title: Angiotensin II induces complex fractionated electrogram in a cultured atrial myocyte monolayer mediated by calcium and sodium-calcium exchanger.
abstract: Angiotensin II (AngII) has been implicated in the mechanism of atrial fibrillation (AF). There may be calcium-dependent pro-fibrillatory effect of AngII on atrial myocytes. We used cultured confluent HL-1 atrial myocyte monolayer with spontaneously propagated depolarization to study direct pro-fibrillatory effect of AngII and its molecular mechanism. AngII stimulation induced fibrillatory-like complex electrogram and calcium wave propagation. AngII shortened action potential duration and augmented calcium transient, thus increasing electrochemical gradient of forward-mode sodium-calcium exchanger (NCX) current and induced frequent irregular afterdepolarizations. AngII increased expression of sodium-calcium exchanger (NCX), further increasing calcium-membrane voltage coupling gain. The fibrillatory effect of AngII was attenuated by NCX blocker SEA0400 and NCX siRNA knockdown. AngII increased expression of L-type calcium channel and augmented calcium transient through PKC and CREB. The fibrillatory effect of AngII was also attenuated by PKC inhibitor chelerythrine and dominant negative form of CREB. In conclusions, AngII itself may electrically contribute to the mechanism of AF through increasing NCX expression and augmenting calcium transient, which is PKC and CREB dependent. Specific genetic knockdown of NCX attenuated calcium mediated afterdepolarization and complex electrogram.
authors.affiliation: Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Chia-Ti
authors.initials: CT
authors.lastname: Tsai
authors.forename: Fu-Tien
authors.initials: FT
authors.lastname: Chiang
authors.forename: Wen-Pin
authors.initials: WP
authors.lastname: Chen
authors.forename: Juey-Jen
authors.initials: JJ
authors.lastname: Hwang
authors.forename: Chuen-Den
authors.initials: CD
authors.lastname: Tseng
authors.forename: Cho-Kai
authors.initials: CK
authors.lastname: Wu
authors.forename: Chih-Chieh
authors.initials: CC
authors.lastname: Yu
authors.forename: Yi-Chih
authors.initials: YC
authors.lastname: Wang
authors.forename: Ling-Ping
authors.initials: LP
authors.lastname: Lai
authors.forename: Jiunn-Lee
authors.initials: JL
authors.lastname: Lin
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D018031:Connexin 43 / Q000378:metabolism; D055724:Electrophysiological Phenomena / Q000187:drug effects*; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D006325:Heart Atria / Q000166:cytology*; D007150:Immunohistochemistry; D015640:Ion Channel Gating / Q000187:drug effects; D051379:Mice; D008839:Microelectrodes; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000378:metabolism*
chemical_list: D020746:Calcium Channels, L-Type; D018031:Connexin 43; D044140:Receptor, Angiotensin, Type 1; D019831:Sodium-Calcium Exchanger; D000804:Angiotensin II; D002118:Calcium