title: Reciprocal regulation of miR-23a and lysophosphatidic acid receptor signaling in cardiomyocyte hypertrophy.
abstract: Earlier, our study demonstrated that lysophosphatidic acid (LPA) receptor mediated cardiomyocyte hypertrophy. However, the subtype-specific functions for LPA1 and LPA3 receptors in LPA-induced hypertrophy have not been distinguished. Growing evidence indicates that microRNAs (miRNAs) are involved in the pathogenesis of cardiac hypertrophy by down-regulating target molecules. The present work therefore aimed at elucidating the functions mediated by different subtypes of LPA receptors and investigating the modulatory role of miRNAs during LPA induced hypertrophy. Experiments were done with cultured neonatal rat cardiomyocytes (NRCMs) exposed to LPA and we showed that knockdown of LPA1 by small interfering RNA (siRNA) enhanced LPA-induced cardiomyocyte hypertrophy, whereas LPA3 silencing repressed hypertrophy. miR-23a, a pro-hypertrophic miRNA, was up-regulated by LPA in cardiomyocytes and its down-regulation reduced LPA-induced cardiomyocyte hypertrophy. Importantly, luciferase reporter assay confirmed LPA1 to be a target of miR-23a, indicating that miR-23a is involved in mediating the LPA-induced cardiomyocyte hypertrophy by targeting LPA1. In addition, knockdown of LPA3, but not LPA1, eliminated miR-23a elevation induced by LPA. And PI3K inhibitor, LY294002, effectively prevented LPA-induced miR-23a expression in cardiomyocytes, suggesting that LPA might induce miR-23a elevation by activating LPA3 and PI3K/AKT pathway. These findings identified opposite subtype-specific functions for LPA1 and LPA3 in mediating cardiomyocyte hypertrophy and indicated LPA1 to be a target of miR-23a, which discloses a link between miR-23a and the LPA receptor signaling in cardiomyocyte hypertrophy.
authors.affiliation: Fuwai Hospital, National Centre for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Beijing, People's Republic of China.
authors.forename: Jinjing
authors.initials: J
authors.lastname: Yang
authors.forename: Yu
authors.initials: Y
authors.lastname: Nie
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Hou
authors.forename: Xiangfeng
authors.initials: X
authors.lastname: Cong
authors.forename: Shengshou
authors.initials: S
authors.lastname: Hu
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008246:Lysophospholipids / Q000633:toxicity; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009025:Morpholines / Q000494:pharmacology; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D049368:Receptors, Lysophosphatidic Acid / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D002867:Chromones; D004791:Enzyme Inhibitors; D008246:Lysophospholipids; D035683:MicroRNAs; D009025:Morpholines; D009124:Muscle Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D049368:Receptors, Lysophosphatidic Acid; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C032881:lysophosphatidic acid