The　proliferation　of　cardiac　fibroblasts　is　implicated　in　the　pathogenesis　of　myocardial　remodeling　and　fibrosis.　Intermediate-conductance　calcium-activated　K+　channels　(K(Ca)3.1　channels)　have　important　roles　in　cell　proliferation.　However,　it　is　unknown　whether　angiotensin　II　(Ang　II),　a　potent　profibrotic　molecule,　would　regulate　K(Ca)3.1　channels　in　cardiac　fibroblasts　and　participate　in　cell　proliferation.　In　the　present　study,　we　investigated　whether　K(Ca)3.1　channels　were　regulated　by　Ang　II,　and　how　the　channel　activity　mediated　cell　proliferation　in　cultured　adult　rat　cardiac　fibroblasts　using　electrophysiology　and　biochemical　approaches.　It　was　found　that　mRNA,　protein,　and　current　density　of　K(Ca)3.1　channels　were　greatly　enhanced　in　cultured　cardiac　fibroblasts　treated　with　1　mu　M　Ang　II,　and　the　effects　were　countered　by　the　angiotensin　type　1　receptor　(AT(1)R)　blocker　losartan,　the　p38-MAPK　inhibitor　SB203580,　the　ERK1/2　inhibitor　PD98059,　and　the　PI3K/Akt　inhibitor　LY294002.　Ang　II　stimulated　cell　proliferation　and　the　effect　was　antagonized　by　the　K(Ca)3.1　blocker　TRAM-34　and　siRNA　targeting　K(Ca)3.1.　In　addition,　Ang　II-induced　increase　of　K(Ca)3.1　expression　was　attenuated　by　transfection　of　activator　protein-1　(AP-1)　decoy　oligodeoxynucleotides.　These　results　demonstrate　for　the　first　time　that　Ang　II　stimulates　cell　proliferation　mediated　by　upregulating　K(Ca)3.1　channels　via　interacting　with　the　AT(1)R　and　activating　AP-1　complex　through　ERK1/2,　p38-MAPK　and　PI3K/Akt　signaling　pathways　in　cultured　adult　rat　cardiac　fibroblasts.　(c)　Crown　Copyright　2013　Published　by　Elsevier　Inc.　All　rights　reserved.