TY - JOUR
T1 - Onset of experimental severe cardiac fibrosis is mediated by overexpression of Angiotensin-converting enzyme 2
AU - Masson, Rachel
AU - Nicklin, Stuart A.
AU - Craig, Margaret Anne
AU - Mcbride, Martin
AU - Gilday, Kirsten
AU - Gregorevic, Paul
AU - Allen, James M.
AU - Chamberlain, Jeffrey S.
AU - Smith, Godfrey
AU - Graham, Delyth
AU - Dominiczak, Anna F.
AU - Napoli, Claudio
AU - Baker, Andrew H.
PY - 2009/4
Y1 - 2009/4
N2 - 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. {Hypertension. 2009;53:694-700.)
AB - 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. {Hypertension. 2009;53:694-700.)
KW - Ace2
KW - Adeno-associated virus
KW - Gene delivery
KW - Hypertension
KW - Myocardium
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U2 - 10.1161/HYPERTENSIONAHA.108.122333
DO - 10.1161/HYPERTENSIONAHA.108.122333
M3 - Article
C2 - 19221212
AN - SCOPUS:64849108788
VL - 53
SP - 694
EP - 700
JO - Hypertension
JF - Hypertension
SN - 0194-911X
IS - 4
ER -