The Scaffold Protein mAKAPβ Orchestrates Cardiac Myocyte Hypertrophic Signaling Required for the Development of Heart Failure
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 (mAKAPβ) serves as a nodal organizer of hypertrophic signaling. However, the relevance of mAKAPβ signalosomes to pathological remodeling and heart failure in vivo remains unknown.
Methods and Results—Employing conditional, cardiac myocyte-specific gene deletion, we now demonstrate that mAKAPβ expression in mice is important for the cardiac hypertrophy induced by pressure overload and catecholamine toxicity. mAKAPβ 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 mAKAPβ knock-out mice (n = 31) died in the 16 weeks of pressure overload (p = 0.02). Accordingly, mAKAPβ knock-out 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 mAKAPβ scaffold, including the decreased phosphorylation of PKD1 and HDAC4 that we reveal to participate in a new mAKAP signaling module. Furthermore, mAKAPβ knock-out inhibited pathological gene expression directed by MEF2 and NFATc transcription factors that associate with the scaffold.
Conclusions—mAKAPβ orchestrates signaling that regulates pathological cardiac remodeling in mice. Targeting of the underlying physical architecture of signaling networks, including mAKAPβ signalosome formation, may constitute an effective therapeutic strategy for the prevention and/or treatment of pathological remodeling and heart failure.
- Received October 22, 2013.
- Accepted May 7, 2014.