosphatidic Acid/Polydopamine-Modified nHA Composite Scaffolds for Enhanced Osteogenesis via Upregulating the Wnt/Beta-Catenin Pathway

“…After further addition of pDA/nHA, the BV/TV value of PP-pDA/nHA-LPA increased by 17.1% to PP-LPA, signifying that the addition of nHA could improve the osteogenesis effect of LPA, and the two could synergistically promote osteogenesis in vivo . In addition, some studies have shown that LPA2 and LPA6 signaling could promote angiogenesis and maintain vascular homeostasis, which is a key part of tissue repair. , This synergistic effect was possibly due to the stable LPA accelerating the migration of osteoblasts while superimposing the properties of HA to promote the proliferation and differentiation of osteoblasts.…”

“…In addition, some studies have shown that LPA2 and LPA6 signaling could promote angiogenesis and maintain vascular homeostasis, which is a key part of tissue repair. 64,65 This synergistic effect was possibly due to the stable LPA accelerating the migration of osteoblasts while superimposing the properties of HA to promote the proliferation and differentiation of osteoblasts.…”

Amphiregulin improves ventricular remodeling after myocardial infarction by modulating autophagy and apoptosis

“…In addition, EGFR inhibition results in ventricular hypertrophy, dilation, and impaired cardiac function in adult murine hearts 20 . PI3K/Akt pathway activation protects against cardiac remodeling 5,21 . Meanwhile, activating the mTORC2‐Akt pathway improves cardiac function after ischemic damage 22,23 .…”

Potential drug targets for myocardial infarction identified through Mendelian randomization analysis and Genetic colocalization

“…[25,26] Notably, PCSK9 (proprotein convertase subtilisin/kexin 9) inhibitors have shown significant reductions in plasma Lp(a) concentration, which may lead to improved coronary outcomes. [27] Pei et al [28] have experimentally demonstrated the potential clinical therapeutic value of targeting LPA-LPA2 to protect the heart from ischemic injury, warranting further clinical attention. Furthermore, APOA5 is believed to be the gene exerting the strongest influence on TG metabolism.…”