title: Upregulation of M₃ muscarinic receptor inhibits cardiac hypertrophy induced by angiotensin II.
abstract: BACKGROUND
  M₃ muscarinic acetylcholine receptor (M₃-mAChR) is stably expressed in the myocardium, but its pathophysiological role remains largely undefined. This study aimed to investigate the role of M₃-mAChR in cardiac hypertrophy induced by angiotensin II (Ang II) and elucidate the underlying mechanisms.
  
  
  METHODS
  Cardiac-specific M₃-mAChR overexpression transgenic (TG) mice and rat H9c2 cardiomyoblasts with ectopic expression of M₃-mAChR were established. Models of cardiac hypertrophy were induced by transverse aortic constriction (TAC) or Ang II infusion in the mice in vivo, and by isoproterenol (ISO) or Ang II treatment of H9c2 cells in vitro. Cardiac hypertrophy was evaluated by electrocardiography (ECG) measurement, hemodynamic measurement and histological analysis. mRNA and protein expression were detected by real-time RT-PCR and Western blot analysis.
  
  
  RESULTS
  M₃-mAChR was upregulated in hypertrophic heart, while M₂-mAChR expression did not change significantly. M₃-mAChR overexpression significantly attenuated the increased expression of atrial natriuretic peptide and β-myosin heavy chain induced by Ang II both in vivo and in vitro. In addition, M₃-mAChR overexpression downregulated AT1 receptor expression and inhibited the activation of MAPK signaling in the heart.
  
  
  CONCLUSIONS
  The upregulation of M₃-mAChR during myocardial hypertrophy could relieve the hypertrophic response provoked by Ang II, and the mechanism may involve the inhibition of MAPK signaling through the downregulation of AT1 receptor.
authors.affiliation: Department of Pharmacology (State-Province key lab of China), Harbin Medical University, Heilongjiang 150081, China. yjlu86@gmail.com.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: Shu
authors.initials: S
authors.lastname: Wang
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.forename: Haoxin
authors.initials: H
authors.lastname: Song
authors.forename: Hongmei
authors.initials: H
authors.lastname: Han
authors.forename: Pengzhou
authors.initials: P
authors.lastname: Hang
authors.forename: Yanan
authors.initials: Y
authors.lastname: Jiang
authors.forename: Lanlan
authors.initials: L
authors.lastname: Wei
authors.forename: Rong
authors.initials: R
authors.lastname: Huo
authors.forename: Lihua
authors.initials: L
authors.lastname: Sun
authors.forename: Xu
authors.initials: X
authors.lastname: Gao
authors.forename: Yanjie
authors.initials: Y
authors.lastname: Lu
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Du
mesh_terms: D000804:Angiotensin II / Q000008:administration & dosage; D000818:Animals; D001794:Blood Pressure; D001835:Body Weight; D006332:Cardiomegaly / Q000139:chemically induced / Q000201:enzymology / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D015536:Down-Regulation; D004789:Enzyme Activation; D006339:Heart Rate; D020935:MAP Kinase Signaling System; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D009928:Organ Specificity; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D043587:Receptor, Muscarinic M3 / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D044140:Receptor, Angiotensin, Type 1; D043587:Receptor, Muscarinic M3; D000804:Angiotensin II
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