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Proc Natl Acad Sci U S A. 2019 Jun 25;116(26):13006-13015. doi: 10.1073/pnas.1900152116. Epub 2019 Jun 12.

Apelin protects against abdominal aortic aneurysm and the therapeutic role of neutral endopeptidase resistant apelin analogs.

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Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, AB T6G 2G3, Canada.
Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, AB T6G 2J2, Canada.
Department of Physiology, University of Alberta, Edmonton, AB T6G 2R7, Canada.
Department of Chemistry, University of Alberta, Edmonton, AB T6G 2N4, Canada.
Department of Biotechnology, Indian Institute of Technology, 247667 Roorkee, Uttarakhand, India.
Centre for Nanotechnology, Indian Institute of Technology, 247667 Roorkee, Uttarakhand, India.
Department of Biochemistry and Molecular Medicine, Faculty of Medicine, University of Montreal, Montreal, QC H3C 3J7, Canada.
Department of Biotechnology, North Orissa University, 757003 Baripada, Odisha, India.
Division of Vascular Surgery, University of Rochester, Rochester, NY 14642.
Attoquant Diagnostics, 1030 Vienna, Austria.
Boston Children's Hospital, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115.
Department of Medical Genetics, Life Sciences Institute, University of British Columbia, Vancouver, BC V6H 3N1, Canada.
Division of Cardiology, Department of Medicine, University of Alberta, Edmonton, AB T6G 2G3, Canada;


Abdominal aortic aneurysm (AAA) remains the second most frequent vascular disease with high mortality but has no approved medical therapy. We investigated the direct role of apelin (APLN) in AAA and identified a unique approach to enhance APLN action as a therapeutic intervention for this disease. Loss of APLN potentiated angiotensin II (Ang II)-induced AAA formation, aortic rupture, and reduced survival. Formation of AAA was driven by increased smooth muscle cell (SMC) apoptosis and oxidative stress in Apln -/y aorta and in APLN-deficient cultured murine and human aortic SMCs. Ang II-induced myogenic response and hypertension were greater in Apln -/y mice, however, an equivalent hypertension induced by phenylephrine, an α-adrenergic agonist, did not cause AAA or rupture in Apln -/y mice. We further identified Ang converting enzyme 2 (ACE2), the major negative regulator of the renin-Ang system (RAS), as an important target of APLN action in the vasculature. Using a combination of genetic, pharmacological, and modeling approaches, we identified neutral endopeptidase (NEP) that is up-regulated in human AAA tissue as a major enzyme that metabolizes and inactivates APLN-17 peptide. We designed and synthesized a potent APLN-17 analog, APLN-NMeLeu9-A2, that is resistant to NEP cleavage. This stable APLN analog ameliorated Ang II-mediated adverse aortic remodeling and AAA formation in an established model of AAA, high-fat diet (HFD) in Ldlr -/- mice. Our findings define a critical role of APLN in AAA formation through induction of ACE2 and protection of vascular SMCs, whereas stable APLN analogs provide an effective therapy for vascular diseases.


ACE2; aneurysm; angiotensin II; apelin; neutral endopeptidase

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