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.

Neonatal mouse hearts can regenerate completely in 21 days after cardiac injury, providing an ideal model to exploring heart regenerative therapeutic targets. The oxidative damage by Reactive Oxygen Species (ROS) is one of the critical reasons for the cell cycle arrest of cardiomyocytes (CMs), which cause mouse hearts losing the capacity to regenerate in 7 days or shorter after birth. As an antioxidant, hydrogen sulfide (H₂S) plays a protective role in a variety of diseases by scavenging ROS produced during the pathological processes. In this study, we found that blocking H₂S synthesis by PAG (H₂S synthase inhibitor) suspended heart regeneration and CM proliferation with ROS deposition increase after cardiac injury (myocardial infarction or apex resection) in 2-day-old mice. NaHS (a H₂S donor) administration improved heart regeneration with CM proliferation and ROS elimination after myocardial infarction in 7-day-old mice. NaHS protected primary neonatal mouse CMs from H₂O₂-induced apoptosis and promoted CM proliferation via SOD2-dependent ROS scavenging. The oxidative DNA damage in CMs was reduced with the elimination of ROS by H₂S. Our results demonstrated for the first time that H₂S promotes heart regeneration and identified NaHS as a potent modulator for cardiac repair.

Lysophosphatidic acid (LPA), one of the simplest phospholipid signaling molecules, participates in formation and disruption of atherosclerotic plaque. Matrix metalloproteinases (MMPs) contribute to atherosclerotic plaque rupture by involving in extracellular matrix (ECM) degradation and then thinning fibrous cap. Our previous study demonstrated that macrophage-derived MMP-9 was associated with coronary plaque instability, but the relationship between LPA and MMP-9 remains unclear. The present work therefore aimed at elucidating association between LPA and MMP-9 and the regulation mechanism of LPA on MMP-9 in macrophages. We found that plasma LPA and MMP-9 levels were correlated positively (r = 0.31, P < 0.05) and both elevated significantly in patients with acute myocardial infarct (AMI). Consistent with peripheral blood levels, histochemical staining indicated that autotaxin (ATX), LPA-producing ectoenzyme, and MMP-9 were expressed frequently in the necrotic core and fibrous cap of human unstable plaques, which might increase the instability of plaque. Experiments in vitro were done with THP-1-derived macrophages and showed that LPA enhanced the expression, secretion and activity of MMP-9 in a time- and dose-dependent manner. Induction of LPA on pro-MMP-9 and active-MMP-9 was confirmed in human peripheral blood monocyte-derived macrophages. PDTC, NF-κB inhibitor, but not inhibitor of AP-1 and PPARγ, effectively prevented LPA-induced MMP-9 expression and NF-κB p65 siRNA decreased MMP-9 transcription, confirming that LPA might induce MMP-9 elevation by activating NF-κB pathway. In addition, knockdown of LPA2 attenuated LPA-induced MMP-9 expression and nucleus p65 levels. These findings revealed that LPA upregulated the expression of MMP-9 through activating NF-κB pathway in the LPA2 dependent manner, hence blocking LPA receptors signaling may provide therapeutic strategy to target plaque destabilization.

Background: Lysophosphatidic acid (LPA) is a small glycerophospholipid that acts as a potent extracellular signal in various biological processes and diseases. Our previous work demonstrated that the expression of the LPA receptors LPA₁ and LPA₃ is elevated in the early postnatal heart. However, the role of this stage-specific expression of LPA₁ and LPA₃ in the heart is unknown.