Exercise, RhoA and Cardioprotection

Aya Matsumoto (2011). Exercise, RhoA and Cardioprotection PhD Thesis, School of Human Movement Studies, The University of Queensland.

       
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Author Aya Matsumoto
Thesis Title Exercise, RhoA and Cardioprotection
School, Centre or Institute School of Human Movement Studies
Institution The University of Queensland
Publication date 2011-08
Thesis type PhD Thesis
Supervisor Jeff Coombes
Barbara Rolfe
Robert Fassett
Susan Marsh
Total pages 149
Total colour pages 5
Total black and white pages 144
Subjects 11 Medical and Health Sciences
Abstract/Summary Regular exercise prevents cardiovascular disease (CVD), however the molecular mechanisms to explain the benefits are not well understood. Recent evidence suggests that exercise-induced changes in endothelial cell morphology and function may play a major role in preventing CVD. In addition, it is becoming clear that reactive oxygen species (ROS) via reduction-oxidation (redox) signalling are involved in some of the exercise training adaptations. Therefore, the aim of this thesis was to investigate mechanisms in which exercise may provide cardiovascular protection. Results from the first study led to subsequent studies focussing on the ras homolog gene family member A (RhoA) pathway and its downstream effector; Rho kinase (ROCK). The first study was an in vivo experiment that investigated the effects of exercise and antioxidant supplementation on endothelial cell gene expression. Rats underwent 14 weeks of exercise training with and without antioxidant supplementation with α-tocopherol and α-lipoic acid. Following the interventions, left ventricular and coronary artery endothelial cells were isolated and gene expression in these cells were measured by microarray. There were diverse expression changes in both endothelial cell types. Specific genes of interest showing change were confirmed using real time RT-PCR. This analysis found a gene involved in cardiovascular disease progression, RhoA, was down-regulated by exercise. The second study used a RhoA/ROCK inhibitor (fasudil) to further investigate the effects of exercise training. In this study the Apolipoprotein E knockout (ApoE-/-) atherosclerotic mouse model was used. After the interventions, the brachiocephalic artery was removed. Plaque morphology, including staining of lipid lesion areas, intima:media ratio, macrophage and smooth muscle cell contents in brachiocephalic artery were analysed. The results indicated that the beneficial effects of exercise are similar, at least in part, to the inhibitory effects on the RhoA/ROCK signalling pathway. The final study was an in vitro investigation examining the interaction between H2O2-activated signalling and the RhoA/ROCK pathway in human aortic endothelial cells (HAEC). Cells were treated with H2O2 for 5, 15 and 30 minutes. In separate experiments, cells were pre-treated with fasudil for one hour before H2O2 stimulation. The results showed that in HAEC, H2O2 induced activation of members of the MAPK pathway, namely ERK, STAT3, JNK, P70S6 kinase, CREB and p38. Most importantly, since pre-treatment with the RhoA/ROCK pathway inhibitor fasudil led xii to significant changes in the activation of ERK, STAT3 and JNK, it is most likely that activation of these important pro-atherogenic mediators occur via the RhoA/ROCK pathway. In summary, the findings of this thesis support the notion that the beneficial effects of exercise training in CVD is due, in part, to the inhibitory effects on RhoA/ROCK signalling pathway in endothelial cells. Furthermore, this redox-sensitive RhoA/ROCK pathway is involved in some of the H2O2-induced MAPK signalling. Taken together, this study contributes to understanding the mechanisms of exercise-induced cardioprotection via the RhoA/ROCK pathway in endothelial cells.
Keyword Exercise
RhoA
ROCK
Endothelial cells
Atherosclerosis
Gene Expression
ApoE-/- mice
Antioxidant
MAPK signalling
Hydrogen Peroxide
Additional Notes Colour = 55, 56, 57, 71, 74 Landscape = 30, 31, 37, 38, 39, 42, 43, 46, 47, 49, 60, 109

 
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Created: Fri, 12 Aug 2011, 08:17:07 EST by Ms Aya Matsumoto on behalf of Library - Information Access Service