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

Cardiovasc Diabetol. 2013 Oct 17:12:151. doi: 10.1186/1475-2840-12-151.


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.

MeSH terms

  • Adult
  • Aged
  • Angiotensin-Converting Enzyme 2
  • Case-Control Studies
  • Cells, Cultured
  • Female
  • Genetic Predisposition to Disease
  • Genotype
  • Humans
  • Hypoxia / enzymology*
  • Insulin / physiology*
  • Insulin Receptor Substrate Proteins / genetics*
  • Male
  • Middle Aged
  • Myocardial Infarction / enzymology
  • Myocardial Infarction / genetics*
  • Myocardium / enzymology
  • Myocytes, Cardiac / enzymology*
  • Peptidyl-Dipeptidase A / metabolism*
  • Phosphatidylinositol 3-Kinases / physiology*
  • Polymorphism, Single Nucleotide
  • Renin-Angiotensin System / physiology
  • Severity of Illness Index
  • Signal Transduction / physiology


  • IRS1 protein, human
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Peptidyl-Dipeptidase A
  • ACE2 protein, human
  • Angiotensin-Converting Enzyme 2