Affiliation:
1. From the Division of Medical Genetics, Department of Internal Medicine, The University of Texas Health Science Center at Houston (Z.Z., A.M.P., S.W., A.J., J.C., P.Z., E.A., C.S.K., D.M.M.)
2. Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, People’s Republic of China (Z.Z.).
Abstract
Objective—
Pharmacological inhibition of the AT1R (angiotensin II type 1 receptor) with losartan can attenuate ascending aortic remodeling induced by transverse aortic constriction (TAC). In this study, we investigated the role of the AT2R (angiotensin II type 2 receptor) and MasR (Mas receptor) in TAC-induced ascending aortic dilation and remodeling.
Approach and Results—
Wild-type C57BL/6J mice were subjected to sham or TAC surgeries in the presence and absence of various drugs. Aortic diameters were assessed by echocardiography, central blood pressure was measured in the ascending aorta 2 weeks post-operation, and histology and gene expression analyses completed. An angiotensin-converting enzyme inhibitor, captopril, decreased systolic blood pressure to the same level as losartan but did not attenuate aortic dilation, adventitial inflammation, medial collagen deposition, elastin breakage, or
Mmp9
(matrix metalloproteinase-9) expression when compared with TAC mice. In contrast, co-administration of captopril with an AT2R agonist, compound 21, attenuated aortic dilation, medial collagen content, elastin breaks, and
Mmp9
expression, whereas co-administration of captopril with a MasR agonist (AVE0991) did not reverse aortic dilation and led to aberrant aortic remodeling. An AT2R antagonist, PD123319, reversed the protective effects of losartan in TAC mice. Treatment with compound 21 alone showed no effect on TAC-induced aortic enlargement, blood pressure, elastin breakage, or
Mmp9
expression.
Conclusions—
Our data indicate that when AT1R signaling is blocked, AT2R activation is a key modulator to prevent aortic dilation that occurs with TAC. These data suggest that angiotensin-converting enzyme inhibitor may not be as effective as losartan for slowing aneurysm growth because losartan requires intact AT2R signaling to prevent aortic enlargement.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine
Cited by
13 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献