title: Feedback mechanisms for cardiac-specific microRNAs and cAMP signaling in electrical remodeling.
abstract: BACKGROUND
  Loss of transient outward K(+) current (Ito) is well documented in cardiac hypertrophy and failure both in animal models and in humans. Electrical remodeling contributes to prolonged action potential duration and increased incidence of arrhythmias. Furthermore, there is a growing body of evidence linking microRNA (miR) dysregulation to the progression of both conditions. In this study, we examined the mechanistic basis underlying miR dysregulation in electrical remodeling and revealed a novel interaction with the adrenergic signaling pathway.
  
  
  RESULTS
  We first used a tissue-specific knockout model of Dicer1 in cardiomyocytes to reveal the overall regulatory effect of miRs on the ionic currents and action potentials. We then validated the inducible cAMP early repressor as a target of miR-1 and took advantage of a clinically relevant model of post myocardial infarction and miR delivery to probe the mechanistic basis of miR dysregulation in electrical remodeling. These experiments revealed the role of inducible cAMP early repressor as a repressor of miR-1 and Ito, leading to prolonged action potential duration post myocardial infarction. In addition, delivery of miR-1 and miR-133a suppressed inducible cAMP early repressor expression and prevented both electrical remodeling and hypertrophy.
  
  
  CONCLUSIONS
  Taken together, our results illuminate the mechanistic links between miRs, adrenergic signaling, and electrical remodeling. They also serve as a proof-of-concept for the therapeutic potential of miR delivery post myocardial infarction.
authors.affiliation: From the Division of Cardiovascular Medicine, Department of Internal Medicine, University of California, Davis (R.M., V.T.,N.L., C.K., H.A.L., P.S., V.L., Y.Z., K.F., A.S., J.E.L., A.A.K., X.-D.Z., N.C.); and Department of Veterans Affairs, Northern California Health Care System, Mather (A.A.K., N.C.).
authors.forename: Richard
authors.initials: R
authors.lastname: Myers
authors.affiliation: From the Division of Cardiovascular Medicine, Department of Internal Medicine, University of California, Davis (R.M., V.T.,N.L., C.K., H.A.L., P.S., V.L., Y.Z., K.F., A.S., J.E.L., A.A.K., X.-D.Z., N.C.); and Department of Veterans Affairs, Northern California Health Care System, Mather (A.A.K., N.C.).
authors.forename: Valeriy
authors.initials: V
authors.lastname: Timofeyev
authors.affiliation: From the Division of Cardiovascular Medicine, Department of Internal Medicine, University of California, Davis (R.M., V.T.,N.L., C.K., H.A.L., P.S., V.L., Y.Z., K.F., A.S., J.E.L., A.A.K., X.-D.Z., N.C.); and Department of Veterans Affairs, Northern California Health Care System, Mather (A.A.K., N.C.).
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.affiliation: From the Division of Cardiovascular Medicine, Department of Internal Medicine, University of California, Davis (R.M., V.T.,N.L., C.K., H.A.L., P.S., V.L., Y.Z., K.F., A.S., J.E.L., A.A.K., X.-D.Z., N.C.); and Department of Veterans Affairs, Northern California Health Care System, Mather (A.A.K., N.C.).
authors.forename: Catherine
authors.initials: C
authors.lastname: Kim
authors.affiliation: From the Division of Cardiovascular Medicine, Department of Internal Medicine, University of California, Davis (R.M., V.T.,N.L., C.K., H.A.L., P.S., V.L., Y.Z., K.F., A.S., J.E.L., A.A.K., X.-D.Z., N.C.); and Department of Veterans Affairs, Northern California Health Care System, Mather (A.A.K., N.C.).
authors.forename: Hannah A
authors.initials: HA
authors.lastname: Ledford
authors.affiliation: From the Division of Cardiovascular Medicine, Department of Internal Medicine, University of California, Davis (R.M., V.T.,N.L., C.K., H.A.L., P.S., V.L., Y.Z., K.F., A.S., J.E.L., A.A.K., X.-D.Z., N.C.); and Department of Veterans Affairs, Northern California Health Care System, Mather (A.A.K., N.C.).
