title: Apelin attenuates the osteoblastic differentiation of aortic valve interstitial cells via the ERK and PI3-K/Akt pathways.
abstract: Aortic valve calcification (AVC), which used to be recognized as a passive and irreversible process, is now widely accepted as an active and regulated process characterized by osteoblastic differentiation of aortic valve interstitial cells (AVICs). Apelin, the endogenous ligand for G-protein-coupled receptor APJ, was found to have protective cardiovascular effects in several studies. However, the effects and mechanisms of apelin on osteoblastic differentiation of AVICs have not been elucidated. Using a pro-calcific medium, we devised a method to produce calcific human AVICs. These cells were used to study the relationship between apelin and the osteoblastic calcification of AVICs and the involved signaling pathways. Alkaline phosphatase (ALP) activity/expression and runt-related transcription factor 2 (Runx2) expression were examined as hallmark proteins in this research. The involved signaling pathways were studied using the extracellular signal-regulated kinase (ERK) inhibitor, PD98059, and the phosphatidylinositol 3-kinase (PI3-K) inhibitor, LY294002. The results indicate that apelin attenuates the expression and activity of ALP, the expression of Runx2, and the formation of mineralized nodules. This protective effect was dependent on the dose of apelin, reaching the maximum at 100 pM, and was connected to activity of ERK and Akt (a downstream effector of PI3-K). The activation of ERK and PI3-K initiated the effects of apelin on ALP activity/expression and Runx2, but PD98059 and LY294002 abolished the effect. These results demonstrate that apelin attenuates the osteoblastic differentiation of AVICs via the ERK and PI3-K/Akt pathway.
authors.affiliation: Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, People's Republic of China.
authors.forename: Zhao-shun
authors.initials: ZS
authors.lastname: Yuan
authors.affiliation: Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, People's Republic of China.
authors.forename: Yang-zhao
authors.initials: YZ
authors.lastname: Zhou
authors.affiliation: Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, People's Republic of China.
authors.forename: Xiao-bo
authors.initials: XB
authors.lastname: Liao
authors.affiliation: Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, People's Republic of China.
authors.forename: Jia-wen
authors.initials: JW
authors.lastname: Luo
authors.affiliation: Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, People's Republic of China.
authors.forename: Kang-jun
authors.initials: KJ
authors.lastname: Shen
authors.affiliation: Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, People's Republic of China.
authors.forename: Ye-rong
authors.initials: YR
authors.lastname: Hu
authors.affiliation: Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, People's Republic of China.
authors.forename: Lu
authors.initials: L
authors.lastname: Gu
authors.affiliation: Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, People's Republic of China.
authors.forename: Jian-ming
authors.initials: JM
authors.lastname: Li
authors.affiliation: Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, People's Republic of China.
authors.forename: Chang-ming
authors.initials: CM
authors.lastname: Tan
authors.affiliation: Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, People's Republic of China. cardiosurgeon0921@gmail.com.
authors.forename: He-ming
authors.initials: HM
authors.lastname: Chen
authors.affiliation: Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, 410011, Hunan, People's Republic of China. mark037100@aliyun.com.
authors.forename: Xin-min
authors.initials: XM
authors.lastname: Zhou
mesh_terms: D000328:Adult; D000469:Alkaline Phosphatase / Q000378:metabolism; D001021:Aortic Valve / Q000166:cytology / Q000378:metabolism / Q000473:pathology*; D001024:Aortic Valve Stenosis / Q000378:metabolism; D000073861:Apelin; D002114:Calcinosis / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D002867:Chromones / Q000737:chemistry; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005419:Flavonoids / Q000737:chemistry; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D009025:Morpholines / Q000737:chemistry; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D010006:Osteoblasts / Q000166:cytology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C115436:APLN protein, human; D000073861:Apelin; D002867:Chromones; D050659:Core Binding Factor Alpha 1 Subunit; D005419:Flavonoids; D036341:Intercellular Signaling Peptides and Proteins; D009025:Morpholines; C493709:RUNX2 protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D000469:Alkaline Phosphatase; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
keywords: APJ; Alkaline phosphatase; Aortic valve calcification; Mineralization; Runt-related transcription factor 2