title: Specific LPA receptor subtype mediation of LPA-induced hypertrophy of cardiac myocytes and involvement of Akt and NFkappaB signal pathways.
abstract: Lysophosphatidic acid (LPA) is a bioactive phospholipid with diverse functions mediated via G-protein-coupled receptors (GPCRs). In view of the elevated levels of LPA in acute myocardial infarction (MI) patients we have conducted studies aimed at identifying specific LPA receptor subtypes and signaling events that may mediate its actions in hypertrophic remodeling. Experiments were carried out in cultured neonatal rat cardiomyocytes (NRCMs) exposed to LPA and in a rat MI model. In NRCMs, LPA-induced hypertrophic growth was completely abrogated by DGPP, an LPA1/LPA3 antagonist. The LPA3 agonist OMPT, but not the LPA2 agonist dodecylphosphate, promoted hypertrophy as examined by 3[H]-Leucine incorporation, ANF-luciferase expression and cell area. In in vivo experiments, LPA1, LPA2 and LPA3 mRNA levels as well as LPA1 and LPA3 protein levels increased together with left ventricular remodeling (LVRM) after MI. In addition, LPA stimulated the phosphorylation of Akt and p65 protein and activated NF-kappaB-luciferase expression. Inhibitors of PI3K (wortmannin), mTOR (rapamycin), and NF-kappaB (PDTC or SN50) effectively prevented LPA-induced 3[H]-Leucine incorporation and ANF-luciferase expression. Furthermore, ERK inhibitors (U0126 and PD98059) suppressed LPA-stimulated activation of NF-kappaB and p65 phosphorylation whereas wortmannin showed no effect on NF-kappaB activation. Our findings indicate that LPA3 and/or LPA1 mediate LPA-induced hypertrophy of NRCMs and that LPA1 and LPA3 may be involved in LVRM of MI rats. Moreover, Akt and NF-kappaB signaling pathways independently implicate in LPA-stimulated myocardial hypertrophic growth.
authors: Research Center for Cardiovascular Regenerative Medicine, the Ministry of Health, Cardiovascular Institute and Fuwai Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
authors: Jinghai
authors: J
authors: Chen
authors: Yuefeng
authors: Y
authors: Chen
authors: Weiquan
authors: W
authors: Zhu
authors: Yu
authors: Y
authors: Han
authors: Bianmei
authors: B
authors: Han
authors: Ruixia
authors: R
authors: Xu
authors: Linzi
authors: L
authors: Deng
authors: Yan
authors: Y
authors: Cai
authors: Xiangfeng
authors: X
authors: Cong
authors: Yuejing
authors: Y
authors: Yang
authors: Shengshou
authors: S
authors: Hu
authors: Xi
authors: X
authors: Chen
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D011756:Diphosphates / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005990:Glycerol / Q000031:analogs & derivatives / Q000494:pharmacology; D006984:Hypertrophy; D008246:Lysophospholipids / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000502:physiology; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000502:physiology*; D063086:Organothiophosphates / Q000494:pharmacology; D010712:Phosphatidic Acids / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D049368:Receptors, Lysophosphatidic Acid / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
chemical_list: C473891:1-oleoyl-2-O-methyl-rac-glycerophosphothionate; D011756:Diphosphates; D004791:Enzyme Inhibitors; D008246:Lysophospholipids; D016328:NF-kappa B; D063086:Organothiophosphates; D010712:Phosphatidic Acids; D049368:Receptors, Lysophosphatidic Acid; C408642:diacylglycerol pyrophosphate; D051057:Proto-Oncogene Proteins c-akt; D005990:Glycerol; C032881:lysophosphatidic acid