title: Arg972 Insulin receptor substrate-1 is associated with decreased serum angiotensin-converting enzyme 2 levels in acute myocardial infarction patients: in vivo and in vitro evidence.
abstract: BACKGROUND
  Activation of the renin-angiotensin system (RAS) plays a critical role in the pathophysiology of myocardial infarction (MI) and the development of heart failure. Both angiotensin-converting enzyme 2 (ACE2) and insulin/insulin receptor substrate-1 (IRS-1) show cardioprotective effects after acute MI. The Arg972 IRS-1 polymorphism is associated with diminished activity of insulin. In the present study, we explored the association among Arg972 IRS-1, acute MI, and serum levels of ACE2.
  
  
  METHODS
  A total of 711 subjects, including 351 subjects with first-time acute MI and 360 subjects without a history of MI were genotyped for Arg972 IRS-1 polymorphism. Serum levels of ACE2 and MI severity scores were determined. Primary human cardiomyocytes with overexpression of wild type IRS-1 or Arg972 IRS-1 or knockdown of endogenous IRS-1 were exposed to normoxia and hypoxia, and the expression levels of ACE2 were determined.
  
  
  RESULTS
  The serum ACE2 level was significantly increased in acute MI patients compared with that of non-MI controls. Compared with wild type IRS-1 carriers, Arg972 IRS-1 carriers exhibited decreased serum ACE2 levels and increased MI severity scores after MI. Our in vitro data demonstrate that impairment of insulin/IRS-1/PI3K signaling by overexpression of Arg972-IRS-1, knockdown of endogenous IRS-1, or PI3K inhibitor can abolish hypoxia-induced IRS-1-associated PI3K activity and ACE2 expression in human cardiomyocytes, which suggests a causal relationship between Arg972-IRS-1 and decreased serum ACE2 levels in acute MI patients. Our in vitro data also indicate that insulin/IRS-1/PI3K signaling is required for ACE2 expression in cardiomyocytes, and that hypoxia can enhance the induction effect of insulin/IRS-1/PI3K signaling on ACE2 expression in cardiomyocytes.
  
  
  CONCLUSIONS
  This study provides the first evidence of crosstalk between insulin/IRS-1/PI3K signaling and RAS after acute MI, thereby adding fresh insights into the pathophysiology and treatment of acute MI.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Xinmin
authors.initials: X
authors.lastname: Zhou
authors.forename: Fenglei
authors.initials: F
authors.lastname: Yu
authors.forename: Jianguo
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Thoracic and Cardiovascular Surgery, Second Xiangya Hospital, Central South University, 138 Renmin Road, Changsha, Hunan 410011, P,R, China. huwen327@yahoo.com.
authors.forename: Wen
authors.initials: W
authors.lastname: Hu
mesh_terms: D000328:Adult; D000368:Aged; D000085962:Angiotensin-Converting Enzyme 2; D016022:Case-Control Studies; D002478:Cells, Cultured; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D000860:Hypoxia / Q000201:enzymology*; D007328:Insulin / Q000502:physiology*; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000201:enzymology / Q000235:genetics*; D009206:Myocardium / Q000201:enzymology; D032383:Myocytes, Cardiac / Q000201:enzymology*; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide; D012084:Renin-Angiotensin System / Q000502:physiology; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000502:physiology
chemical_list: D000085962:Angiotensin-Converting Enzyme 2; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D007703:Peptidyl-Dipeptidase A; D019869:Phosphatidylinositol 3-Kinases; C526292:IRS1 protein, human; C000705307:ACE2 protein, human