Angiotensin-converting enzyme 2 suppresses pathological hypertrophy, myocardial fibrosis, and cardiac dysfunction

Circulation. 2010 Aug 17;122(7):717-28, 18 p following 728. doi: 10.1161/CIRCULATIONAHA.110.955369. Epub 2010 Aug 2.


Background: Angiotensin-converting enzyme 2 (ACE2) is a pleiotropic monocarboxypeptidase capable of metabolizing several peptide substrates. We hypothesized that ACE2 is a negative regulator of angiotensin II (Ang II)-mediated signaling and its adverse effects on the cardiovascular system.

Methods and results: Ang II infusion (1.5 mg x kg(-1) x d(-1)) for 14 days resulted in worsening cardiac fibrosis and pathological hypertrophy in ACE2 knockout (Ace2(-/y)) mice compared with wild-type (WT) mice. Daily treatment of Ang II-infused wild-type mice with recombinant human ACE2 (rhACE2; 2 mg x kg(-1) x d(-1) IP) blunted the hypertrophic response and expression of hypertrophy markers and reduced Ang II-induced superoxide production. Ang II-mediated myocardial fibrosis and expression of procollagen type I alpha 1, procollagen type III alpha 1, transforming growth factor-beta1, and fibronectin were also suppressed by rhACE2. Ang II-induced diastolic dysfunction was inhibited by rhACE2 in association with reduced plasma and myocardial Ang II and increased plasma Ang 1-7 levels. rhACE2 treatment inhibited Ang II-mediated activation of protein kinase C-alpha and protein kinase C-beta1 protein levels and phosphorylation of the extracellular signal-regulated 1/2, Janus kinase 2, and signal transducer and activator of transcription 3 signaling pathways in wild-type mice. A subpressor dose of Ang II (0.15 mg . kg(-1) . d(-1)) resulted in a milder phenotype that was strikingly attenuated by rhACE2 (2 mg x kg(-1) x d(-1) IP). In adult ventricular cardiomyocytes and cardiofibroblasts, Ang II-mediated superoxide generation, collagen production, and extracellular signal-regulated 1/2 signaling were inhibited by rhACE2 in an Ang 1-7-dependent manner. Importantly, rhACE2 partially prevented the development of dilated cardiomyopathy in pressure-overloaded wild-type mice.

Conclusions: Elevated Ang II induced hypertension, myocardial hypertrophy, fibrosis, and diastolic dysfunction, which were exacerbated by ACE2 deficiency, whereas rhACE2 attenuated Ang II- and pressure-overload-induced adverse myocardial remodeling. Hence, ACE2 is an important negative regulator of Ang II-induced heart disease and suppresses adverse myocardial remodeling.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / administration & dosage
  • Angiotensin II / antagonists & inhibitors
  • Angiotensin II / biosynthesis
  • Angiotensin-Converting Enzyme 2
  • Animals
  • CHO Cells
  • Cardiomegaly / enzymology*
  • Cardiomegaly / pathology
  • Cardiomegaly / physiopathology
  • Cardiomegaly / prevention & control*
  • Cells, Cultured
  • Collagen Type I, alpha 1 Chain
  • Cricetinae
  • Cricetulus
  • Down-Regulation / physiology*
  • Fibrosis
  • Humans
  • Hypertrophy, Left Ventricular / enzymology*
  • Hypertrophy, Left Ventricular / pathology
  • Hypertrophy, Left Ventricular / prevention & control*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocardium / enzymology*
  • Myocardium / pathology*
  • Peptidyl-Dipeptidase A / administration & dosage
  • Peptidyl-Dipeptidase A / deficiency*
  • Peptidyl-Dipeptidase A / physiology
  • Recombinant Proteins / administration & dosage


  • Col1a1 protein, mouse
  • Collagen Type I, alpha 1 Chain
  • Recombinant Proteins
  • Angiotensin II
  • Peptidyl-Dipeptidase A
  • ACE2 protein, human
  • Ace2 protein, mouse
  • Angiotensin-Converting Enzyme 2