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


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.
Zhong
JiuChang
J
Division of Cardiology, Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Alberta, T6G 2S2, Canada.
Basu
Ratnadeep
R
Guo
Danny
D
Chow
Fung L
FL
Byrns
Simon
S
Schuster
Manfred
M
Loibner
Hans
H
Wang
Xiu-hua
XH
Penninger
Josef M
JM
Kassiri
Zamaneh
Z
Oudit
Gavin Y
GY
D000804:Angiotensin II / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D016466:CHO Cells; D006332:Cardiomegaly / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D002478:Cells, Cultured; D000090602:Collagen Type I, alpha 1 Chain; D006224:Cricetinae; D003412:Cricetulus; D015536:Down-Regulation / Q000502:physiology*; D005355:Fibrosis; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology*; D007703:Peptidyl-Dipeptidase A / Q000008:administration & dosage / Q000172:deficiency* / Q000502:physiology; D011994:Recombinant Proteins / Q000008:administration & dosage
C000716128:Col1a1 protein, mouse; D000090602:Collagen Type I, alpha 1 Chain; D011994:Recombinant Proteins; D000804:Angiotensin II; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2