Angiotensin (Ang) A is formed by the decarboxylation of the N terminal residue of AngII. The present study determined whether this one amino acid change impacted effects of AngII on abdominal aortic aneurysm (AAA) formation in mice. Computational analyses implicated that AngA had comparable binding affinity to both AngII type 1 and 2 receptors as AngII. To compare effects of these two octapeptides in vivo, male low-density lipoprotein receptor (Ldlr) or apolipoprotein E (Apoe) deficient mice were infused with either AngII or AngA (1 μg/kg/min) for 4 weeks. While AngII infusion induced AAA consistently in both mouse strains, the equivalent infusion rate of AngA did not lead to AAA formation. We also determined whether co-infusion of AngA would influence AngII-induced aortic aneurysm formation in male Apoe−/− mice. Co-infusion of the same infusion rate of AngII and AngA did not change AngII-induced AAA formation. Since it was reported that a 10-fold higher concentration of AngA elicited comparable vasoconstrictive responses as AngII, we compared a 10-fold higher rate (10 μg/kg/min) of AngA infusion into male Apoe−/− mice with AngII (1 μg/kg/min). This rate of AngA led to abdominal aortic dilation in three of ten mice, but no aortic rupture, whereas the 10-fold lower rate of AngII infusion led to abdominal aortic dilation or rupture in eight of ten mice. In conclusion, AngA, despite only being one amino acid different from AngII, has diminished effects on aortic aneurysmal formation, implicating that the first amino acid of AngII has important pathophysiological functions.
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The research work reported in this manuscript was supported by the National Basic Research Program of China [973 Program, grant number 2014CB965103 (to J.W.)], Grants from National Natural Science Foundation of China [grant number 81320108003, 31371498 (to J.W.)]; Grants from National Key Research and Development Program of China [grant number 81500876 (to Y.C.X.)]; and Grants from Natural Science Foundation of Zhejiang Province [grant number LQ16H020003 (to Y.C.X.)]. Ldlr−/− mouse study was supported by NIH grants of the United States [HL133723 and HL139748 (to A.D. and H.S.L.)].
Wang, Ya; Xu, Yinchuan; Wu, Congqing; Xia, Hongguang; Wang, Yingchao; Nan, Jinliang; Chen, Jinghai; Yu, Hong; Zhu, Wei; Shi, Peng; Daugherty, Alan; Lu, Hong S.; and Wang, Jian'an, "One Amino Acid Change of Angiotensin II Diminishes Its Effects on Abdominal Aortic Aneurysm" (2019). Saha Cardiovascular Research Center Faculty Publications. 43.