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Activation of G protein-coupled estrogen receptor 1 induces coronary artery relaxation via Epac/Rap1-mediated inhibition of RhoA/Rho kinase pathway in parallel with PKA.
PLoS One. 2017; 12(3):e0173085.Plos

Abstract

Previously, we reported that cAMP/PKA signaling is involved in GPER-mediated coronary relaxation by activating MLCP via inhibition of RhoA pathway. In the current study, we tested the hypothesis that activation of GPER induces coronary artery relaxation via inhibition of RhoA/Rho kinase pathway by cAMP downstream targets, exchange proteins directly activated by cAMP (Epac) as well as PKA. Our results show that Epac inhibitors, brefeldin A (BFA, 50 μM), or ESI-09 (20 μM), or CE3F4 (100 μM), all partially inhibited porcine coronary artery relaxation response to the selective GPER agonist, G-1 (0.3-3 μM); while concurrent administration of BFA and PKI (5 μM), a PKA inhibitor, almost completely blocked the relaxation effect of G-1. The Epac specific agonist, 8-CPT-2Me-cAMP (007, 1-100 μM), induced a concentration-dependent relaxation response. Furthermore, the activity of Ras-related protein 1 (Rap1) was up regulated by G-1 (1 μM) treatment of porcine coronary artery smooth muscle cells (CASMCs). Phosphorylation of vasodilator-stimulated phosphoprotein (p-VASP) was elevated by G-1 (1 μM) treatment, but not by 007 (50 μM); and the effect of G-1 on p-VASP was blocked by PKI, but not by ESI-09, an Epac antagonist. RhoA activity was similarly down regulated by G-1 and 007, whereas ESI-09 restored most of the reduced RhoA activity by G-1 treatment. Furthermore, G-1 decreased PGF2α-induced p-MYPT1, which was partially reversed with either ESI-09 or PKI; whereas, concurrent administration of ESI-09 and PKI totally prevented the inhibitory effect of G-1. The inhibitory effects of G-1 on p- MLC levels in CASMCs were mostly restored by either ESI-09 or PKI. These results demonstrate that activation of GPER induces coronary artery relaxation via concurrent inhibition of RhoA/Rho kinase by Epac/Rap1 and PKA. GPER could be a potential drug target for preventing and treating cardiovascular diseases.

Authors+Show Affiliations

Department of Physiology and Pharmacology, Texas A&M University, College Station, TX, United States of America.Department of Physiology and Pharmacology, Texas A&M University, College Station, TX, United States of America. Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.Department of Physiology and Pharmacology, Texas A&M University, College Station, TX, United States of America. Department of Cardiovascular Medicine, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.Department of Physiology and Pharmacology, Texas A&M University, College Station, TX, United States of America.Department of Physiology and Pharmacology, Texas A&M University, College Station, TX, United States of America. Women's Health Division, Michael E. DeBakey Institute, Texas A&M University, College Station, TX, United States of America.Department of Physiology and Pharmacology, Texas A&M University, College Station, TX, United States of America.Department of Physiology and Pharmacology, Texas A&M University, College Station, TX, United States of America. Women's Health Division, Michael E. DeBakey Institute, Texas A&M University, College Station, TX, United States of America.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28278256

Citation

Yu, Xuan, et al. "Activation of G Protein-coupled Estrogen Receptor 1 Induces Coronary Artery Relaxation Via Epac/Rap1-mediated Inhibition of RhoA/Rho Kinase Pathway in Parallel With PKA." PloS One, vol. 12, no. 3, 2017, pp. e0173085.
Yu X, Zhang Q, Zhao Y, et al. Activation of G protein-coupled estrogen receptor 1 induces coronary artery relaxation via Epac/Rap1-mediated inhibition of RhoA/Rho kinase pathway in parallel with PKA. PLoS One. 2017;12(3):e0173085.
Yu, X., Zhang, Q., Zhao, Y., Schwarz, B. J., Stallone, J. N., Heaps, C. L., & Han, G. (2017). Activation of G protein-coupled estrogen receptor 1 induces coronary artery relaxation via Epac/Rap1-mediated inhibition of RhoA/Rho kinase pathway in parallel with PKA. PloS One, 12(3), e0173085. https://doi.org/10.1371/journal.pone.0173085
Yu X, et al. Activation of G Protein-coupled Estrogen Receptor 1 Induces Coronary Artery Relaxation Via Epac/Rap1-mediated Inhibition of RhoA/Rho Kinase Pathway in Parallel With PKA. PLoS One. 2017;12(3):e0173085. PubMed PMID: 28278256.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Activation of G protein-coupled estrogen receptor 1 induces coronary artery relaxation via Epac/Rap1-mediated inhibition of RhoA/Rho kinase pathway in parallel with PKA. AU - Yu,Xuan, AU - Zhang,Qiao, AU - Zhao,Yan, AU - Schwarz,Benjamin J, AU - Stallone,John N, AU - Heaps,Cristine L, AU - Han,Guichun, Y1 - 2017/03/09/ PY - 2016/02/05/received PY - 2017/02/15/accepted PY - 2017/3/10/entrez PY - 2017/3/10/pubmed PY - 2017/8/31/medline SP - e0173085 EP - e0173085 JF - PloS one JO - PLoS One VL - 12 IS - 3 N2 - Previously, we reported that cAMP/PKA signaling is involved in GPER-mediated coronary relaxation by activating MLCP via inhibition of RhoA pathway. In the current study, we tested the hypothesis that activation of GPER induces coronary artery relaxation via inhibition of RhoA/Rho kinase pathway by cAMP downstream targets, exchange proteins directly activated by cAMP (Epac) as well as PKA. Our results show that Epac inhibitors, brefeldin A (BFA, 50 μM), or ESI-09 (20 μM), or CE3F4 (100 μM), all partially inhibited porcine coronary artery relaxation response to the selective GPER agonist, G-1 (0.3-3 μM); while concurrent administration of BFA and PKI (5 μM), a PKA inhibitor, almost completely blocked the relaxation effect of G-1. The Epac specific agonist, 8-CPT-2Me-cAMP (007, 1-100 μM), induced a concentration-dependent relaxation response. Furthermore, the activity of Ras-related protein 1 (Rap1) was up regulated by G-1 (1 μM) treatment of porcine coronary artery smooth muscle cells (CASMCs). Phosphorylation of vasodilator-stimulated phosphoprotein (p-VASP) was elevated by G-1 (1 μM) treatment, but not by 007 (50 μM); and the effect of G-1 on p-VASP was blocked by PKI, but not by ESI-09, an Epac antagonist. RhoA activity was similarly down regulated by G-1 and 007, whereas ESI-09 restored most of the reduced RhoA activity by G-1 treatment. Furthermore, G-1 decreased PGF2α-induced p-MYPT1, which was partially reversed with either ESI-09 or PKI; whereas, concurrent administration of ESI-09 and PKI totally prevented the inhibitory effect of G-1. The inhibitory effects of G-1 on p- MLC levels in CASMCs were mostly restored by either ESI-09 or PKI. These results demonstrate that activation of GPER induces coronary artery relaxation via concurrent inhibition of RhoA/Rho kinase by Epac/Rap1 and PKA. GPER could be a potential drug target for preventing and treating cardiovascular diseases. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/28278256/Activation_of_G_protein_coupled_estrogen_receptor_1_induces_coronary_artery_relaxation_via_Epac/Rap1_mediated_inhibition_of_RhoA/Rho_kinase_pathway_in_parallel_with_PKA_ L2 - https://dx.plos.org/10.1371/journal.pone.0173085 DB - PRIME DP - Unbound Medicine ER -