Lpar2, short for Lysophosphatidic acid receptor 2, is a G-protein-coupled receptor. Lysophosphatidic acid (LPA) binds to Lpar2, and this interaction activates multiple signaling pathways, such as the PI3K-Akt/PLC-Raf1-Erk and PKD1-CD36 pathways, which are crucial for regulating cell proliferation, migration, and angiogenesis [1,3]. It plays an overall important role in maintaining cellular homeostasis and is involved in various physiological and pathological processes. Genetic models, like knockout mice, are valuable for studying its functions.

In global Lpar2 knockout (Lpar2-KO) mice, Lpar2 deficiency leads to increased vascular leak, disrupting vascular endothelium homeostasis, impairing heart function, and increasing early mortality after myocardial infarction. There are also larger scar sizes, increased fibrosis, and reduced vascular density in the heart, as well as attenuated blood flow recovery after femoral artery ligation [1]. In renal cancer, LPAR2-overexpressing cells show enhanced proliferation, clone formation, and migration in response to LPA, while LPAR2 antagonist suppresses these actions. In vivo, LPAR2-overexpressing cells-derived solid tumors have increased growth and metastasis [2]. In gastric cancer, knockdown of LPAR2 robustly reduces LPA-induced β-catenin activity and the associated changes in energy metabolism [3]. In non-steroidal anti-inflammatory drug (NSAID)-induced mouse enteropathy, Lpar2 -/- mice have earlier-occurring mucosal enteropathy and neutrophil recruitment, but lower levels of inflammatory mediators [4].

In conclusion, Lpar2 is essential for maintaining vascular endothelium homeostasis, regulating cancer cell behaviors, and influencing energy metabolism and mucosal integrity in different disease conditions. The use of Lpar2 KO mouse models has significantly contributed to understanding its role in myocardial infarction, renal cancer, gastric cancer, and NSAID-induced enteropathy, providing potential therapeutic targets for these diseases.

References:

1. Pei, Jianqiu, Cai, Lin, Wang, Fang, Zheng, Zhe, Chen, Xi. 2022. LPA2 Contributes to Vascular Endothelium Homeostasis and Cardiac Remodeling After Myocardial Infarction. In Circulation research, 131, 388-403. doi:10.1161/CIRCRESAHA.122.321036. https://pubmed.ncbi.nlm.nih.gov/35920162/

2. Wang, Yuewu, Qi, Zhimin, Li, Ze, Bai, Shuyu, Damirin, Alatangaole. 2022. LPAR2-mediated action promotes human renal cell carcinoma via MAPK/NF-κB signaling to regulate cytokine network. In Journal of cancer research and clinical oncology, 149, 2041-2055. doi:10.1007/s00432-022-04197-6. https://pubmed.ncbi.nlm.nih.gov/35857125/

3. Ara, Hosne, Subedi, Utsab, Sharma, Papori, Miriyala, Sumitra, Panchatcharam, Manikandan. 2022. Alteration of Cellular Energy Metabolism through LPAR2-Axin2 Axis in Gastric Cancer. In Biomolecules, 12, . doi:10.3390/biom12121805. https://pubmed.ncbi.nlm.nih.gov/36551233/

4. Hutka, Barbara, Várallyay, Anett, László, Szilvia B, Gyires, Klára, Zádori, Zoltán S. 2023. A dual role of lysophosphatidic acid type 2 receptor (LPAR2) in nonsteroidal anti-inflammatory drug-induced mouse enteropathy. In Acta pharmacologica Sinica, 45, 339-353. doi:10.1038/s41401-023-01175-7. https://pubmed.ncbi.nlm.nih.gov/37816857/