Apelin signaling antagonizes Ang II effects in mouse models of atherosclerosis
Open Access
- 1 September 2008
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 118 (10), 3343-3354
- https://doi.org/10.1172/jci34871
Abstract
Apelin and its cognate G protein–coupled receptor APJ constitute a signaling pathway with a positive inotropic effect on cardiac function and a vasodepressor function in the systemic circulation. The apelin-APJ pathway appears to have opposing physiological roles to the renin-angiotensin system. Here we investigated whether the apelin-APJ pathway can directly antagonize vascular disease-related Ang II actions. In ApoE-KO mice, exogenous Ang II induced atherosclerosis and abdominal aortic aneurysm formation; we found that coinfusion of apelin abrogated these effects. Similarly, apelin treatment rescued Ang II–mediated increases in neointimal formation and vascular remodeling in a vein graft model. NO has previously been implicated in the vasodepressor function of apelin; we found that apelin treatment increased NO bioavailability in ApoE-KO mice. Furthermore, infusion of an NO synthase inhibitor blocked the apelin-mediated decrease in atherosclerosis and aneurysm formation. In rat primary aortic smooth muscle cells, apelin inhibited Ang II–mediated transcriptional regulation of multiple targets as measured by reporter assays. In addition, we demonstrated by coimmunoprecipitation and fluorescence resonance energy transfer analysis that the Ang II and apelin receptors interacted physically. Taken together, these findings indicate that apelin signaling can block Ang II actions in vascular disease by increasing NO production and inhibiting Ang II cellular signaling.This publication has 57 references indexed in Scilit:
- In vivo genetic profiling and cellular localization of apelin reveals a hypoxia-sensitive, endothelial-centered pathway activated in ischemic heart failureAmerican Journal of Physiology-Heart and Circulatory Physiology, 2008
- Requirement of Apelin-Apelin Receptor System for Oxidative Stress-Linked AtherosclerosisThe American Journal of Pathology, 2007
- Direct effects of apelin on cardiomyocyte contractility and electrophysiologyBiochemical and Biophysical Research Communications, 2007
- Heterodimerization and surface localization of G protein coupled receptorsBiochemical Pharmacology, 2007
- Down-regulation of cardiac apelin system in hypertrophied and failing hearts: Possible role of angiotensin II–angiotensin type 1 receptor systemJournal of Molecular and Cellular Cardiology, 2006
- Angiotensin II and tumor necrosis factor-alpha upregulate survivin and Kruppel-like factor 5 in smooth muscle cells: Potential relevance to vein graft hyperplasiaSurgery, 2006
- Strain-Dependent Vascular Remodeling Phenotypes in Inbred MiceThe American Journal of Pathology, 2000
- Isolation and Characterization of a Novel Endogenous Peptide Ligand for the Human APJ ReceptorBiochemical and Biophysical Research Communications, 1998
- Spontaneous Hypercholesterolemia and Arterial Lesions in Mice Lacking Apolipoprotein EScience, 1992
- Generation of mice carrying a mutant apolipoprotein E gene inactivated by gene targeting in embryonic stem cells.Proceedings of the National Academy of Sciences of the United States of America, 1992