authors.forename: Padmini
authors.initials: P
authors.lastname: Sirish
authors.affiliation: From the Division of Cardiovascular Medicine, Department of Internal Medicine, University of California, Davis (R.M., V.T.,N.L., C.K., H.A.L., P.S., V.L., Y.Z., K.F., A.S., J.E.L., A.A.K., X.-D.Z., N.C.); and Department of Veterans Affairs, Northern California Health Care System, Mather (A.A.K., N.C.).
authors.forename: Victor
authors.initials: V
authors.lastname: Lau
authors.affiliation: From the Division of Cardiovascular Medicine, Department of Internal Medicine, University of California, Davis (R.M., V.T.,N.L., C.K., H.A.L., P.S., V.L., Y.Z., K.F., A.S., J.E.L., A.A.K., X.-D.Z., N.C.); and Department of Veterans Affairs, Northern California Health Care System, Mather (A.A.K., N.C.).
authors.forename: Yinuo
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: From the Division of Cardiovascular Medicine, Department of Internal Medicine, University of California, Davis (R.M., V.T.,N.L., C.K., H.A.L., P.S., V.L., Y.Z., K.F., A.S., J.E.L., A.A.K., X.-D.Z., N.C.); and Department of Veterans Affairs, Northern California Health Care System, Mather (A.A.K., N.C.).
authors.forename: Kiran
authors.initials: K
authors.lastname: Fayyaz
authors.affiliation: From the Division of Cardiovascular Medicine, Department of Internal Medicine, University of California, Davis (R.M., V.T.,N.L., C.K., H.A.L., P.S., V.L., Y.Z., K.F., A.S., J.E.L., A.A.K., X.-D.Z., N.C.); and Department of Veterans Affairs, Northern California Health Care System, Mather (A.A.K., N.C.).
authors.forename: Anil
authors.initials: A
authors.lastname: Singapuri
authors.affiliation: From the Division of Cardiovascular Medicine, Department of Internal Medicine, University of California, Davis (R.M., V.T.,N.L., C.K., H.A.L., P.S., V.L., Y.Z., K.F., A.S., J.E.L., A.A.K., X.-D.Z., N.C.); and Department of Veterans Affairs, Northern California Health Care System, Mather (A.A.K., N.C.).
authors.forename: Javier E
authors.initials: JE
authors.lastname: Lopez
authors.affiliation: From the Division of Cardiovascular Medicine, Department of Internal Medicine, University of California, Davis (R.M., V.T.,N.L., C.K., H.A.L., P.S., V.L., Y.Z., K.F., A.S., J.E.L., A.A.K., X.-D.Z., N.C.); and Department of Veterans Affairs, Northern California Health Care System, Mather (A.A.K., N.C.).
authors.forename: Anne A
authors.initials: AA
authors.lastname: Knowlton
authors.affiliation: From the Division of Cardiovascular Medicine, Department of Internal Medicine, University of California, Davis (R.M., V.T.,N.L., C.K., H.A.L., P.S., V.L., Y.Z., K.F., A.S., J.E.L., A.A.K., X.-D.Z., N.C.); and Department of Veterans Affairs, Northern California Health Care System, Mather (A.A.K., N.C.). nchiamvimonvat@ucdavis.edu xdzhang@ucdavis.edu.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Zhang
authors.affiliation: From the Division of Cardiovascular Medicine, Department of Internal Medicine, University of California, Davis (R.M., V.T.,N.L., C.K., H.A.L., P.S., V.L., Y.Z., K.F., A.S., J.E.L., A.A.K., X.-D.Z., N.C.); and Department of Veterans Affairs, Northern California Health Care System, Mather (A.A.K., N.C.). nchiamvimonvat@ucdavis.edu xdzhang@ucdavis.edu.
authors.forename: Nipavan
authors.initials: N
authors.lastname: Chiamvimonvat
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D064752:Atrial Remodeling / Q000235:genetics*; D015153:Blotting, Western; D006332:Cardiomegaly / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000235:genetics* / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000096:biosynthesis / Q000235:genetics*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D018408:Patch-Clamp Techniques; D060888:Real-Time Polymerase Chain Reaction; D043244:Ribonuclease III / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D035683:MicroRNAs; D000242:Cyclic AMP; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases
keywords: cAMP; electrical remodeling; ion channel; microRNA; myocardial infarction