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Pathogenic mechanisms of norepinephrine in cardiac injury in vitro. / 副腎上腺素在人工培養心臟纖維細胞的差別影響 / CUHK electronic theses & dissertations collection / Fu shen shang xian su zai ren gong pei yang xin zang xian wei xi bao de cha bie ying xiangJanuary 2008 (has links)
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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Sympathetic sprouting and changes in nociceptive sensory innervation in the glabrous skin of the rat hind paw following partial peripheral nerve injuryYen, Laurene Dao-Pei. January 2007 (has links)
Previous studies have suggested that sympathetic sprouting in the periphery may contribute to the development and persistence of sympathetically-maintained pain in animal models of neuropathic pain. The purpose of this thesis was to examine morphological changes in the cutaneous innervation in rats after chronic constriction injury (CCI) to the sciatic nerve. More specifically, this study addresses the question of whether sympathetic fibres sprout de novo into the upper dermis of the rat hindpaw skin after CCI of the sciatic nerve. We also determined changes in peptidergic sensory innervation following CCI. / At several periods post-injury, hind paw skin was harvested and processed using a monoclonal antibody against dopamine-beta-hydroxylase to detect sympathetic fibres and a polyclonal antibody against calcitonin gene-related peptide to identify peptidergic sensory fibres. We observed migration and branching of sympathetic fibres into the upper dermis of the hind paw skin, from where they were normally absent. This migration was first detected at 2 weeks, peaked at 4 to 6 weeks and lasted for at least 20 weeks post-lesion. At 8 weeks post-lesion, there was a dramatic increase in the density of peptidergic fibres in the upper dermis. Quantification revealed that densities of peptidergic fibres 8 weeks post-lesion were significantly above levels of sham animals. Interestingly, the ectopic sympathetic fibres did not innervate blood vessels but formed a novel association and wrapped around sprouted peptidergic nociceptive fibres. Our data show a long-term sympathetic and sensory innervation change in the rat hind paw skin after the chronic constriction injury. This novel fibre arrangement after nerve lesion may play an important role in the development and persistence of sympathetically-maintained neuropathic pain after partial nerve lesions.
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Sympathetic sprouting and changes in nociceptive sensory innervation in the glabrous skin of the rat hind paw following partial peripheral nerve injuryYen, Laurene Dao-Pei. January 2007 (has links)
No description available.
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