title: M3-mAChR stimulation exerts anti-apoptotic effect via activating the HIF-1α/HO-1/VEGF signaling pathway in H9c2 rat ventricular cells.
abstract: BACKGROUND
  The protective role of M(3)-mAChR against apoptosis has been identified previously. However, the underlying mechanisms remain unclear. This study was performed to clarify the signaling pathways of the anti-apoptotic effect mediated by activation of M(3)-mAChR in cultured cardiac H9c2 cells.
  
  
  METHODS
  Both H9c2 rat ventricular cells and H9c2 cells with stable expression of M(3)-mAChR were used.
  
  
  RESULTS
  Activation of M(3)-mAChR by cabarchol produced protective effect on etoposide-induced apoptosis in H9c2 cells. Forced overexpression of M(3)-mAChR in H9c2 cells further enhanced this effect. Application of 4-diphenyl-acetoxy-N-methyl-piperidine methiodide (inhibitor of M(3)-mAChR), YC-1 [inhibitor of hypoxia-inducible factor 1, (HIF-1], or ZnPP (inhibitor of heme oxygenase-1)abrogated carbacol-induced cardioprotection, respectively. Moreover, the expression of HIF-1α, HO-1, and vascular endothelial growth factor (VEGF) were enhanced after the activation of M3-mAChR, and the induction of HO-1 and VEGF was reversed by HIF-1α inhibitor YC-1.
  
  
  CONCLUSIONS
  These findings indicated that M(3)-mAChR upregulates HO-1 and VEGF expression likely through induction of HIF-1α, which at least partly underlies the cytoprotection of M(3)-mAChR activation in H9c2 cells.
authors.affiliation: Key Laboratory of Cardiovascular Medicine Research, Harbin Medical University, Ministry of Education, Harbin, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Hui
authors.forename: Yanli
authors.initials: Y
authors.lastname: Zhao
authors.forename: Ning
authors.initials: N
authors.lastname: Ma
authors.forename: Yahui
authors.initials: Y
authors.lastname: Peng
authors.forename: Zhenwei
authors.initials: Z
authors.lastname: Pan
authors.forename: Chaoxia
authors.initials: C
authors.lastname: Zou
authors.forename: Pengxia
authors.initials: P
authors.lastname: Zhang
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Du
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002217:Carbachol / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology; D018929:Cell Culture Techniques; D002460:Cell Line; D005047:Etoposide / Q000494:pharmacology; D006352:Heart Ventricles / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015151:Immunoblotting; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D043587:Receptor, Muscarinic M3 / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D002316:Cardiotonic Agents; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D043587:Receptor, Muscarinic M3; D042461:Vascular Endothelial Growth Factor A; C467498:vascular endothelial growth factor A, rat; D005047:Etoposide; D002217:Carbachol; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat