Apelin signaling antagonizes Ang II effects in mouse models of atherosclerosis
Hyung J. Chun, … , Euan A. Ashley, Thomas Quertermous
Hyung J. Chun, … , Euan A. Ashley, Thomas Quertermous
Published October 1, 2008; First published September 2, 2008
Citation Information: J Clin Invest. 2008;118(10):3343-3354. https://doi.org/10.1172/JCI34871.
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Research Article Cardiology

Apelin signaling antagonizes Ang II effects in mouse models of atherosclerosis

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.

Authors

Hyung J. Chun, Ziad A. Ali, Yoko Kojima, Ramendra K. Kundu, Ahmad Y. Sheikh, Rani Agrawal, Lixin Zheng, Nicholas J. Leeper, Nathan E. Pearl, Andrew J. Patterson, Joshua P. Anderson, Philip S. Tsao, Michael J. Lenardo, Euan A. Ashley, Thomas Quertermous

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Figure 1

Apelin inhibits atherosclerosis in the ApoE-null model.

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Apelin inhibits atherosclerosis in the ApoE-null model. (A) Apelin-A...
(A) Apelin-ApoE double-knockout and ApoE-KO mice were fed normal chow or high-fat Western diet, and atherosclerosis burden was evaluated by en face analysis of the thoracoabdominal aorta. Apelin-ApoE double-knockout mice developed significantly greater atherosclerotic lesions compared with ApoE-KO mice on both diets (2.53-fold increase, *P < 0.01 for normal chow; 1.50-fold increase, *P < 0.01 for Western diet). (B) Coinfusion of apelin mitigated the increased atherosclerotic lesion burden caused by Ang II when coadministered by osmotic minipump (*P < 0.01, Ang II compared with saline; †P < 0.001, Ang II plus apelin compared with Ang II). Animals receiving Ang II and hydralazine had an atherosclerosis burden similar to that seen in the Ang II group. Administration of the NOS inhibitor l-NAME mitigated the beneficial effects of apelin, bringing atherosclerotic lesion burden to similar levels as mice infused with Ang II alone. (C) ApoE-KO mice treated with Ang II for 4 weeks showed a significant increase in aneurysm formation, and this effect was mitigated by apelin treatment. Administration of hydralazine with Ang II did not protect ApoE-KO mice from aneurysm formation. Mice treated with Ang II plus apelin plus l-NAME demonstrated aneurysm formation similar to Ang II mice. Representative aortas are shown for each experimental group. Original magnification, ×5.