David B Hood

Publications (5)23.3 Total impact

• Article: Identification of potent and selective amidobipyridyl inhibitors of protein kinase D.

  Erik L Meredith, Kimberly Beattie, Robin Burgis, Michael Capparelli, Joseph Chapo, Lucian Dipietro, Gabriel Gamber, Istvan Enyedy, David B Hood, Vinayak Hosagrahara, [......], Craig Plato, Chang Rao, Olga Rozhitskaya, Nicolas Soldermann, Clayton Springer, Maurice van Eis, Richard B Vega, Wanlin Yan, Qingming Zhu, Lauren G Monovich
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  ABSTRACT: The synthesis and biological evaluation of potent and selective PKD inhibitors are described herein. The compounds described in the present study selectively inhibit PKD among other putative HDAC kinases. The PKD inhibitors of the present study blunt phosphorylation and subsequent nuclear export of HDAC4/5 in response to diverse agonists. These compounds further establish the central role of PKD as an HDAC4/5 kinase and enhance the current understanding of cardiac myocyte signal transduction. The in vivo efficacy of a representative example compound on heart morphology is reported herein.
  Journal of Medicinal Chemistry 08/2010; 53(15):5422-38. · 4.80 Impact Factor
• Article: A novel kinase inhibitor establishes a predominant role for protein kinase D as a cardiac class IIa histone deacetylase kinase.

  Lauren Monovich, Richard B Vega, Erik Meredith, Karl Miranda, Chang Rao, Michael Capparelli, Douglas D Lemon, Dillon Phan, Keith A Koch, Joseph A Chapo, David B Hood, Timothy A McKinsey
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  ABSTRACT: Class IIa histone deacetylases (HDACs) repress genes involved in pathological cardiac hypertrophy. The anti-hypertrophic action of class IIa HDACs is overcome by signals that promote their phosphorylation-dependent nuclear export. Several kinases have been shown to phosphorylate class IIa HDACs, including calcium/calmodulin-dependent protein kinase (CaMK), protein kinase D (PKD) and G protein-coupled receptor kinase (GRK). However, the identity of the kinase(s) responsible for phosphorylating class IIa HDACs during cardiac hypertrophy has remained controversial. We describe a novel and selective small molecule inhibitor of PKD, bipyridyl PKD inhibitor (BPKDi). BPKDi blocks signal-dependent phosphorylation and nuclear export of class IIa HDACs in cardiomyocytes and concomitantly suppresses hypertrophy of these cells. These studies define PKD as a principal cardiac class IIa HDAC kinase.
  FEBS letters 12/2009; 584(3):631-7. · 3.54 Impact Factor
• Article: Suppression of HDAC nuclear export and cardiomyocyte hypertrophy by novel irreversible inhibitors of CRM1.

  Lauren Monovich, Keith A Koch, Robin Burgis, Ekundayo Osimboni, Thierry Mann, Daniel Wall, Jinhai Gao, Yan Feng, Richard B Vega, Benjamin A Turner, David B Hood, Andy Law, Philip J Papst, David Koditek, Joseph A Chapo, Brian G Reid, Lawrence S Melvin, Nikos C Pagratis, Timothy A McKinsey
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  ABSTRACT: Histone deacetylase 5 (HDAC5) represses expression of nuclear genes that promote cardiac hypertrophy. Agonism of a variety of G protein coupled receptors (GPCRs) triggers phosphorylation-dependent nuclear export of HDAC5 via the CRM1 nuclear export receptor, resulting in derepression of pro-hypertrophic genes. A cell-based high-throughput screen of a commercial compound collection was employed to identify compounds with the ability to preserve the nuclear fraction of GFP-HDAC5 in primary cardiomyocytes exposed to GPCR agonists. A hit compound potently inhibited agonist-induced GFP-HDAC5 nuclear export in cultured neonatal rat ventricular myocytes (NRVMs). A small set of related compounds was designed and synthesized to evaluate structure-activity relationship (SAR). The results demonstrated that inhibition of HDAC5 nuclear export was a result of compounds irreversibly reacting with a key cysteine residue in CRM1 that is required for its function. CRM1 inhibition by the compounds also resulted in potent suppression of cardiomyocyte hypertrophy. These studies define a novel class of anti-hypertrophic compounds that function through irreversible inhibition of CRM1-dependent nuclear export.
  Biochimica et Biophysica Acta 06/2009; 1789(5):422-31. · 4.66 Impact Factor
• Article: Canonical transient receptor potential channels promote cardiomyocyte hypertrophy through activation of calcineurin signaling.

