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

著者: Wang Wang, Mengcheng Shen, Conrad Fischer, Ratnadeep Basu, Saugata Hazra, Pierre Couvineau, Manish Paul, Faqi Wang, Sandra Toth, Doran Mix, Marko Poglitsch, Norma P. Gerard, Michel Bouvier, John C. Vederas, Josef Penninger, Zamaneh Kassiri, Gavin Y. Oudit - Proceedings of the National Academy of Sciences, PNAS 2019 被引用: 63

Significance Vascular diseases remain a major health burden, and AAAs lack effective medical therapy. We demonstrate a seminal role for APLN in AAA pathogenesis based on loss-of-function and gain-of-function approaches and included human vascular SMCs and AA tissue obtained from patients. We identified NEP as a dominant inactivating enzyme for native APLN-17. This allowed us to design and synthesize a stable and bioactive APLN analog resistant to NEP degradation that showed profound therapeutic effects against AAA. Our study clearly defines the APLN pathway as a central node in the pathogenesis of AAA and elucidate a therapeutic strategy of enhancing the APLN pathway by using a stable APLN analog to treat AAA.