title: Hypoxia-induced endothelial-mesenchymal transition is associated with RASAL1 promoter hypermethylation in human coronary endothelial cells.
abstract: Cardiac fibrosis is integral in chronic heart disease, and one of the cellular processes contributing to cardiac fibrosis is endothelial-to-mesenchymal transition (EndMT). We recently found that hypoxia efficiently induces human coronary artery endothelial cells (HCAEC) to undergo EndMT through a hypoxia inducible factor-1α (HIF1α)-dependent pathway. Promoter hypermethylation of Ras-Gap-like protein 1 (RASAL1) has also been recently associated with EndMT progression and cardiac fibrosis. Our findings suggest that HIF1α and transforming growth factor (TGF)/SMAD signalling pathways synergistically regulate hypoxia-induced EndMT through both DNMT3a-mediated hypermethylation of RASAL1 promoter and direct SNAIL induction. The findings indicate that multiple cascades may be activated simultaneously to mediate hypoxia-induced EndMT.
authors.affiliation: Department of Cardiology and Pneumology, University Medical Center of Göttingen, Georg-August University, Göttingen, Germany.|German Centre for Cardiovascular Research (DZHK), Göttingen, Germany.
authors.forename: Xingbo
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Cardiology and Pneumology, University Medical Center of Göttingen, Georg-August University, Göttingen, Germany.|German Centre for Cardiovascular Research (DZHK), Göttingen, Germany.
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Tan
authors.affiliation: Department of Cardiology and Pneumology, University Medical Center of Göttingen, Georg-August University, Göttingen, Germany.
authors.forename: Melanie S
authors.initials: MS
authors.lastname: Hulshoff
authors.affiliation: Department of Cardiology and Pneumology, University Medical Center of Göttingen, Georg-August University, Göttingen, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Wilhelmi
authors.affiliation: German Centre for Cardiovascular Research (DZHK), Göttingen, Germany.|Department of Nephrology and Rheumatology, University Medical Center of Göttingen, Georg-August University, Göttingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Zeisberg
authors.affiliation: Department of Cardiology and Pneumology, University Medical Center of Göttingen, Georg-August University, Göttingen, Germany.|German Centre for Cardiovascular Research (DZHK), Göttingen, Germany.
authors.forename: Elisabeth M
authors.initials: EM
authors.lastname: Zeisberg
mesh_terms: D019898:Autocrine Communication; D015687:Cell Hypoxia; D003331:Coronary Vessels / Q000473:pathology*; D018899:CpG Islands / Q000235:genetics; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics*; D000090205:DNA Methyltransferase 3A; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology*; D020690:GTPase-Activating Proteins / Q000235:genetics* / Q000378:metabolism; D020868:Gene Silencing; D006801:Humans; D008648:Mesoderm / Q000473:pathology*; D008954:Models, Biological; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: C000717967:DNMT3A protein, human; D020690:GTPase-Activating Proteins; C580923:RASAL1 protein, human; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A
keywords: DNMT3a; EndMT; RASAL1; hypoxia; methylation