Cardiac hypertrophy is the primary compensatory response of the heart to chronic stress. In disease, this non- mitotic growth is accompanied by changes in gene expression, ion fluxes and metabolism that affects cardiac contractility, and induces myocyte apoptosis and interstitial fibrosis. At the core of these physiological changes is the altered transcription of key genes that mediate cardiac remodeling. Hence, understanding the mechanism that regulate gene expression has attracted significant attention for clinical applications. Histone deacetylases (HDAC) of the class IIa family (including HDAC4, 5 and 9) are signal-responsive regulators of gene expression and are thought to repress cardiac hypertrophy via protein-protein interactions with transcription factors. Phosphorylation by pro-hypertrophic signaling enzymes such as Protein kinase D (PKD) stimulates the nuclear export of HDACs, thereby promoting the gene transcription required for cardiac hypertrophy. In contrast, acute beta-adrenergic stimulation and activation of Protein Kinase A induces nuclear retention of HDAC5. However, chronic beta-adrenergic stimulation, as seen in disease, results in a PKA-mediated increased in nuclear export, suggesting PKA is responsible for both retention and export of HDAC under different conditions We propose that chronic beta-adrenergic stimulation induces the expression of the salt-inducible kinase I (SIK1), another HDAC kinase. Our funded parent proposal finds the A-Kinase anchoring protein mAKAPb is required for the short term PKA regulation of HDAC5. Preliminary evidence suggests that mAKAPb also mediates the nuclear export of HDAC5 seen in chronic beta-adrenergic stimulation, presumably via the association with SIK1. The goal of this supplement is to test the hypothesis that the binding of SIK1 by mAKAPb is required for the regulation of HDAC5 and induction of cardiac hypertrophy. This will be tested by developing reagents to disrupt the association by defining the domain on mAKAPb that is required for SIK1 association (Aim1), investigate the importance of mAKAPb-SIK1 binding for PKA-mediated SIK1 protein stabilization and export of HDAC5 (Aim2), and determine the functional significance of complex formation for induction of cardiac hypertrophy (Aim3).
Heart Failure is a syndrome of major public health significance accountable for nearly 300,000 deaths each year. It is estimated that 5.1 million US citizens suffer from heart failure, with nearly 825,000 new cases diagnosed annually. A better understanding of the cellular mechanisms that control cardiac remodeling, including myocyte hypertrophy, may yield better therapeutic regimens with decreased mortality.
