Apelin is a positive regulator of ACE2 in failing hearts
Teruki Sato, … , Yumiko Imai, Keiji Kuba
Teruki Sato, … , Yumiko Imai, Keiji Kuba
Published November 1, 2013
Citation Information: J Clin Invest. 2013;123(12):5203-5211. https://doi.org/10.1172/JCI69608.
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Research Article Cardiology

Apelin is a positive regulator of ACE2 in failing hearts

Abstract

Angiotensin converting enzyme 2 (ACE2) is a negative regulator of the renin-angiotensin system (RAS), catalyzing the conversion of Angiotensin II to Angiotensin 1-7. Apelin is a second catalytic substrate for ACE2 and functions as an inotropic and cardioprotective peptide. While an antagonistic relationship between the RAS and apelin has been proposed, such functional interplay remains elusive. Here we found that ACE2 was downregulated in apelin-deficient mice. Pharmacological or genetic inhibition of angiotensin II type 1 receptor (AT1R) rescued the impaired contractility and hypertrophy of apelin mutant mice, which was accompanied by restored ACE2 levels. Importantly, treatment with angiotensin 1-7 rescued hypertrophy and heart dysfunctions of apelin-knockout mice. Moreover, apelin, via activation of its receptor, APJ, increased ACE2 promoter activity in vitro and upregulated ACE2 expression in failing hearts in vivo. Apelin treatment also increased cardiac contractility and ACE2 levels in AT1R-deficient mice. These data demonstrate that ACE2 couples the RAS to the apelin system, adding a conceptual framework for the apelin-ACE2–angiotensin 1-7 axis as a therapeutic target for cardiovascular diseases.

Authors

Teruki Sato, Takashi Suzuki, Hiroyuki Watanabe, Ayumi Kadowaki, Akiyoshi Fukamizu, Peter P. Liu, Akinori Kimura, Hiroshi Ito, Josef M. Penninger, Yumiko Imai, Keiji Kuba

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Figure 5

Apelin upregulates ACE2 expression in vivo and in vitro.

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Apelin upregulates ACE2 expression in vivo and in vitro. (A) Western blo...
(A) Western blot for ACE2 in the hearts of mice infused with apelin-13 or apelin-12. Hearts were harvested after 2 weeks of apelin peptide infusions. Bar graphs show quantifications (n = 4–6 per group). (B) ACE2 expression in primary cardiomyocytes isolated from wild-type mice treated with either vehicle or apelin-13 peptides (1 μM) for 24 hours. (C) ACE2 promoter assay using the luciferase reporter plasmids ACE2 (–1119/+103)-luc, ACE2 (–252/+103)-luc, ACE2 (–202/+103)-luc, or ACE2 (-230/+1)-luc in combination with APJ expression vectors in Vero E6 cells. Cells were either left untreated or treated with 1 μM apelin-13 peptide (apelin-13). (D) Dose dependency of apelin on ACE2 promoter activation in Vero E6 cells. (E) Effects of AT1R expression on apelin-induced ACE2 promoter (–252/+103) activity in HEK293T cells transfected with control mock vectors (Mock), APJ expression vectors (APJ), or a combination of APJ and AT1R vectors (APJ + AT1R) and treated with or without apelin-13. n = 3 per group in at least 2 independent experiments. All values represent mean ± SEM. *P < 0.05; **P < 0.01.