Collections > Electronic Theses and Dissertations > Effect of adrenomedullin over-expression in the cardiovascular system during development and disease
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Since the discovery of adrenomedullin (Adm - gene; AM - protein) in 1993, many roles for this widely expressed peptide have been described in the cardiovascular system. Numerous studies have determined that circulating levels of AM in human blood are elevated during many disease conditions, leading to questions about the feasibility of using this peptide as a biomarker of disease severity, as well as inquiries into the function of elevated AM in these contexts. In order to evaluate the effect of elevated AM during disease, gene-targeting techniques were used to generate mice that constitutively over-express Adm, abbreviated as Admhi/hi. The initial phenotypical analysis of this line revealed that Admhi/hi mice have enlarged hearts due to hyperplasia during development. Through genetic approaches, we determined that Adm over-expression primarily in the epicardium promotes this cardiac hyperplasia. Analysis of Adm expression levels between male and female Admhi/hi animals led to the unexpected finding that female Admhi/hi mice express Adm at levels 60-times greater than wildtype controls in the heart; whereas Admhi/hi males over-express Adm by 3-fold in the heart. Previous studies have demonstrated that Adm expression can be induced by estrogen; however, the potential for estrogen-induced negative regulation of Adm had not been explored. We found that many estrogen-induced microRNAs target the 3'UTR of Adm, including the novel microRNA, miR-879, to balance Adm expression in the female heart. Finally, many groups have demonstrated that AM provides protection to the heart during cardiovascular disease. Nonetheless, whether the physiological elevation of AM during human disease affects disease progression remains unknown. We asked whether constitutive over-expression of AM in the context of chronic hypertension provided any benefit by crossing the renin transgenic mouse model of hypertension to the Admhi/hi line. From this study, we found that Adm over-expression did not alter the degree of hypertrophy or fibrosis in the heart. However, the results from this study are inconclusive, as the renin transgenic mice with wildtype levels of Adm did not exhibit the cardiac fibrosis previously reported, indicating that the mixed genetic background of our experimental animals alters cardiovascular pathology independent of Adm status.