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.

The apelinergic system in the developing lung: Expression and signaling

“…Whether APJ multimeric species observed in the fetal and adult pulmonary tissues in our study correspond to homo-or hetero-multiples of the receptor is still not known and could only be clarified by further studies. Nonetheless, it was already demonstrated in vitro that APJ can form heterodimers with angiotensin II AT1 receptor [7]. Moreover immunohistochemical studies performed in our lab revealed that all renin-angiotensin system components, including AT1 and .…”

“…Currently the relation between these two systems is described to be a direct interaction of the two systems at both molecular and transcriptional levels to mediate opposing physiological actions [2]. APJ and AT1 receptor-receptor interactions are presently accounted as the potential molecular mechanism of crosstalk responsible for this reciprocal counter-regulation between apelin and Ang II pathways, since it was observed in vitro that the respective receptors can form heterodimers and that this heterodimerisation influences downstream signaling [7]. Our observations on fetal lung growth are in accordance with others reporting that the proposed effects of the apelin-APJ system are opposite to those of the Ang II-AT1 receptor pathway [7,44].…”

Oxido-reductive regulation of vascular remodeling by receptor tyrosine kinase ROS1

“…Levels of ROS1 phosphorylation were higher in Gpx1 -/-Apoe -/-mice (P < 0.05) without differences in ROS1 protein. in basal medium (SmBM) for 72 hours, according to conventional protocols (45). In vitro ROS1 inhibition studies were completed by adding 40 μM genistein to the cell-culture media.…”

“…Human coronary artery SMCs (HCASMCs) and aorta/stented vessel lysates (n ≥ 5 per group) were used for immunoprecipitation and immunoblotting performed using a previously described method (45).…”

“…Histomorphometric analysis of aortic atherosclerosis lesion area and stented vessel processing and analysis were performed as previously described (5). Immunohistochemistry was performed as described previously (45).…”