Apelin signaling antagonizes Ang II effects in mouse models of atherosclerosis
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
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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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 4

Apelin increases vascular wall NO bioavailability and suppresses disease-related O2•– production.

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Apelin increases vascular wall NO bioavailability and suppresses disease...
(A) EPR spectroscopy was employed to measure NO in lung homogenates of ApoE-KO mice. Apelin infusion increased net lung NO levels compared with saline-treated controls (***P < 0.001). Inhibition of NOS by l-NAME attenuated net NO levels in apelin (*P < 0.05) and Ang II plus apelin (†P < 0.05) lung homogenates, suggesting apelin stimulates NOS activity. (B) Aortic O2•– production, measured by lucigenin, was attenuated in apelin-treated mice (**P < 0.01) and increased in Ang II–treated mice (#P < 0.001) compared with saline-treated controls. Incubation with l-NAME increased luminescence in apelin-infused mice (**P < 0.01, intra-group comparison), suggesting apelin stimulated NO was quenching O2•– produced in the vessel wall. Luminescence was reduced in apelin-treated mice, even when coadministered with Ang II compared with animals treated with Ang II alone (††P < 0.01). (C) Dihydroethidium (DHE) fluorescence microscopy allowed topographic assessment of O2•– production in the vessel wall. There was no significant difference in endothelial O2•– production among the different experimental groups. Apelin decreased O2•– production compared with the saline control group for both the medial and adventitial vessel layers (78%, ***P < 0.001; 88%, ***P < 0.001, respectively). Apelin also decreased O2•– production in the media and adventitia when combined with Ang II, compared with the Ang II alone animals, although to a lesser degree (53%, ††P < 0.01; 45%, ††P < 0.01, respectively). Aortic elastic laminae exhibit green autofluorescence. White arrows denote endothelial O2•– producing cells, and white arrowheads denote medial O2•– producing cells. Scale bar: 5 μm.