Browsing by Subject "cardiac hypertrophy"
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Item Effects of Testosterone on Obesity-Related Cardiac Hypertrophy and Fibrosis(2009-08-01) Wilson, Ana Kaye; Joan F. Carroll; James L. Caffrey; Robert T. MalletWilson, Ana Kaye. Effects of testosterone on obesity-related cardiac hypertrophy and fibrosis. Master of Science (Integrative Physiology), August 2009, 71 pp, 3 tables, 6 figures. Both testosterone and obesity are known to increase renin-angiotensin system activity, leading to cardiovascular dysfunction. This study determined the interactive effects of obesity and testosterone on left ventricular hypertrophy and cardiac fibrotic factors. Male New Zealand White rabbits were fed a lean or 10% added fat diet. After 12 weeks, fat-fed rabbits exhibited increased left ventricular weight (6.05±0.16 vs. 4.75±0.10 g, respectively, p≤0.05) and cardiomyocyte cross-sectional area compared to lean rabbits (372.3±19.0 vs. 305.0±13.4μm2, respectively; p≤0.01). These effects were attenuated by both castration and treatment with the angiotensin type 1 receptor blocker, losartan. Obese rabbits did not exhibit increased myocardial collagen as expected. However, castration and losartan treatment increased matrix metalloproteinase-2 (MMP-2) activity in obese rabbits. Despite the effects of castration hypertrophy and MMP-2 activity, castration did not attenuate plasma renin activity of aldosterone. These data suggest that testosterone contributes to obesity-related left ventricular hypertrophy and decreases collagen degradation, independent of renin activity.Item The Role of 14-3-3 in the Signaling of Cardiac Hypertrophy(2002-01-01) Ellis, Joel James; Stephen R. Grant; Neeraj Agarwall; Glenn DillonEllis, Joel J., The Role of 14-3-3 in the Signaling of Cardiac Hypertrophy. Master of Science (Biotechnology), January, 2002, 97pp., 21 illustrations, bibliography, 46 titles. The METF2 family of transcription factors is regulated by class II histone deacetylaces in the nucleus. MEF2-dependent gene expression in cardiomyocytes is augmented by the 14-3-3 chaperone family which binds and sequesters class II HDACs in the cytoplasm upon the activation of CaM kinase I & IV. A 14-3-3β mutant was made by conservatively substituting aspartate for serine 60 and serine 65. In MEF2 enhancer-reporter transfection assays, expression of the 14-3-3β double mutant silenced transcription mediated by CaM KI & IV in both cardiomyocytes and vascular smooth muscle cells. Co-expression of the 14-3-3β double mutant was also able to suppress MEF2 enhancer activation by phenylephrine in cardiomyocytes and vascular smooth muscle cells. Mammalian two-hybrid cloning of the 14-3-3β wild-type and double mutant genes will allow analysis of the protein-protein interaction between the different 14-3-3β monomers. These data suggest that 14-3-3β plays a critical role in the silencing of MEF2 mediated hypertrophy-sensitive gene transcription.Item Urotensin II-Mediated Cardiac Hypertrophic Gene Induction Requires Cam Kinase Kinase(2006-12-01) Valencia, Thomas G.; Grant, Stephen R.; Das, Hriday K.; Shepard, AllanThomas G. Valencia, Urotensin II-mediated cardiac hypertrophic gene induction requires CaM kinase kinase. Doctor of Philosophy (Biomedical Sciences), December 2006, 191 pp, 2 tables, 42 illustrations, references, 163 titles. Cardiac hypertrophy arises from various forms of physical stress that result in an increased workload and decreased cardiac output. Therefore, cardiac hypertrophy is the common compensatory mechanism employed by the heart to maintain a normal cardiac output. Gq-coupled receptors such as the angiotensin II receptor (AngIIR) and the endothelin-1 receptor (ET-1R) are capable of activating the CaMK and MAPK cascades and are involved in cardiac hypertrophy. Mechanical stress has been shown to result in the release of both AngII and ET-1 from the heart leading to an autocrine stimulation of myocyte hypertrophy. The Urotensin II receptor (UIIR) is coupled to Gq and is expressed in the healthy adult heart at low levels and becomes over-expressed under pathological conditions that leads to hypertrophy. UII is capable of inducing hypertrophy in cardiomyoctyes only when sufficient receptor is expressed. In this study, the mechanism by which UII becomes expressed was examined as was the mechanisms through which UII induces hypertrophy of cardiomyocytes. Data described in this dissertation demonstrated of UIIR message and protein. UII was able to stimulate the promoter activity of ANF and SkA and the transcriptional activity of MEF2 in a CaMKK-dependent manner. UII stimulation of ANF, BNP, βMHC and SkA gene expression was dependent on CaMKK. UII stimulation caused the CaMKK-dependent activation of CaMKI. CaMKI completely rescued UII stimulation of ANF and SkA promoter activities as well as MEF2 activity with CaMKK pharmacologically inhibited. We demonstrated that the UII-induced activation of p38 and ERK1/2 MAP kinases was dependent on CaMKK suggesting a novel cross-talk mechanism not previously described in cardiomyoctyes. Both UII- and CaMKI-mediated induction of ANF, SkA and MEF2 reporter activities was dependent on p38 and ERK1/2. Taken together, these data identify CaMKK as a central mediator in Gq activation of hypertrophy by UII.