101. Angiotensin-Converting Enzyme 2 Metabolizes and Partially Inactivates Pyr-Apelin-13 and Apelin-17: Physiological Effects in the Cardiovascular System
- Author
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Maikel Farhan, Catherine Llorens-Cortes, Tyler McDonald, Brent A. McLean, John C. Vederas, Allan G. Murray, Wang Wang, Saugata Hazra, Manish Paul, Shaun M. K. McKinnie, and Gavin Y. Oudit
- Subjects
0301 basic medicine ,medicine.medical_specialty ,Cardiotonic Agents ,Myocardial Reperfusion Injury ,Pharmacology ,Peptidyl-Dipeptidase A ,Cardiovascular System ,Nitric oxide ,03 medical and health sciences ,chemistry.chemical_compound ,Mice ,Adipokines ,Internal medicine ,Drug Discovery ,Internal Medicine ,medicine ,Animals ,Humans ,Computer Simulation ,Peptide Metabolism ,chemistry.chemical_classification ,fungi ,Protective Factors ,Apelin ,030104 developmental biology ,Endocrinology ,Enzyme ,chemistry ,Vasoconstriction ,Angiotensin-converting enzyme 2 ,Knockout mouse ,Intercellular Signaling Peptides and Proteins ,Angiotensin-Converting Enzyme 2 ,Signal transduction ,hormones, hormone substitutes, and hormone antagonists ,Function (biology) ,Half-Life ,Protein Binding - Abstract
Apelin peptides mediate beneficial effects on the cardiovascular system and are being targeted as potential new drugs. However, apelin peptides have extremely short biological half-lives, and improved understanding of apelin peptide metabolism may lead to the discovery of biologically stable analogues with therapeutic potential. We examined the ability of angiotensin-converting enzyme 2 (ACE2) to cleave and inactivate pyr-apelin 13 and apelin 17, the dominant apelin peptides. Computer-assisted modeling shows a conserved binding of pyr-apelin 13 and apelin 17 to the ACE2 catalytic site. In ACE2 knockout mice, hypotensive action of pyr-apelin 13 and apelin 17 was potentiated, with a corresponding greater elevation in plasma apelin levels. Similarly, pharmacological inhibition of ACE2 potentiated the vasodepressor action of apelin peptides. Biochemical analysis confirmed that recombinant human ACE2 can cleave pyr-apelin 13 and apelin 17 efficiently, and apelin peptides are degraded slower in ACE2-deficient plasma. The biological relevance of ACE2-mediated proteolytic processing of apelin peptides was further supported by the reduced potency of pyr-apelin 12 and apelin 16 on the activation of signaling pathways and nitric oxide production from endothelial cells. Importantly, although pyr-apelin 13 and apelin 17 rescued contractile function in a myocardial ischemia–reperfusion model, ACE2 cleavage products, pyr-apelin 12 and 16, were devoid of these cardioprotective effects. We designed and synthesized active apelin analogues that were resistant to ACE2-mediated degradation, thereby confirming that stable apelin analogues can be designed as potential drugs. We conclude that ACE2 represents a major negative regulator of apelin action in the vasculature and heart.
- Published
- 2015