Peroxisome proliferation activated receptor-Gamma : macrophage effects on cardiac collagen homeostasis after myocardial infarction / Marshall W. Nichols.
| Author/creator | Nichols, Marshall W. author. |
| Other author | Katwa, Laxmansa, degree supervisor. |
| Other author | East Carolina University. Department of Biology. |
| Format | Theses and dissertations |
| Production | 2008. |
| Description | 91 leaves : illustrations (some color) ; 29 cm |
| Supplemental Content | Access via ScholarShip |
| Subjects |
| Summary | Peroxisome Proliferator Activated Receptor (PPAR) Gamma agonists are actively being used worldwide to treat insulin resistance in patients with type II diabetes mellitus. These agonists are synthetic ligands designed to increase insulin sensitivity by up regulating the expression of genes under the promoter control of the Peroxisome Proliferator Response Elements in the nucleus of metabolically active cells. This activation leads to increased lipid mobility and decreased insulin resistance providing a more efficient handling of metabolic products by individual cells [24], Along with this primary purpose, agonism of PPAR receptors, specifically PPAR-delta, produces side effects. A recent clinical study review found evidence that a side effect of these agonists could potentially be causing an increase in the incident and severity of MI in diabetics taking Rosiglitazone (a synthetic PPAR-delta ligand) over a control group [25]. The reasons for this increased risk are still unknown. PPAR-delta is active in hundreds of different pathways in many different cell types throughout the body. This study is specifically testing the hypothesis that PPAR-delta activation in macrophages plays an important role in the process of fibrosis during repair of a myocardial infarction. This fibrosis is predominantly the laying down of collagens I and III by fibroblasts and myofibroblasts. The phenotypic switch of fibroblasts to myofibroblasts results directly in a change in the collagen I to collagen III ratio, which has been shown to be indicative of the effectiveness of remodeling. Using wild type and PPAR-delta knockout mice (macrophage specific knockout) both with and without myocardial infarction, the study uses histological and phenotypic expression analysis to analyze the effects of the absence of this nuclear receptor protein. Histological analysis includes measurements of left ventricular volume, left ventricular wall thickness and a percent measurement of infarct size compared between groups. Phenotypic expression analysis consists of relative expression analysis of seven known remodeling factors via PCR amplification. This study found that at the mRNA expression level, collagens I and III, Matrix Metalloproteinases 1 and 9, as well as Tissue Inhibitors of Metalloproteinases 1 and 2 all saw significant increases in the PPAR-delta knockout with MI group over other groups (significance indicated by P < 0.05). These results were not reflected at the tissue level indicating either a rate change in the process of fibrosis in the absence of macrophage PPAR-delta or an insignificance of macrophage PPAR-delta on the final outcomes of fibrotic response. This is a novel study in that no research into the role of the macrophage PPAR-delta in the post-MI remodeling process in the macrophage PPAR-delta knockout mouse model has been recorded to date and the expression profile of remodeling factors post-Ml may suggest advantageous or deleterious effects of PPAR-delta agonists on the remodeling process. |
| General note | Presented to the faculty of the Department of Biology. |
| General note | Advisor: Laxmansa C. Katwa |
| Dissertation note | M.S. East Carolina University 2008 |
| Bibliography note | Includes bibliographical references (leaves 88-91). |
| Genre/form | Academic theses. |
| Genre/form | Academic theses. |
| Genre/form | Thèses et écrits académiques. |
Availability
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|---|---|---|---|---|
| Joyner | University Archives | ASK AT SPECIAL COLLECTIONS DESK | ✔ Available | Request Material |
| Electronic Resources | ✔ Available |