Department of Pharmacology and Toxicology Theses and Dissertations

Permanent URI for this collectionhttps://hdl.handle.net/10675.2/321985

This collection contains theses and dissertations submitted by graduate students under the Department of Pharmacology and Toxicology for either a Master of Science degree or a Doctor of Philosophy degree.

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Browsing Department of Pharmacology and Toxicology Theses and Dissertations by Subject "Biological sciences"

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    Circadian Clock in Angiotensin II Induced Hypertension and Vascular Disease
    (2015) Pati, Paramita; Department of Pharmacology and Toxicology
    Hypertension remains a major risk factor for cardiovascular disease and death. While clinical studies and guideline recommendations underscore the benefits of reducing sodium intake in the treatment of high blood pressure, recent human data suggest that underlying conditions of disease may confound these positive effects of low salt diets. Herein, we examined the influence of circadian dysfunction during experimental hypertension caused by angiotensin II (Ang II), a key peptide in blood pressure regulation. While a low salt diet caused the expected decrease in blood pressure in wild type (WT) mice, mice with disruption of the circadian clock exhibited a paradoxical response to low salt. Mice with disruption in the circadian clock component Period (Period-knockout/KO mice), were abolished in blood pressure rhythm due to an increase in daytime blood pressure. This impairment in blood pressure rhythm in Per-KO mice on the low salt diet was restored to rhythmic oscillation by the angiotensin receptor blocker losartan. Similarly, exogenous administration of Ang Il caused a non-dipping blood pressure phenotype in the Per-KO mice on a normal salt diet, which resulted in pathological thickening of the vasculature indicative of vascular disease. These effects were related to circadian rhythm as impairment in blood pressure caused by low salt was recapitulated in WT mice induced to circadian derangement by a shortened light cycle. Further thickening of the vasculature and increased renin levels were observed in Per-KO mice on a chronic low salt diet but not in WT mice. Moreover, disruption of the Period gene altered ATI receptor expression and other components of the renin-angiotensin system. These data suggest that circadian dysfunction may compromise the benefits of a low salt diet and support recent clinical data that raise caution to sodium restriction as a therapy for hypertension.
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    Involvement of arginase upregulation in diabetes- and angiotensin II-induced vascular dysfunction
    (2015) Bhatta, Anil; Department of Pharmacology and Toxicology
    Cardiovascular disease (CVD) is the number 1 killer of men and women in the United States and the world. Diabetes, hypertension, obesity, and aging are some of the risk factors for CVD. A major cause of morbidity and mortality in CVD is vascular dysfunction, which progresses rapidly as the risk factors progress. Vascular dysfunction is characterized by a constellation of blood flow reducing pathologies, including impaired vasorelaxation and elevated arterial stiffening. The mechanisms leading to these vascular abnormalities are not well understood. We tested the hypothesis that arginase, an enzyme in the urea cycle, mediates vascular dysfunction in hypertension and obesity related diabetes. Arginase (ARG) can compete with nitric oxide (NO) synthase for their common substrate, L-arginine. Increased arginase can also provide more ornithine for synthesis of polyamines via ornithine decarboxylase (ODC) and proline/collagen via ornithine aminotransferase (OAT), leading to vascular cell proliferation and collagen formation, respectively. We hypothesized that elevated arginase activity is involved in Ang II-induced vascular dysfunction and that limiting its activity can prevent these changes. We tested this by studies in C57BL/6J mice lacking one copy of the ARG1 gene that were treated with Ang II (1 mg/kg/day, 4 weeks). We demonstrated that Ang II induces smooth muscle cell proliferation, collagen synthesis, and arterial fibrosis and stiffness via a mechanism involving increased arginase activity. Furthermore, we examined the role of arginase in vascular dysfunctions and pathologies associated with obesity-related type 2 diabetes in mice fed with high-fat/high-sucrose (HFHS) diet for 6 months. This model produced a clinical presentation and pathophysiological relevance to the human condition in obesity related type 2 diabetes. We demonstrated that HFHS diet impaired endothelial dependent vasorelaxation and increased arterial stiffness in WT mice, but not in mice treated with arginase inhibitor ABH. Endothelial cell specific knockout of ARG1 (EC-A1-/-) in mice also prevented HFHS induced vascular dysfunctions. Aortic perivascular collagen deposition was significantly higher in HFHS mice compared to normal diet. Furthermore, marked increase in vascular cell adhesion molecule expression and macrophage infiltration into the aortic walls was observed with HFHS diet. Additionally, plasma lipid peroxidase activity, a measure of systemic oxidative stress, was also markedly increased in HFHS mice. These changes were prevented in ABH treated mice and EC-A1-/- mice. These studies suggest that enhanced ARG1 activity promotes vascular dysfunctions associated with elevated Ang II levels or obesity related diabetes.