| First Author | Kritzer MD | Year | 2014 |
| Journal | Circ Heart Fail | Volume | 7 |
| Issue | 4 | Pages | 663-72 |
| PubMed ID | 24812305 | Mgi Jnum | J:214288 |
| Mgi Id | MGI:5588685 | Doi | 10.1161/CIRCHEARTFAILURE.114.001266 |
| Citation | Kritzer MD, et al. (2014) The scaffold protein muscle A-kinase anchoring protein beta orchestrates cardiac myocyte hypertrophic signaling required for the development of heart failure. Circ Heart Fail 7(4):663-72 |
| abstractText | BACKGROUND: Cardiac myocyte hypertrophy is regulated by an extensive intracellular signal transduction network. In vitro evidence suggests that the scaffold protein muscle A-kinase anchoring protein beta (mAKAPbeta) serves as a nodal organizer of hypertrophic signaling. However, the relevance of mAKAPbeta signalosomes to pathological remodeling and heart failure in vivo remains unknown. METHODS AND RESULTS: Using conditional, cardiac myocyte-specific gene deletion, we now demonstrate that mAKAPbeta expression in mice is important for the cardiac hypertrophy induced by pressure overload and catecholamine toxicity. mAKAPbeta targeting prevented the development of heart failure associated with long-term transverse aortic constriction, conferring a survival benefit. In contrast to 29% of control mice (n=24), only 6% of mAKAPbeta knockout mice (n=31) died in the 16 weeks of pressure overload (P=0.02). Accordingly, mAKAPbeta knockout inhibited myocardial apoptosis and the development of interstitial fibrosis, left atrial hypertrophy, and pulmonary edema. This improvement in cardiac status correlated with the attenuated activation of signaling pathways coordinated by the mAKAPbeta scaffold, including the decreased phosphorylation of protein kinase D1 and histone deacetylase 4 that we reveal to participate in a new mAKAP signaling module. Furthermore, mAKAPbeta knockout inhibited pathological gene expression directed by myocyte-enhancer factor-2 and nuclear factor of activated T-cell transcription factors that associate with the scaffold. CONCLUSIONS: mAKAPbeta orchestrates signaling that regulates pathological cardiac remodeling in mice. Targeting of the underlying physical architecture of signaling networks, including mAKAPbeta signalosome formation, may constitute an effective therapeutic strategy for the prevention and treatment of pathological remodeling and heart failure. |
