The scaffold protein muscle a-kinase anchoring protein β orchestrates cardiac myocyte hypertrophic signaling required for the development of heart failure

Michael D. Kritzer, Jinliang Li, Catherine L. Passariello, Marjorie Gayanilo, Hrishikesh Thakur, Joseph Dayan, Kimberly Dodge-Kafka, Michael S. Kapiloff

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

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 β (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. Using 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 knockout mice (n=31) died in the 16 weeks of pressure overload (P=0.02). Accordingly, mAKAPβ 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 mAKAPβ 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, mAKAPβ 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. 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 treatment of pathological remodeling and heart failure.

Original languageEnglish (US)
Pages (from-to)663-672
Number of pages10
JournalCirculation: Heart Failure
Volume7
Issue number4
DOIs
StatePublished - Jul 1 2014

Keywords

  • Heart failure
  • Hypertrophy
  • Signal transduction

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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