| First Author | Li X | Year | 2014 |
| Journal | Cardiovasc Res | Volume | 104 |
| Issue | 2 | Pages | 270-9 |
| PubMed ID | 25225170 | Mgi Jnum | J:230190 |
| Mgi Id | MGI:5755740 | Doi | 10.1093/cvr/cvu209 |
| Citation | Li X, et al. (2014) Carvedilol reverses cardiac insufficiency in AKAP5 knockout mice by normalizing the activities of calcineurin and CaMKII. Cardiovasc Res 104(2):270-9 |
| abstractText | AIMS: Cardiac beta-adrenergic receptors (beta-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 beta-ARs. We examined the function of AKAP5 in regulating cardiac haemodynamics and size, and the role of beta-ARs and Ca(2+)-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 beta1-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 beta-ARs in this phenomenon. |
