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This dissertation, Modulation of Vascular Function by Genistein Through CAMP-PKA Signaling Cascade in Porcine Coronary Artery by Wai-hung, William, Ng, 伍偉鴻, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled Modulation of Vascular Function by Genistein through cAMP-PKA Signaling Cascade in Porcine Coronary Artery Submitted by William Wai Hung Ng for the degree of Master of Philosophy at the University of Hong Kong in October 2006 Pre-menopausal women enjoy a lower risk of atherosclerosis than men or their post-menopausal counterparts. This is attributed to the vascular protective effect of estrogen, which is partly explained by enhancement of nitric oxide (NO) release from vascular endothelium. However, the use of estrogen as vascular protective agent is not practical due to increased risk of breast and endometrial cancer, and feminization in male. Meanwhile, the consumption of soy containing diet may reduce the risk of cardiovascular disease. Genistein is the major isoflavone present in soy exhibiting estrogenic property. Genistein thus belongs to the class of phytoestrogen. We propose genistein could enhance NO release from vascular endothelium or upregulate eNOS expression in endothelium, thus explaining the vascular protective effect of soy consumption. However, 30 minute incubation of genistein in various concentrations -5 -8 (10 to 10 M) did not alter NO release from endothelial cells. Incubation of -5 -8 genistein at various concentrations (10 to 10 M) for 12 hours did not change the IIlevel of expression of eNOS from the endothelium. Genistein did not alter the NO component of endothelium dependent vasorelaxation function. Previous reports in our laboratory demonstrated the enhancement of endothelium-independent relaxation and impairment of agonist-induced contraction of porcine coronary artery by genistein. The action of genistein was observed in a -5.5 concentration of 10 M, which is the concentration attainable after regular consumption of soy-containing diet. The action of genistein was found to be dependent on the 3'-5' cyclic adenosine monophosphate - protein kinase A (cAMP-PKA) signaling pathway. We hypothesize genistein could stimulate PKA activity in vascular smooth muscle (VSM), thus leading to vasorelaxation. Porcine -4.5 coronary artery smooth muscle tissue was used as a model. 10 M genistein directly -5.5 enhanced PKA activity in VSM. Genistein at 10 M exerted potentiating effect with -7 -7 10 M forskolin, on PKA activity. 10 M forskolin itself gave negligible effect on PKA activity in VSM. The PKA potentiating effect of genistein could be blocked by SQ 22536, an adenylate cyclase inhibitor, but NF 449, a Gs protein inhibitor did not alter the PKA potentiating effect of genistein. Therefore, the target of genistein in the cAMP-PKA pathway lies in adenylate cyclase. Genistein acts synergistically with forskolin in activation of adenylate cyclase, thus raising intracellular cAMP IIIconcentration and leading to PKA activation. This may explain the vasorelaxing effect of genistein, and open the way of using genistein as a prophylactic agent in the prevention of ischaemic heart disease. Word Count: 398 words Signed: .................................. IV DOI: 10.5353/th_b3719125 Subjects: Coronary arteriesIsoflavonesNitric oxide

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