Local and systemic AngII (angiotensin II) levels are regulated by ACE2 (angiotensin-converting enzyme 2), which is reduced in diabetic tissues. In the present study, we examine the effect of ACE2 deficiency on the early cardiac and vascular changes associated with experimental diabetes. Streptozotocin diabetes was induced in male C57BL6 mice and Ace2-KO (knockout) mice, and markers of RAS (renin–angiotensin system) activity, cardiac function and injury were assessed after 10 weeks. In a second protocol, diabetes was induced in male ApoE (apolipoprotein E)-KO mice and ApoE/Ace2-double-KO mice, and plaque accumulation and markers of atherogenesis assessed after 20 weeks. The induction of diabetes in wild-type mice led to reduced ACE2 expression and activity in the heart, elevated circulating AngII levels and reduced cardiac Ang-(1–7) [angiotensin-(1–7)] levels. This was associated structurally with thinning of the LV (left ventricular) wall and mild ventricular dilatation, and histologically with increased cardiomyocyte apoptosis on TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling) staining and compensatory hypertrophy denoted by an increased cardiomyocyte cross-sectional area. By contrast Ace2-KO mice failed to increase circulating AngII concentration, experienced a paradoxical fall in cardiac AngII levels and no change in Ang-(1–7) following the onset of diabetes. At the same time the major phenotypic differences between Ace2-deficient and Ace2-replete mice with respect to BP (blood pressure) and cardiac hypertrophy were eliminated following the induction of diabetes. Consistent with findings in the heart, the accelerated atherosclerosis that was observed in diabetic ApoE-KO mice was not seen in diabetic ApoE/Ace2-KO mice, which experienced no further increase in plaque accumulation or expression in key adhesion molecules beyond that seen in ApoE/Ace2-KO mice. These results point to the potential role of ACE2 deficiency in regulating the tissue and circulating levels of AngII and their sequelae in the context of diabetes, as well as the preservation or augmentation of ACE2 expression or activity as a potential therapeutic target for the prevention of CVD (cardiovascular disease) in diabetes.
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Research Article|
July 03 2012
Interaction of diabetes and ACE2 in the pathogenesis of cardiovascular disease in experimental diabetes
Chris Tikellis;
Chris Tikellis
1Baker IDI Heart and Diabetes Institute, PO Box 6492, St Kilda Central, Melbourne 8008, Australia
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Raelene Pickering;
Raelene Pickering
1Baker IDI Heart and Diabetes Institute, PO Box 6492, St Kilda Central, Melbourne 8008, Australia
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Despina Tsorotes;
Despina Tsorotes
1Baker IDI Heart and Diabetes Institute, PO Box 6492, St Kilda Central, Melbourne 8008, Australia
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Xiao-Jun Du;
Xiao-Jun Du
1Baker IDI Heart and Diabetes Institute, PO Box 6492, St Kilda Central, Melbourne 8008, Australia
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Helen Kiriazis;
Helen Kiriazis
1Baker IDI Heart and Diabetes Institute, PO Box 6492, St Kilda Central, Melbourne 8008, Australia
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Thu-Phuc Nguyen-Huu;
Thu-Phuc Nguyen-Huu
1Baker IDI Heart and Diabetes Institute, PO Box 6492, St Kilda Central, Melbourne 8008, Australia
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Geoffrey A. Head;
Geoffrey A. Head
1Baker IDI Heart and Diabetes Institute, PO Box 6492, St Kilda Central, Melbourne 8008, Australia
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Mark E. Cooper;
Mark E. Cooper
1Baker IDI Heart and Diabetes Institute, PO Box 6492, St Kilda Central, Melbourne 8008, Australia
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Merlin C. Thomas
1Baker IDI Heart and Diabetes Institute, PO Box 6492, St Kilda Central, Melbourne 8008, Australia
Correspondence: Professor Merlin Thomas (email Merlin.Thomas@bakeridi.edu.au).
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Publisher: Portland Press Ltd
Received:
December 19 2011
Revision Received:
May 22 2012
Accepted:
May 23 2012
Accepted Manuscript online:
May 23 2012
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© The Authors Journal compilation © 2012 Biochemical Society
2012
Clin Sci (Lond) (2012) 123 (8): 519–529.
Article history
Received:
December 19 2011
Revision Received:
May 22 2012
Accepted:
May 23 2012
Accepted Manuscript online:
May 23 2012
Citation
Chris Tikellis, Raelene Pickering, Despina Tsorotes, Xiao-Jun Du, Helen Kiriazis, Thu-Phuc Nguyen-Huu, Geoffrey A. Head, Mark E. Cooper, Merlin C. Thomas; Interaction of diabetes and ACE2 in the pathogenesis of cardiovascular disease in experimental diabetes. Clin Sci (Lond) 1 October 2012; 123 (8): 519–529. doi: https://doi.org/10.1042/CS20110668
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