Abstract P102: Apelin Regulates the Function of Angiotensin II Type 1 Receptor Through APJ
Apelin and its G protein-coupled receptor (GPCR) APJ, which is most closely related to the angiotensin II (Ang II) type 1 receptor (AT1) but Ang II does not bind to APJ, are potent regulators of the cardiovascular system. Although recent studies have suggested that apelin-APJ reverses the function of Ang II-AT1, the mechanism remains unclear because the accumulating evidences indicates that apelin-APJ may contribute to both cardioprotection and pathological progression. In APJ and AT1 co-expression human embryonic kidney (HEK) 293 cells, we found that APJ and AT1 created receptor heterodimers. Co-expression with APJ significantly suppressed the phosphorylated extracellular signal-regulated kinases 1/2 (pERK1/2) induced by Ang II-AT1, whereas apelin eliminated this ligand-independent function of APJ out of relation to its heterodimerization. The pharmacologically non-activated APJ upon apelin stimulation elicited by the Gi/o-specific inhibitor pertussis toxin (PTX) restituted the pERK1/2 level similar to that of AT1 and APJ co-expression without apelin stimulation. However, the co-expression of the beta-2-adrenergic receptor (β2AR) or the pharmacologically non-activated Ang II type 2 receptor (AT2) induced by the AT2-specific antagonist, PD123319, did not suppress pERK1/2 through Ang II-AT1. Pretreatment with 30 nM of the AT1 blocker (ARB) TA-606A suppressed 50% of the AT1-mediated pERK1/2, whereas this suppression raised to 75% when the non-activated APJ was co-expressed. In contrast, 120 nM of TA-606A only reached 34% suppression when it was co-expressed with activated APJ with apelin. Taken together, we demonstrated that apelin may regulate the function of AT1. Non-activated APJ may suppress Ang II-AT1 signaling, whereas this ligand-independent function was diminished with apelin activation. These results may contribute to ARB treatment in the clinical setting.
- © 2011 by American Heart Association, Inc.