{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T20:53:06Z","timestamp":1791147186212,"version":"4.1.0"},"reference-count":64,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"6","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[2014,3,14]]},"abstract":"<jats:sec>\n                    <jats:title>\n                      <jats:underline>Rationale:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>\n                      \u03b2-Adrenoceptor activation contributes to sudden death risk in heart failure. Chronic \u03b2-adrenergic stimulation, as occurs in patients with heart failure, causes potentially arrhythmogenic reductions in slow delayed-rectifier K\n                      <jats:sup>+<\/jats:sup>\n                      current (I\n                      <jats:sub>Ks<\/jats:sub>\n                      ).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Objective:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>\n                      To assess the molecular mechanisms of I\n                      <jats:sub>Ks<\/jats:sub>\n                      downregulation caused by chronic \u03b2-adrenergic activation, particularly the role of exchange protein directly activated by cAMP (Epac).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Methods and Results:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>\n                      Isolated guinea pig left ventricular cardiomyocytes were incubated in primary culture and exposed to isoproterenol (1 \u03bcmol\/L) or vehicle for 30 hours. Sustained isoproterenol exposure decreased I\n                      <jats:sub>Ks<\/jats:sub>\n                      density (whole cell patch clamp) by 58% (\n                      <jats:italic>P<\/jats:italic>\n                      &lt;0.0001), with corresponding decreases in potassium voltage-gated channel subfamily E member 1 (KCNE1) mRNA and membrane protein expression (by 45% and 51%, respectively). Potassium voltage-gated channel, KQT-like subfamily, member 1 (KCNQ1) mRNA expression was unchanged. The \u03b21-adrenoceptor antagonist 1-[2-((3-Carbamoyl-4-hydroxy)phenoxy)ethylamino]-3-[4-(1-methyl-4-trifluoromethyl-2-imidazolyl)phenoxy]-2-propanol dihydrochloride (CGP-20712A) prevented isoproterenol-induced I\n                      <jats:sub>Ks<\/jats:sub>\n                      downregulation, whereas the \u03b2\n                      <jats:sub>2<\/jats:sub>\n                      -antagonist ICI-118551 had no effect. The selective Epac activator 8-pCPT-2\u2032-O-Me-cAMP decreased I\n                      <jats:sub>Ks<\/jats:sub>\n                      density to an extent similar to isoproterenol exposure, and adenoviral-mediated knockdown of Epac1 prevented isoproterenol-induced I\n                      <jats:sub>Ks<\/jats:sub>\n                      \/KCNE1 downregulation. In contrast, protein kinase A inhibition with a cell-permeable highly selective peptide blocker did not affect I\n                      <jats:sub>Ks<\/jats:sub>\n                      downregulation. 1,2-Bis(o-aminophenoxy)ethane-N,N,N\u2032,N\u2032-tetraacetate-AM acetoxymethyl ester (BAPTA-AM), cyclosporine, and inhibitor of nuclear factor of activated T cell (NFAT)-calcineurin association-6 (INCA6) prevented I\n                      <jats:sub>Ks<\/jats:sub>\n                      reduction by isoproterenol and INCA6 suppressed isoproterenol-induced KCNE1 downregulation, consistent with signal-transduction via the Ca\n                      <jats:sup>2+<\/jats:sup>\n                      \/calcineurin\/NFAT pathway. Isoproterenol induced nuclear NFATc3\/c4 translocation (immunofluorescence), which was suppressed by Epac1 knockdown. Chronic in vivo administration of isoproterenol to guinea pigs reduced I\n                      <jats:sub>Ks<\/jats:sub>\n                      density and KCNE1 mRNA and protein expression while inducing cardiac dysfunction and action potential prolongation. Selective in vivo activation of Epac via sp-8-pCPT-2\u2032-O-Me-cAMP infusion decreased I\n                      <jats:sub>Ks<\/jats:sub>\n                      density and KCNE1 mRNA\/protein expression.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>\n                      <jats:underline>Conclusions:<\/jats:underline>\n                    <\/jats:title>\n                    <jats:p>\n                      Prolonged \u03b2\n                      <jats:sub>1<\/jats:sub>\n                      -adrenoceptor stimulation suppresses I\n                      <jats:sub>Ks<\/jats:sub>\n                      by downregulating KCNE1 mRNA and protein via Epac-mediated Ca\n                      <jats:sup>2+<\/jats:sup>\n                      \/calcineurin\/NFAT signaling. These results provide new insights into the molecular basis of K\n                      <jats:sup>+<\/jats:sup>\n                      channel remodeling under sustained adrenergic stimulation.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circresaha.113.302982","type":"journal-article","created":{"date-parts":[[2014,2,7]],"date-time":"2014-02-07T21:07:09Z","timestamp":1391807229000},"page":"993-1003","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":54,"title":["Exchange Protein Directly Activated by cAMP Mediates Slow Delayed-Rectifier Current Remodeling by Sustained \u03b2-Adrenergic Activation in Guinea Pig Hearts"],"prefix":"10.1161","volume":"114","author":[{"given":"Mona","family":"Aflaki","sequence":"first","affiliation":[{"name":"From the Department of Medicine, Research Center, Montreal Heart Institute, Universit\u00e9 de Montr\u00e9al, Montreal, Quebec, Canada (M.A., X.-Y.Q., L.X., B.O., A.T., X.L., A.M., Y.S., J.-C.T., S.N.); and Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada (M.A., S.N.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Yan","family":"Qi","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Research Center, Montreal Heart Institute, Universit\u00e9 de Montr\u00e9al, Montreal, Quebec, Canada (M.A., X.-Y.Q., L.X., B.O., A.T., X.L., A.M., Y.S., J.-C.T., S.N.); and Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada (M.A., S.N.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Xiao","sequence":"additional","affiliation":[{"name":"From the Department of Medicine, Research Center, Montreal Heart Institute, Universit\u00e9 de Montr\u00e9al, Montreal, Quebec, Canada (M.A., X.-Y.Q., L.X., B.O., A.T., X.L., A.M., Y.S., J.-C.T., S.N.); and Department of Pharmacology and Therapeutics, McGill 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