Onset of experimental severe cardiac fibrosis is mediated by overexpression of Angiotensin-converting enzyme 2.
Angiotensin-converting enzyme (ACE) 2 is a recently identified homologue of ACE. There is great interest in the therapeutic benefit for ACE2 overexpression in the heart. However, the role of ACE2 in the regulation of cardiac structure and function, as well as maintenance of systemic blood pressure, remains poorly understood. In cell culture, ACE2 overexpression led to markedly increased myocyte volume, assessed in primary rabbit myocytes. To assess ACE2 function in vivo, we used a recombinant adeno-associated virus 6 delivery system to provide 11-week overexpression of ACE2 in the myocardium of stroke-prone spontaneously hypertensive rats. ACE2, as well as the ACE inhibitor enalapril, significantly reduced systolic blood pressure. However, in the heart, ACE2 overexpression resulted in cardiac fibrosis, as assessed by histological analysis with concomitant deficits in ejection fraction and fractional shortening measured by echocardiography. Furthermore, global gene expression profiling demonstrated the activation of profibrotic pathways in the heart mediated by ACE2 gene delivery. This study demonstrates that sustained overexpression of ACE2 in the heart in vivo leads to the onset of severe fibrosis.
Masson
Rachel
R
BHF GCRC, University of Glasgow, 126 University Place, Glasgow, G12 8TA United Kingdom.
Nicklin
Stuart A
SA
Craig
Margaret Anne
MA
McBride
Martin
M
Gilday
Kirsten
K
Gregorevic
Paul
P
Allen
James M
JM
Chamberlain
Jeffrey S
JS
Smith
Godfrey
G
Graham
Delyth
D
Dominiczak
Anna F
AF
Napoli
Claudio
C
Baker
Andrew H
AH
D000085962:Angiotensin-Converting Enzyme 2; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004656:Enalapril / Q000494:pharmacology; D005355:Fibrosis; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic; D018014:Gene Transfer Techniques; D006331:Heart Diseases / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology*; D006973:Hypertension / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D008297:Male; D032383:Myocytes, Cardiac / Q000473:pathology; D007703:Peptidyl-Dipeptidase A / Q000235:genetics*; D011134:Polysaccharides; D051381:Rats; D011918:Rats, Inbred SHR; D012720:Severity of Illness Index; D014161:Transduction, Genetic; D014463:Ultrasonography
D000806:Angiotensin-Converting Enzyme Inhibitors; D011134:Polysaccharides; D004656:Enalapril; C040642:SHU 454; D007703:Peptidyl-Dipeptidase A; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2