title: Death, cardiac dysfunction, and arrhythmias are increased by calmodulin kinase II in calcineurin cardiomyopathy.
abstract: BACKGROUND
  Activation of cellular Ca2+ signaling molecules appears to be a fundamental step in the progression of cardiomyopathy and arrhythmias. Myocardial overexpression of the constitutively active Ca2+-dependent phosphatase calcineurin (CAN) causes severe cardiomyopathy marked by left ventricular (LV) dysfunction, arrhythmias, and increased mortality rate, but CAN antagonist drugs primarily reduce hypertrophy without improving LV function or risk of death.
  
  
  RESULTS
  We found that activity and expression of a second Ca2+-activated signaling molecule, calmodulin kinase II (CaMKII), were increased in hearts from CAN transgenic mice and that CaMKII-inhibitory drugs improved LV function and suppressed arrhythmias. We devised a genetic approach to "clamp" CaMKII activity in CAN mice to control levels by interbreeding CAN transgenic mice with mice expressing a specific CaMKII inhibitor in cardiomyocytes. We developed transgenic control mice by interbreeding CAN transgenic mice with mice expressing an inactive version of the CaMKII-inhibitory peptide. CAN mice with CaMKII inhibition had reduced risk of death and increased LV and ventricular myocyte function and were less susceptible to arrhythmias. CaMKII inhibition did not reduce transgenic overexpression of CAN or expression of endogenous CaMKII protein or significantly reduce most measures of cardiac hypertrophy.
  
  
  CONCLUSIONS
  CaMKII is a downstream signal in CAN cardiomyopathy, and increased CaMKII activity contributes to cardiac dysfunction, arrhythmia susceptibility, and longevity during CAN overexpression.
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, Tenn, USA.
authors.forename: Michelle S C
authors.initials: MS
authors.lastname: Khoo
authors.forename: Jingdong
authors.initials: J
authors.lastname: Li
authors.forename: Madhu V
authors.initials: MV
authors.lastname: Singh
authors.forename: Yingbo
authors.initials: Y
authors.lastname: Yang
authors.forename: Prince
authors.initials: P
authors.lastname: Kannankeril
authors.forename: Yuejin
authors.initials: Y
authors.lastname: Wu
authors.forename: Chad E
authors.initials: CE
authors.lastname: Grueter
authors.forename: Xiaoqun
authors.initials: X
authors.lastname: Guan
authors.forename: Carmine V
authors.initials: CV
authors.lastname: Oddis
authors.forename: Rong
authors.initials: R
authors.lastname: Zhang
authors.forename: Lisa
authors.initials: L
authors.lastname: Mendes
authors.forename: Gemin
authors.initials: G
authors.lastname: Ni
authors.forename: Ernest C
authors.initials: EC
authors.lastname: Madu
authors.forename: Jinying
authors.initials: J
authors.lastname: Yang
authors.forename: Martha
authors.initials: M
authors.lastname: Bass
authors.forename: Rey J
authors.initials: RJ
authors.lastname: Gomez
authors.forename: Brian E
authors.initials: BE
authors.lastname: Wadzinski
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Colbran
authors.forename: Mark E
authors.initials: ME
authors.lastname: Anderson
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D001145:Arrhythmias, Cardiac / Q000201:enzymology* / Q000235:genetics / Q000517:prevention & control; D001596:Benzylamines / Q000494:pharmacology / Q000627:therapeutic use; D019703:Calcineurin / Q000096:biosynthesis / Q000502:physiology*; D020013:Calcium Signaling; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured / Q000187:drug effects / Q000502:physiology; D016757:Death, Sudden, Cardiac / Q000209:etiology* / Q000517:prevention & control; D004195:Disease Models, Animal; D004790:Enzyme Induction; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D007545:Isoproterenol / Q000633:toxicity; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D010446:Peptide Fragments / Q000235:genetics / Q000502:physiology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D000096926:Benzenesulfonamides
chemical_list: D001596:Benzylamines; D019703:Calcineurin; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D007545:Isoproterenol; D010446:Peptide Fragments; D012333:RNA, Messenger; D013449:Sulfonamides; C072105:KN 93; D000096926:Benzenesulfonamides