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G protein‐coupled estrogen receptor mediates relaxation of coronary arteries via cAMP/PKA‐dependent activation of MLCP (1065.14)
Author(s) -
Yu Xuan,
Stallone John,
Han Guichun
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1065.14
Subject(s) - rhoa , gper , myosin light chain phosphatase , protein kinase a , chemistry , myosin light chain kinase , vasodilation , medicine , rho associated protein kinase , endocrinology , vascular smooth muscle , agonist , signal transduction , microbiology and biotechnology , phosphorylation , receptor , biology , estrogen receptor , biochemistry , smooth muscle , cancer , breast cancer
Activation of GPER exerts a protective effect in hypertension and ischemia‐reperfusion models and relaxes arteries in vitro. However, the mechanism of GPER‐mediated vascular regulation is far from complete. The objective of this study is to test the hypothesis that GPER induced porcine coronary arteries relaxation is via cAMP/PKA signaling. We used isometric tension study, Western blotting and kinase activity essays. Our findings revealed that coronary artery relaxation to GPER agonist G‐1 (0.3‐3 μM) was associated with increased cAMP production in a concentration‐dependent manner. Furthermore, inhibition of adenylyl cyclase with SQ‐22538 (100 μM) or inhibition of PKA with either Rp‐8‐CPT‐cAMPS (5 μM) or PKI (5 μM) attenuated G‐1‐induced relaxation of coronary arteries preconstricted with PGF2α (1 µM). G‐1 also increased PKA activity in coronary artery smooth muscle cells (CASMC). To determine downstream signals of cAMP/PKA cascade, we measured RhoA activity in CASMC and myosin light chain phosphatase (MLCP) activity in artery rings by detecting phosphorylation of its regulatory myosin‐targeting subunit (pMYPT1). G‐1 decreased PGF2α induced pMYPT1, while Rp‐8‐CPT‐cAMPS prevented this inhibition of G‐1. RhoA activity was down regulated by G‐1, whereas GPER antagonist G36 restored it. Lastly, an inhibitor of the interaction between PKA and A kinase anchoring protein, MFMP‐API‐1 (100 µM), attenuated G‐1‐mediated relaxation and pMYPT1 response. We conclude that localized cAMP/PKA signaling is involved in GPER‐mediated coronary vasodilation by activating MLCP via inhibition of RhoA pathway.