  Erik W Bush, David B Hood, Philip J Papst, Joseph A Chapo, Wayne Minobe, Michael R Bristow, Eric N Olson, Timothy A McKinsey
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  ABSTRACT: The calcium/calmodulin-dependent phosphatase calcineurin plays a central role in the control of cardiomyocyte hypertrophy in response to pathological stimuli. Although calcineurin is present at high levels in normal heart, its activity appears to be unaffected by calcium during the course of a cardiac cycle. The mechanism(s) whereby calcineurin is selectively activated by calcium under pathological conditions has remained unclear. Here, we demonstrate that diverse signals for cardiac hypertrophy stimulate expression of canonical transient receptor potential (TRPC) channels. TRPC consists of a family of seven membrane-spanning nonselective cation channels that have been implicated in the nonvoltage-gated influx of calcium in response to G protein-coupled receptor signaling, receptor tyrosine kinase signaling, and depletion of internal calcium stores. TRPC3 expression is up-regulated in multiple rodent models of pathological cardiac hypertrophy, whereas TRPC5 expression is induced in failing human heart. We demonstrate that TRPC promotes cardiomyocyte hypertrophy through activation of calcineurin and its downstream effector, the nuclear factor of activated T cells transcription factor. These results define a novel role for TRPC channels in the control of cardiac growth, and suggest that a TRPC-derived pool of calcium contributes to selective activation of calcineurin in diseased heart.
  Journal of Biological Chemistry 12/2006; 281(44):33487-96. · 4.77 Impact Factor
• Article: The CRM1 nuclear export receptor controls pathological cardiac gene expression.

  Brooke C Harrison, Charles R Roberts, David B Hood, Meghan Sweeney, Jody M Gould, Erik W Bush, Timothy A McKinsey
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  ABSTRACT: Diverse pathological insults trigger a cardiac remodeling process during which myocytes undergo hypertrophy, with consequent decline in cardiac function and eventual heart failure. Multiple transcriptional regulators of pathological cardiac hypertrophy are controlled at the level of subcellular distribution. For example, prohypertrophic transcription factors belonging to the nuclear factor of activated T cells (NFAT) and GATA families are subject to CRM1-dependent nuclear export but are rapidly relocalized to the nucleus in response to cues for hypertrophic growth. Here, we demonstrate that the antihypertrophic chromatin-modifying enzyme histone deacetylase 5 (HDAC5) is shuttled out of the cardiomyocyte nucleus via a CRM1-mediated pathway in response to diverse signals for hypertrophy. CRM1 antagonists block the agonist-mediated nuclear export of HDAC 5 and repress pathological gene expression and associated hypertrophy of cultured cardiomyocytes. Conversely, CRM1 activity is dispensable for nonpathological cardiac gene activation mediated by thyroid hormone and insulin-like growth factor 1, agonists that fail to trigger the nuclear export of HDAC5. These results suggest a selective role for CRM1 in derepression of pathological cardiac genes via its neutralizing effects on antihypertrophic factors such as HDAC5. Pharmacological approaches targeting CRM1-dependent nuclear export in heart muscle may have salutary effects on cardiac function by suppressing maladaptive changes in gene expression evoked by stress signals.
  Molecular and Cellular Biology 01/2005; 24(24):10636-49. · 5.53 Impact Factor