Browsing by Subject "Histone Deacetylase Inhibitors"
Now showing 1 - 3 of 3
- Results Per Page
- Sort Options
Item Inhibition of Class I HDACs Blunts Cardiac Hypertrophy via TSC2-Dependent mTOR Repression(2014-11-21) Morales Medina, Cyndi Raquel; Rothermel, Beverly A.; Levine, Beth; Yin, Helen L.; Turer, Aslan T.; Hill, Joseph A.Stress-induced pathological hypertrophy is observed in most forms of heart disease. If left unchecked, pathological remodeling can lead to heart failure. Histone deacetylases (HDACs) participate in the progression of pathological cardiac growth, and small molecule inhibitors of HDACs can both reduce and regress pathological hypertrophy. The mammalian target of rapamycin complex 1 (mTORC1) is an important regulator of cell growth. It has been shown that mTORC1 is active during cardiac hypertrophy, leading to increased protein synthesis. Inhibiting mTORC1 can repress pathological remodeling. Interestingly, pan-HDAC inhibitors target mTOR activity in some cancer models. Therefore, we hypothesized that class I HDACs regulate cardiac hypertrophy in an mTOR-dependent manner. To test this hypothesis, neonatal rat ventricular myocytes (NRVMs) were exposed to a variety of growth stimuli, and class I HDACs were inhibited by either pharmacological means or by knockdown of individual HDAC isoforms. We found that HDAC1, HDAC2 and HDAC3 act together to facilitate pathological and physiological cardiomyocyte hypertrophy. In addition, inhibition of class I HDACs decreases mTOR activation by hypertrophic growth stimuli. HDAC inhibition also decreased mTOR activity in the setting of pressure overload using an in vivo surgical model of transverse aortic constriction (TAC). Adult mice with conditional cardiomyocyte-specific knockout of both HDAC1 and HDAC2 together had improved function following TSC surgery as well as decreased mTOR activity. Tuberin (TSC2) is a component of the tuberin-hamartin complex, which inhibits mTOR. We found that inhibition of class I HDACs by either genetic knockdown or using small molecules increased expression of TSC2 in both NRVMs and embryonic stem cell-derived cardiomyocytes. Furthermore, using siRNA we observed that TSC2 is required for HDAC-dependent inhibition of mTOR in NRVMs. These findings point to mTOR, and TSC2-dependent control of mTOR, as critical components of the mechanism through which HDAC inhibitors blunt pathological cardiac growth. Together, these results enhance our understanding of the function of HDACs in cardiac pathology and facilitate the ultimate translational application of HDAC inhibitors in the treatment of heart disease.Item Progranulin Biology: Small Molecule Enhancers of Progranulin Expression and Biochemical Analysis of Granulin Receptors(2012-12-05) Cenik, Basar 1981-; Terman, Jonathan R.; Herz, Joachim; Yu, Gang; Bezprozvanny, IlyaFrontotemporal dementia (FTD) is the second most common presenile dementia syndrome. Mutations in the GRN gene account for about 20% of patients with familial FTD. The protein encoded by GRN, progranulin, is a secreted glycoprotein with growth factor-like and immunomodulatory activities. Human progranulin contains seven granulin domains (denoted granulins A through F) that can be individually liberated following proteolytic cleavage. It is uncertain whether the holoprotein, the granulins or both mediate the biological effects of progranulin. All pathogenic GRN mutations result in haploinsufficiency and decreased extracellular progranulin. Therefore, increasing progranulin expression from the wild-type allele or (pro)granulin receptor agonists may be therapeutic in FTD. The overall goals of the work presented here were to identify small molecule enhancers of progranulin expression and (pro)granulin receptors that can be drug targets for the treatment and prevention of GRN deficient FTD. As described here, I discovered that suberoylanilide hydroxamic acid (SAHA), an FDA-approved histone deacetylase (HDAC) inhibitor, enhances GRN expression and nearly normalizes progranulin levels in haploinsufficient primary human cells from GRN mutation carriers. I also discovered that granulin A binds three proteins in solubilized extracts of rodent brain membranes: wolframin, excitatory amino acid transporter 1 (EAAT1), and the α3 subunit of the Na+/K+ ATPase. I argue that these proteins are candidates for a putative granulin receptor.Item [Southwestern News](2003-07-28) Shields, Amy; Morrison, Susan