Gap junction channels, formed by hexamers of connexins, are the molecular conduits for conduction of electrical signals between cardiac cells. It is generally believed that the pattern, density, and functional state of gap junction channels modulates the speed and direction of action potential propagation. This makes gap junctions of potentially great significance to conditions with abnormal conduction, e.g. ischemic and hypertrophic heart disease. The structural substrate for arrhythmogenesis in these myocardial diseases is uncertain but may involve gap junction channels. Immunostaining has shown loss of connexin43 (Cx43) in the infarct zone with profuse and disorganized Cx43 localization in the border zone. left ventricular hypertrophy is also characterized by myocardial remodeling and perhaps connexins are part of the remodeling. The process of gap junction channel formation & degradation is largely unknown. In our prior work, specific antibodies to Cx43 have been produced and the distribution of Cx43 characterized in different myocardial tissues. We have also developed an in vitro model to study the turnover of connexins. This project aims to test the hypothesis that change in the pattern and amount of connexins (i.e. remodeling) is one of the primary structural alterations associated with abnormal conduction in ischemic and hypertrophic heart disease. We will also test the subhypotheses that i) neurohormonal inputs to the cardiomyocytes modulate redistribution of connexins and ii) that the expression and localization of connexins is modulated by mechanical force. The experiments will address the following specific aims: 1. To characterize the amount and distribution of connexins in normal and infarcted myocardium and investigate the role of sympathetic/ parasympathetic inputs in the regulation of connexin expression. 2. To characterize connexin distribution in normal, hypertrophic and atrophic myocardium and determine if neurohormonal factors alter connexin expression. 3. To determine the role of mechanical and neurohormonal factors in modulating expression and localization of connexins. We shall use biochemical and immunohistochemical techniques, confocal microscopy, transgenic animals, and cultured cardiomyocytes to carry out the studies. Better understanding of connexin remodeling may lead to new insights into abnormal conduction and development of arrhythmias in ischemic and hypertrophic heart disease.
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