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Angiotensin-converting enzyme 2 is an essential regulator of heart function

Abstract

Cardiovascular diseases are predicted to be the most common cause of death worldwide by 2020. Here we show that angiotensin-converting enzyme 2 (ace2) maps to a defined quantitative trait locus (QTL) on the X chromosome in three different rat models of hypertension. In all hypertensive rat strains, ACE2 messenger RNA and protein expression were markedly reduced, suggesting that ace2 is a candidate gene for this QTL. Targeted disruption of ACE2 in mice results in a severe cardiac contractility defect, increased angiotensin II levels, and upregulation of hypoxia-induced genes in the heart. Genetic ablation of ACE on an ACE2 mutant background completely rescues the cardiac phenotype. But disruption of ACER, a Drosophila ACE2 homologue, results in a severe defect of heart morphogenesis. These genetic data for ACE2 show that it is an essential regulator of heart function in vivo.

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Figure 1: Association of ACE2 and hypertension in the rat.
Figure 2: ACE2-deficient mice.
Figure 3: Loss of ACE2 results in severe contractile dysfunction.
Figure 4: Upregulation of hypoxia markers and increased angiotensin II levels in the absence of ACE2.
Figure 5: ACE/ACE2 double mutant mice do not develop cardiac dysfunction.
Figure 6: Expression of heart progenitor markers in Drosophila ACER mutant embryos.

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Acknowledgements

We thank D. Ganten for supplying us with tissue from SHRSP rats. Eve and Tin antibodies were a gift from M. Frasch. We acknowledge the Samuel Lunenfeld Research Institute's CMHD Mouse Physiology Facility for their technical screening services. This study was supported by Amgen and by grants from the Israel Science Foundation and the German–Israeli Foundation for Scientific Research and Development to C.Y. and Y.Y. J.M.P. holds a Canadian Research Chair in Cell Biology. M.A.C. is supported in part by a Canadian Institutes of Health Research fellowship.

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Correspondence to Josef M. Penninger.

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Crackower, M., Sarao, R., Oudit, G. et al. Angiotensin-converting enzyme 2 is an essential regulator of heart function. Nature 417, 822–828 (2002). https://doi.org/10.1038/nature00786

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