title: Identification of Amino Acid Residues in Angiotensin II Type 1 Receptor Sensing Mechanical Stretch and Function in Cardiomyocyte Hypertrophy.
abstract: OBJECTIVE
  Angiotensin II (AngII) type 1 receptor (AT1R) could be activated by mechanical stress without the involvement of AngII during the development of cardiac hypertrophy. We aimed to identify sensing sites of AT1R for activation by mechanical stretch.
  
  
  METHODS
  We constructed several site-directed mutations of AT1R (AT1R(K199Q), AT1R(L212F), AT1R(Q257A) and AT1R(C289A)), transfected them respectively into COS7 cells or angiotensinogen knockout cardiomyocytes (ATG(−/−)-CMs), and observed cellular events after mechanical stretch.
  
  
  RESULTS
  AngII-induced phosphorylation of ERKs and Jak2, and redistribution of Gαq11 in AT1R(WT)- COS7 or -ATG(−/−)-CMs were dramatically decreased in AT1R(K199Q)- or AT1R(Q257A)- COS7 cells or -ATG(−/−)- CMs, while those effects induced by mechanical stretch were greatly suppressed in COS7 cells or ATG(−/−)-CMs expressing AT1R(L212F), AT1R(Q257A) or AT1R(C289A) compared with these cells expressing AT1R(WT). AngII-induced hypertrophic responses (the increase in hypertrophic genes expression and cross-sectional area) in AT1R(WT)- ATG(−/−)-CMs were partly abolished in AT1R(K199Q)-ATG(−/−)- CMs or AT1R(Q257A) -ATG(−/−)-CMs, while these responses induced by mechanical stretch were greatly inhibited in ATG(−/−)-CMs overexpressing AT1R(L212F), AT1R(Q257A )or AT1R(C289A).
  
  
  CONCLUSIONS
  These results indicated that Leu212, Gln257 and Cys289 in AT1R are not only sensing sites for mechanical stretch but also functional amino residues for activation of the receptor and cardiomyocytes hypertrophy induced by mechanical stretch.
authors: Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital and Institutes of Biomedical Sciences, Fudan University, Shanghai, China.
authors: Guoliang
authors: G
authors: Jiang
authors: Hui
authors: H
authors: Gong
authors: Yuhong
authors: Y
authors: Niu
authors: Chunjie
authors: C
authors: Yang
authors: Shijun
authors: S
authors: Wang
authors: Zhidan
authors: Z
authors: Chen
authors: Yong
authors: Y
authors: Ye
authors: Ning
authors: N
authors: Zhou
authors: Guoping
authors: G
authors: Zhang
authors: Junbo
authors: J
authors: Ge
authors: Yunzeng
authors: Y
authors: Zou
mesh_terms: D000596:Amino Acids / Q000378:metabolism*; D000808:Angiotensinogen / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D019556:COS Cells; D006332:Cardiomegaly / Q000378:metabolism* / Q000503:physiopathology; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D053614:Janus Kinase 2 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000502:physiology*; D010766:Phosphorylation / Q000502:physiology; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D013314:Stress, Mechanical
chemical_list: D000596:Amino Acids; D044140:Receptor, Angiotensin, Type 1; D000808:Angiotensinogen; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2