Item – Theses Canada

​
OCLC number
299222678
Link(s) to full text
LAC copy
LAC copy
Author
Tsuji, Matthew R. S.,1981-
Title
The role of heme oxygenase-1 in pro-oxidant-induced cardiac hypertrophy.
Degree
M. Sc. -- Queen's University, 2006
Publisher
Ottawa : Library and Archives Canada = Bibliothèque et Archives Canada, [2007]
Description
2 microfiches
Notes
Includes bibliographical references.
Abstract
Cardiac hypertrophy is a compensatory response to maintain ejection fraction and normalize wall stress in face of hemodynamic overload. Oxidative stress (OS) plays a major role in activating the signaling pathways involved in inducing cardiac hypertrophy. Previous work showed that hemin reduces hypertrophy and enhances cardiac performance 'in vivo' in response to pressure overload, in association with reduced OS and increased heme oxygenase-1 (HO-1) expression. I hypothesized hemin inhibits pro-oxidant induced cardiomyocyte hypertrophy by a mechanism that is, at least partially dependent on HO-1 activation and the hypertrophic effect of hemin/HO-1 is mediated via downstream inhibition of pro-hypertrophic kinases. OS and hypertrophy were induced in HL-1 murine cardiomyocytes by exposure to 200 [mu]M hydrogen peroxide (H2O2). In order to determine the direct effects of HO-1/hemin, cardiomyocytes were transduced with adenovirus for HO-1 or pre-treated with 25 [mu]M hemin, 24 hours prior to H2O2 treatment. Cell size was measured using planar morphometry, flow cytometry analysis of forward scatter and 3H-leucine incorporation 48 hours after H2O2 exposure. Activities of Akt, GSK3[beta] and p70S6K were determined using phospho-specific antibodies. Pre-treatment with hemin significantly decreased reactive oxygen species generation and led to a concomitant reduction in cell size and leucine incorporation 48 hours after H2O2 exposure. The pro-hypertrophic effect of H 2O2 was partially reversed by pre-treatment with the anti-oxidant N-acetyl cysteine. The effect of hemin was mimicked by exogenous HO-1 over-expression using adenovirus and was inhibited by pre-treatment with HO-1 short interfering RNA. Adenoviral HO-1 over-expression did not significantly alter the time course of ERK 42/44, Akt, GSK3[beta] or p70S6K phosphorylation in response to H2O2, suggesting that the anti-hypertrophic action of HO-1 is unlikely mediated via inhibition of these hypertrophic kinases. However, both hemin treatment and HO-1 over-expression reduced the transcriptional activity of NF-[kappa]B, suggesting that the anti-hypertrophic effects of hemin/HO-1 may be mediated, at least in part by inhibition of NF-[kappa]B-induced activation of the hypertrophic gene program. These results demonstrate that hemin, presumably via induction of HO-1 activity, is a novel anti-hypertrophic agent against pro-oxidant induced cardiomyocyte growth and may yield therapeutic potential in treatment of cardiac hypertrophy and prevention of heart failure.
ISBN
9780494188309
0494188308