Department of Cardiovascular Surgery, Saitama Medical Center, Saitama, Japan.
Hypertens Res. 2011 Jun;34(6):701-6. doi: 10.1038/hr.2011.19. Epub 2011 Mar 17.
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 AT(1) 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-AT(1) 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.
Apelin 和其 G 蛋白偶联受体 APJ 是心血管系统的有力调节者。最近的研究表明，apelin-APJ 可逆转血管紧张素 II（Ang II）-血管紧张素 II 型 1 受体（AT(1)）的功能。然而，由于越来越多的证据表明 apelin-APJ 可能有助于心脏保护和病理进展，因此其机制仍不清楚。在人胚肾 293 细胞中，我们发现 APJ 的共表达显著抑制了 Ang II-AT(1)诱导的细胞外信号调节激酶 1/2（ERK1/2）的磷酸化，而 apelin 通过激活 APJ 消除了这种抑制，而无需其异二聚化。用 Gi/o 特异性抑制剂百日咳毒素（PTX）预处理可恢复 ERK1/2 磷酸化水平，与 Ang II-AT(1)和 apelin 刺激无共表达时相似。相比之下，β-2 肾上腺素能受体或经药理学非激活的 Ang II 型 2 受体（AT(2)）的共表达，经 AT(2)特异性拮抗剂 PD123319 预处理后，不会通过 AT(1)影响 ERK1/2 磷酸化。用 30 nM 的 AT(1)阻滞剂（ARB）TA-606A 抑制 50%的 AT(1)介导的 ERK1/2 磷酸化，而当无配体或无 PTX 共表达非激活的 APJ 时，30 nM 的 TA-606A 抑制率达到 75%。然而，当与激活的 APJ 并用 apelin 共表达时，120 nM 的 TA-606A 未能达到目标磷酸化。基于这些结果，我们证明非激活的 APJ 可能抑制 Ang II-AT(1)信号，而这种配体非依赖性功能随着 apelin 的激活而减弱。这些结果可能与 apelin-APJ 在临床领域对 ARB 治疗的潜在贡献有关。
