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Heterozygote loss of ACE2 is sufficient to increase the susceptibility to heart disease

Journal of Molecular Medicine volume 92, pages 847–858 (2014)Cite this article

Abstract

Angiotensin-converting enzyme 2 (ACE2) metabolizes Ang II into Ang 1–7 thereby negatively regulating the renin-angiotensin system. However, heart disease in humans and in animal models is associated with only a partial loss of ACE2. ACE2 is an X-linked gene; and as such, we tested the clinical relevance of a partial loss of ACE2 by using female ACE2+/+ (wildtype) and ACE2+/− (heterozygote) mice. Pressure overload in ACE2+/− mice resulted in greater LV dilation and worsening systolic and diastolic dysfunction. These changes were associated with increased myocardial fibrosis, hypertrophy, and upregulation of pathological gene expression. In response to Ang II infusion, there was increased NADPH oxidase activity and myocardial fibrosis resulting in the worsening of Ang II-induced diastolic dysfunction with a preserved systolic function. Ang II-mediated cellular effects in cultured adult ACE2+/− cardiomyocytes and cardiofibroblasts were exacerbated. Ang II-mediated pathological signaling worsened in ACE2+/− hearts characterized by an increase in the phosphorylation of ERK1/2 and JNK1/2 and STAT-3 pathways. The ACE2+/− mice showed an exacerbated pressor response with increased vascular fibrosis and stiffness. Vascular superoxide and nitrotyrosine levels were increased in ACE2+/− vessels consistent with increased vascular oxidative stress. These changes occurred with increased renal fibrosis and superoxide production. Partial heterozygote loss of ACE2 is sufficient to increase the susceptibility to heart disease secondary to pressure overload and Ang II infusion.

Key message

  • Heart disease in humans with idiopathic dilated cardiomyopathy is associated with a partial loss of ACE2.

  • Heterozygote female ACE2 mutant mice showed enhanced susceptibility to pressure overload-induced heart disease.

  • Heterozygote female ACE2 mutant mice showed enhanced susceptibility to Ang II-induced heart and vascular diseases.

  • Partial loss of ACE2 is sufficient to enhance the susceptibility to heart disease.

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Acknowledgments

Gavin Y. Oudit is a Clinician-Investigator of the Alberta Innovates – Health Solutions, Distinguish Clinician Scientist of the Heart and Stroke Foundation of Canada and Canadian Institutes of Health Research, and Canada Research Chair in Heart Failure. Vaibhav B. Patel is supported by Alberta Innovates - Health Solutions and Heart and Stroke Foundation of Canada Fellowship. Nirmal Parajuli is supported by Heart and Stroke Foundation of Canada Fellowship.

Conflict of Interest

None declared.

Funding

This work was supported by the Canadian Institutes of Health Research and Alberta Innovates – Health Solutions.

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Authors and Affiliations

  1. Division of Cardiology, Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, AB, T6G 2S2, Canada

    Wang Wang, Vaibhav B. Patel, Nirmal Parajuli, Zuocheng Wang, Tharmarajan Ramprasath & Gavin Y. Oudit

  2. Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, Canada

    Wang Wang, Vaibhav B. Patel, Nirmal Parajuli, Dong Fan, Ratnadeep Basu, Zuocheng Wang, Tharmarajan Ramprasath, Zamaneh Kassiri & Gavin Y. Oudit

  3. Department of Physiology, University of Alberta, Edmonton, Canada

    Wang Wang, Dong Fan, Ratnadeep Basu, Zamaneh Kassiri & Gavin Y. Oudit

  4. Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria

    Josef M. Penninger

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  1. Wang Wang
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  2. Vaibhav B. Patel
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Correspondence to Gavin Y. Oudit.

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Wang, W., Patel, V.B., Parajuli, N. et al. Heterozygote loss of ACE2 is sufficient to increase the susceptibility to heart disease. J Mol Med 92, 847–858 (2014). https://doi.org/10.1007/s00109-014-1149-y

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  • DOI: https://doi.org/10.1007/s00109-014-1149-y

Keywords

  • Renin-angiotensin system
  • Angiotensin-converting enzyme 2
  • NADPH oxidase
  • Heart failure
  • Sex