ACE2 overexpression inhibits hypoxia-induced collagen production by cardiac fibroblasts.
Cardiac remodelling is a key risk factor for the development of heart failure in the chronic phase following myocardial infarction. Our previous studies have shown an anti-remodelling role of ACE2 (angiotensin-converting enzyme 2) in vivo during hypertension and that these protective effects are mediated through increased circulating levels of Ang-(1-7) [angiotensin-(1-7)]. In the present study, we have demonstrated that cardiac myocytes have modest ACE2 activity, whereas cardiac fibroblasts do not exhibit any endogenous activity. As fibroblasts are the major cell type found in an infarct zone following a myocardial infarction, we examined the effects of ACE2 gene delivery to cultured cardiac fibroblasts after acute hypoxic exposure. Cardiac fibroblasts from 5-day-old Sprague-Dawley rat hearts were grown to confluence and transduced with a lentiviral vector containing murine ACE2 cDNA under transcriptional control by the EF1alpha (elongation factor 1alpha) promoter (lenti-ACE2). Transduction of fibroblasts with lenti-ACE2 resulted in a viral dose-dependent increase in ACE2 activity. This was associated with a significant attenuation of both basal and hypoxia/re-oxygenation-induced collagen production by the fibroblasts. Cytokine production, specifically TGFbeta (transforming growth factor beta), by these cells was also significantly attenuated by ACE2 expression. Collectively, these results indicate that: (i) endogenous ACE2 activity is observed in cardiac myocytes, but not in cardiac fibroblasts; (ii) ACE2 overexpression in the cardiac fibroblast attenuates collagen production; and (iii) this prevention is probably mediated by decreased expression of cytokines. We conclude that ACE2 expression, limited to cardiac fibroblasts, may represent a novel paradigm for in vivo therapy following acute ischaemia.
Grobe
Justin L
JL
Department of Pharmacodynamics, University of Florida, Gainesville, FL 32610, USA.
Der Sarkissian
Shant
S
Stewart
Jillian M
JM
Meszaros
J Gary
JG
Raizada
Mohan K
MK
Katovich
Michael J
MJ
D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology; D002478:Cells, Cultured; D003094:Collagen / Q000096:biosynthesis*; D005347:Fibroblasts / Q000378:metabolism*; D005822:Genetic Vectors; D016086:Lentivirus / Q000235:genetics; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014161:Transduction, Genetic; D016212:Transforming Growth Factor beta / Q000378:metabolism
D016212:Transforming Growth Factor beta; D003094:Collagen; D007703:Peptidyl-Dipeptidase A; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2