Carvedilol reverses cardiac insufficiency in AKAP5 knockout mice by normalizing the activities of calcineurin and CaMKII

Xin Li, Shannon M. Matta, Ryan D. Sullivan, Suleiman W. Bahouth

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Aims 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 Ca2+-regulated intracellular signalling pathways in this phenomenon. Methods and 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.

Original languageEnglish (US)
Pages (from-to)270-279
Number of pages10
JournalCardiovascular research
Volume104
Issue number2
DOIs
StatePublished - Nov 1 2014
Externally publishedYes

Keywords

  • AKAP
  • b-Adrenergic receptors
  • Calcineurin
  • Calmodulin kinase
  • Cardiac hypertrophy

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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