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Background and objective. Cardiovascular disease (CVD) is the most important life-threatening disease. The heart is densely innervated with sympathetic fibers, however prolonged sympathetic activation can damage the heart, resulting in chronic heart failure. Recent findings suggest that norepinephrine (NE) may contribute to cardiac fibrosis and a loss of cardiomyocytes due to apoptosis. Many studies demonstrate that NE is able to induce transforming growth factor-beta (TGF-beta), connective tissue growth factor (CTGF) and vascular endothelial cell growth factor (VEGF), which are two key mediators during the cardiac remodeling process. Nowadays most of the studies in cardiac remodeling are focusing on myocytes, whereas a few studies have been paid to the role of the cardiac fibroblasts (CF). In this thesis, the role of NE in cardiac fibrosis and apoptosis was investigated in CF. The mechanisms by which NE induced TGF-beta, CTGF and VEGF expression in CF were examined. Furthermore, the therapeutic potentials in cardiac fibrosis by blocking NE with adrenergic receptor antagonists were explored. / Conclusions. NE is a pathogenic molecule involving cardiac remodeling. NE exhibited its fibrotic and apoptotic effects on CF in a concentration-dependent mariner. Up-regulation of the TGF-P/CTGF pathway could be a critical mechanism of NE-induced cardiac fibrosis, while NE was capable of activating Bax-Capase 3 to cause CF apoptosis. The presence of CTGF/VEGF complex in CF in response to NE may contribute to the inhibition of angiogenesis, which may be other mechanism of ischemic heart injury. These findings indicate that an increase in NE production associated with over activation of sympathetic system is harmful to the heart and may be a major cause of chronic heart failure. Furthermore, the ability of adrenergic receptor antagonists to block NE-induced cardiac fibrosis suggest the therapeutic approach by using NE receptor antagonists for patients with chronic heart diseases. / Methods and results. Rat CF was isolated, characterized, and stimulated with NF (0.01 to 100 muM for 6 to 72h). Procollagens (I and III), TGF-beta1, bax, bclXL, CTGF and VEGF gene expressions were measured by real-time PCR method. Collagen protein level was measured by Sirius red-based colorimetric method and Western blot. CTGF protein level, VEGF concentration, cell viability, apoptosis caspase 3 activity was measured by Western blot, ELISA, MTT assay cytometry, and flurogenic assay kit, respectively. Results showed that NE at concentrations of 0.01 to 0.1 muM was capable of up-regulating procollagens, TGF-beta1 and CTGF expression (ail p<0.05). However, NE at higher concentrations (10 to 100 muM) significantly induced CF apoptosis (p<0.01). This was demonstrated by a significant increase in bax gene expression and caspase-3 activity, while inhibiting bclXL gene expression. At this higher concentration of NE, CTGF expression was inhibited, whereas VEGF expression was promoted. However, using immunoprecipitation, the CTGF/VEGF complex was found in CF in response to NE, thereby inhibiting angiogenesis such as tube formation in cultured endothelial cells. Interestingly, addition of NE receptor antagonists produced differential effects on procollagen expression and apoptosis. For example, carvedilol and doxazosin, the alpha-receptor-associated non-selective antagonists, were able to inhibit NE-stimulated procollagens expression, but this was not inhibited by specific beta-receptor antagonists, metoprolol and propranolol, suggesting that NE signals through the alpha-receptor to mediate cardiac fibrosis. Interestingly, all four types of adrenoceptor antagonists had no effect on NE-induced CF apoptosis, which suggests that NE induces CF apoptosis via a receptor-independent mechanism. / Lai, Ka Bik. / Adviser: Yu Cheuk Man. / Source: Dissertation Abstracts International, Volume: 70-06, Section: B, page: 3419. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2008. / Includes bibliographical references (leaves 160-199). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

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