Cytochrome c oxidase (COX) gene expression profile and IGF-I signaling in hypertensive cardiac hypertrophy
| Autor: | Wei-Wen, 郭薇雯 |
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| Rok vydání: | 2005 |
| Druh dokumentu: | 學位論文 ; thesis |
| Popis: | 93 1.It is well known that pressure overload leads to cardiac hypertrophy. The physiological, biochemical, or molecular mechanisms, that underlie the myocyte enlargement occurring during cardiac hypertrophy are not completely understood. The contribution of the mitochondrial components, the main source of energy for the hypertrophic growth of the heart, is not well understood. In the present study, using a model system, complete coarctation of the rat abdominal aorta was used to study the rapid development of cardiac hypertrophy. One to two days after surgery, we observed significantly higher blood pressure and cardiac hypertrophy, which remained constantly high afterwards. We found that mitochondrial COX protein level and enzyme activity increased as the heart enlarged and, however, dropped even lower than baseline 20 days following surgery. We also found an early increased level of cytochrome c oxidase (COX) mRNA determined by in situ hybridization and dot blotting assays in the hypertrophied hearts, though the increased level had dropped to the baseline 20 days after surgery. In addition, the COX protein was significantly lower in natural hypertension-induced hypertrophic hearts in spontaneously hypertensive rats (SHR) and stroke-prone SHR (SPSHR) than in normotensive rats (WKY) throughout the whole period of 12 weeks. Taken together, the lower efficiency of mitochondrial activity in the enlarged hearts of rats with long-term complete coarctation or SHR and SPSHR could be, at least partially, the cause of hypertensive cardiac disease in these two models. Additionally, the rapid cardiac hypertrophy induced by experimental complete coarctation was accompanied by a disproportionate increase in COX activity, which was suggested to maintain the cardiac energy-producing capacity in overloaded hearts. 2.Insulin-like growth factor-I (IGF-I) signaling is reported to contribute to the modulation of blood pressure and set in survival and hypertrophic responses in cardiac tissue. However, whether the IGF-I signaling normally acts in cardiac tissues of hypertensive rats is unknown. In this study, using spontaneously hypertensive rats (SHR) and stroke prone spontaneously hypertensive rats (SPSHR), both with early blood pressure increases, and Wistar-Kyoto (WKY) as controls, we measured the hypertrophic and IGF-I signaling activity changes in rat hearts at 4, 6 and 12 weeks of age. Both SHR and SPSHR were found to have significantly increased blood pressures and ratios of heart- and left ventricle- to body weight at 12 weeks of age. However, IGF-IR and its downstream signaling, including the protein levels of PI3K and phosphorylated Akt, known to maintain physiological cardiac hypertrophy and cardiomyocyte survival, were downregulated. The results of dot blotting showed that cardiac mRNA levels of IGF-I in hypertensive rats were higher than those in controls starting from the age of 4 weeks. This difference suggests the increased ligand IGF-I mRNA levels may be a compensatory response caused by the impaired IGF-I signaling. Moreover, enhanced cardiac cytosolic cytochrome-c, a mitochondria-dependent apoptotic pathway component, tended to occur in both hypertensive rats, although it did not reach a significant level. These findings indicate that impaired IGF-IR signaling occurs at early stages, and it may contribute, at least partially, to the development of hypertension and pathological cardiac hypertrophy and to cardiomyocyte apoptosis at later stages in SHR and SPSHR. |
| Databáze: | Networked Digital Library of Theses & Dissertations |
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