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 EF1α (elongation factor 1α) 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 TGFβ (transforming growth factor β), 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.
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October 2007
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Research Article|
September 12 2007
ACE2 overexpression inhibits hypoxia-induced collagen production by cardiac fibroblasts
Justin L. Grobe;
Justin L. Grobe
1
*Department of Pharmacodynamics, University of Florida, Gainesville, FL 32610, U.S.A.
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Shant Der Sarkissian;
Shant Der Sarkissian
†Department of Physiology and Functional Genomics, University of Florida, Gainesville, FL 32610, U.S.A.
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Jillian M. Stewart;
Jillian M. Stewart
*Department of Pharmacodynamics, University of Florida, Gainesville, FL 32610, U.S.A.
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J. Gary Meszaros;
J. Gary Meszaros
‡Department of Physiology and Pharmacology, Northeastern Ohio Universities College of Medicine, Rootstown, OH 44272, U.S.A.
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Mohan K. Raizada;
Mohan K. Raizada
†Department of Physiology and Functional Genomics, University of Florida, Gainesville, FL 32610, U.S.A.
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Michael J. Katovich
*Department of Pharmacodynamics, University of Florida, Gainesville, FL 32610, U.S.A.
Correspondence: Professor Michael J. Katovich (email katovich@cop.ufl.edu).
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Publisher: Portland Press Ltd
Received:
May 14 2007
Accepted:
June 29 2007
Accepted Manuscript online:
June 29 2007
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2007 Biochemical Society
2007
Clin Sci (Lond) (2007) 113 (8): 357–364.
Article history
Received:
May 14 2007
Accepted:
June 29 2007
Accepted Manuscript online:
June 29 2007
Citation
Justin L. Grobe, Shant Der Sarkissian, Jillian M. Stewart, J. Gary Meszaros, Mohan K. Raizada, Michael J. Katovich; ACE2 overexpression inhibits hypoxia-induced collagen production by cardiac fibroblasts. Clin Sci (Lond) 1 October 2007; 113 (8): 357–364. doi: https://doi.org/10.1042/CS20070160
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