title: 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.forename: Teruki
authors.initials: T
authors.lastname: Sato
authors.forename: Takashi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Watanabe
authors.forename: Ayumi
authors.initials: A
authors.lastname: Kadowaki
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Fukamizu
authors.forename: Peter P
authors.initials: PP
authors.lastname: Liu
authors.forename: Akinori
authors.initials: A
authors.lastname: Kimura
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ito
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Imai
authors.forename: Keiji
authors.initials: K
authors.lastname: Kuba
mesh_terms: D054392:Adipokines; D000803:Angiotensin I / Q000096:biosynthesis / Q000627:therapeutic use; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology / Q000627:therapeutic use; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D000073861:Apelin; D000075244:Apelin Receptors; D025461:Feedback, Physiological; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006333:Heart Failure / Q000188:drug therapy / Q000503:physiopathology*; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000187:drug effects; D010446:Peptide Fragments / Q000096:biosynthesis / Q000627:therapeutic use; D007703:Peptidyl-Dipeptidase A / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic; D044140:Receptor, Angiotensin, Type 1 / Q000172:deficiency; D043562:Receptors, G-Protein-Coupled / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D018631:ras Proteins / Q000502:physiology
chemical_list: D054392:Adipokines; C544066:Agtr1a protein, mouse; D047228:Angiotensin II Type 1 Receptor Blockers; D000073861:Apelin; D000075244:Apelin Receptors; C402826:Apln protein, mouse; C491285:Aplnr protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D010446:Peptide Fragments; D044140:Receptor, Angiotensin, Type 1; D043562:Receptors, G-Protein-Coupled; D011993:Recombinant Fusion Proteins; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; D018631:ras Proteins; C118790:angiotensin I (1-7)