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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

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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 6

AT1R-independent effects of apelin on ACE2 induction.

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AT1R-independent effects of apelin on ACE2 induction.
(A–C) Heart functi...
(A–C) Heart function measurements. Representative M-mode echocardiography images (A) and measurements of percentage of FS (B) of TAC- or sham-treated wild-type and Agtr1a–/– mice receiving apelin-13 or vehicle for 2 weeks. (C and D) Reduction of cardiac hypertrophy in TAC-treated Agtr1a–/– mice by apelin-13. Macroscopic heart images (C) and heart weight to body weight ratios (D) of wild-type and Agtr1a–/– mice treated with apelin-13 or vehicle. n = 5–6 per group. Scale bars: 3 mm. (E and F) Real-time PCR analysis for mRNA expression of βMHC (E) and ACE2 (F) of TAC- or sham-treated wild-type and Agtr1a–/– mice receiving apelin-13 or vehicle for 2 weeks. (G) Western blot for ACE2 in total protein lysates from hearts of Agtr1a–/– mice treated with vehicle and apelin-13 under TAC. n = 8–11 per group. Right panel shows quantification of ACE2 protein expression normalized to GAPDH. All values represent mean ± SEM. *P < 0.05; **P < 0.01.

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