Non-activated APJ suppresses the angiotensin II type 1 receptor, whereas apelin-activated APJ acts conversely

作者：Sun Xiao; Iida Shinichiro; Yoshikawa Ayumu; Senbonmatsu Rina; Imanaka Kazuhito; Maruyama Kei; Nishimura Shigeyuki; Inagami Tadashi; Senbonmatsu Takaaki^*

来源：Hypertension Research, 2011, 34(6): 701-706.

DOI：10.1038/hr.2011.19

• apelin
• APJ
• angiotensin II type 1 receptor
• angiotensin II type 1 receptor blocker

Apelin and its G-protein-coupled receptor APJ are potent regulators of the cardiovascular system. Recent studies have suggested that apelin-APJ reverses the function of angiotensin II (Ang II)-the Ang II type 1 receptor (AT(1)). However, the mechanism remains unclear because of the accumulating evidences that apelin-APJ may contribute to both cardioprotection and pathological progression. In human embryonic kidney 293 cells, we found that coexpression with APJ significantly suppressed the phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) induced by Ang II-AT(1), whereas apelin abolished this attenuation through activated APJ independently of its heterodimerization. Pretreatment with the Gi/o-specific inhibitor pertussis toxin (PTX) restituted the ERK1/2 phosphorylation level similar to that found with AT1 and APJ coexpression without apelin stimulation. In contrast, coexpression of the beta-2-adrenergic receptor or the pharmacologically non-activated Ang II type 2 receptor (AT(2)) pretreated with the AT(2)-specific antagonist, PD123319, did not affect ERK1/2 phosphorylation through AT(1). Pretreatment with 30 nM of the AT(1) blocker (ARB) TA-606A suppressed 50% of the AT(1)-mediated ERK1/2 phosphorylation, whereas 30 nM of TA-606A achieved 75% suppression when the non-activated APJ was coexpressed without ligand or PTX. However, 120 nM of TA-606A failed to reach the target phosphorylation when it was coexpressed with activated APJ with apelin. Based on these results, we demonstrated that non-activated APJ may suppress Ang II-AT1 signaling, whereas this ligand-independent function was diminished with apelin activation. These results may be relevant to the potential contribution of apelin-APJ to ARB treatment in the clinical realm. Hypertension Research (2011) 34, 701-706; doi: 10.1038/hr. 2011.19; published online 17 March 2011

• 出版日期2011-6