title: Carvedilol reverses cardiac insufficiency in AKAP5 knockout mice by normalizing the activities of calcineurin and CaMKII.
abstract: OBJECTIVE
  Cardiac β-adrenergic receptors (β-AR) are key regulators of cardiac haemodynamics and size. The scaffolding protein A-kinase anchoring protein 79/150 (AKAP5) is a key regulator of myocardial signalling by β-ARs. We examined the function of AKAP5 in regulating cardiac haemodynamics and size, and the role of β-ARs and Ca(2+)-regulated intracellular signalling pathways in this phenomenon.
  
  
  RESULTS
  We used echocardiographic, histological, genetic, and biochemical methods to examine the effect of ablation of AKAP5 on cardiac haemodynamics, size, and signalling in mice. AKAP5(-/-) mice exhibited enhanced signs of cardiac dilatation and dysfunction that progressed with age. Infusions of isoprenaline worsened cardiac haemodynamics in wild-type (WT) mice only, but increased the ratio of heart-to-body weight equally in WT and in AKAP5(-/-) mice. Mechanistically, loss of AKAP5 was associated with enhanced activity of cardiac calmodulin kinase II (CaMKII) and calcineurin (CaN) as indexed by nuclear factor of activated T-cell-luciferase activity. Loss of AKAP5 interfered with the recycling of cardiac β1-ARs, which was mediated in part by CaN binding to AKAP5. Carvedilol reversed cardiac hypertrophy and haemodynamic deficiencies in AKAP5(-/-) mice by normalizing the activities of cardiac CaN and CaMKII.
  
  
  CONCLUSIONS
  These findings identify a novel cardioprotective role for AKAP5 that is mediated by regulating the activities of cardiac CaN and CaMKII and highlight a significant role for cardiac β-ARs in this phenomenon.
authors.affiliation: Department of Pharmacology, The University of Tennessee Health Sciences Center, 874 Union Avenue, Memphis, TN 38163, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Pharmacology, The University of Tennessee Health Sciences Center, 874 Union Avenue, Memphis, TN 38163, USA.
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Matta
authors.affiliation: Department of Comparative Medicine, The University of Tennessee Health Sciences Center, Memphis, TN, USA.
authors.forename: Ryan D
authors.initials: RD
authors.lastname: Sullivan
authors.affiliation: Department of Pharmacology, The University of Tennessee Health Sciences Center, 874 Union Avenue, Memphis, TN 38163, USA sbahouth@uthsc.edu.
authors.forename: Suleiman W
authors.initials: SW
authors.lastname: Bahouth
mesh_terms: D054758:A Kinase Anchor Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D018674:Adrenergic Antagonists / Q000494:pharmacology*; D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism*; D002227:Carbazoles / Q000494:pharmacology*; D000077261:Carvedilol; D002478:Cells, Cultured; D006439:Hemodynamics / Q000187:drug effects; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D050778:NFATC Transcription Factors / Q000378:metabolism; D011412:Propanolamines / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D018342:Receptors, Adrenergic, beta-1 / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors; D018487:Ventricular Dysfunction, Left / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D016277:Ventricular Function, Left / Q000187:drug effects*
chemical_list: D054758:A Kinase Anchor Proteins; D018674:Adrenergic Antagonists; C520665:Akap5 protein, mouse; C415703:Akap5 protein, rat; D002227:Carbazoles; D050778:NFATC Transcription Factors; D011412:Propanolamines; D018342:Receptors, Adrenergic, beta-1; D000077261:Carvedilol; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D019703:Calcineurin
keywords: AKAP; Calcineurin; Calmodulin kinase II; Cardiac hypertrophy; β-Adrenergic receptors