The vascular system transports components essential to the survival of the individual and acts as a barrier to substances that may injure the organism. Atherosclerosis is a dynamic, lesion producing disease of the arterial system that compromises the functioning of the organ by occlusive and thrombogenic processes. This investigation was undertaken to elucidate some of the normal biochemical processes related to the development of atherosclerosis. A significant part of the investigation was directed toward developing and combining methods and protocols to obtain the data in a concerted manner. A postmitochondnal supernatant of bovine aorta, using mevalonate-2-�����C as the substrate, was employed in the investigation. Methods included paper, thin layer, and silica gel chromatography; gel filtration, high performance liquid chromatography (HPLC), and mass spectrometry. This current research demonstrated direct incorporation of mevalonate-2- �����C into the trans-methyiglutaconic shunt intermediates. The aorta also contains alcohol dehydrogenase activity, which converts dimethylallyl alcohol and isopentenol to dimethylacrylic acid, a constituent of the trans-methylgiutaconate Small, radioactive peptides, named Nketewa as a group, were biosynthesized using mevalonate-2-�����C as the substrate. They were shown to pass through a 1000 D membrane. Acid hydrolysis and dabsyl-HPLC analysis defined the composition of the Nketewa peptides. One such peptide, Nketewa 1, had a molecular weight of 1038 and a sequence of his-gly-val-cys-phe-ala-ser-met (HGVCFASM), with a farnesyl group linked via thioether linkage to the cysteine residue. Methods were developed for the concerted investigation of the trans-methylglutaconate shunt, the isolation of mevalonate-2-�����C labeled peptides, and characteristics of neutral and acidic metabolites of mevalonate. The question as to whether or not mevalonate was the direct precursor was answered in the affirmative. These results contribute to the understanding of the biochemistry of the vessel wall and the associated atherogenic processes. Mevalonate-derived volatile and acidic compounds may represent an alternate metabolic pathway. The prenylated Nicetewa peptide may be, as are other prenylated peptides, participants in the intracellular signaling process, release of cytokines, expansion of extracellular matrix, and calcium release. / Graduation date: 2001

Hypertension is the number one cause of death worldwide. Low-grade inflammation has been identified as one of the mechanisms contributing to blood pressure elevation and remodeling of the vasculature in hypertension. Mechanisms involved in vascular inflammation and hypertension remain elusive. Vasoactive peptides such as endothelin-1 (ET-1) and angiotensin II (Ang II), oxidative stress and infiltration of immune cells are increased in cardiovascular tissues of hypertensive individuals. Since the vasculature is a major regulator of blood pressure levels, the hypothesis has been proposed that vascular inflammatory responses contribute to development of hypertension. / Objectives of this thesis were 1) to investigate the role of T cells in development of vascular inflammation observed in genetically hypertensive rats, 2) to identify vascular sources of reactive oxygen species production in mineralocorticoid-induced hypertension and 3) to study the effect of peroxisome proliferator-activated receptor (PPAR)-gamma activators on vascular pro-inflammatory signaling pathways in Ang II-induced hypertension. / The first study that is part of this thesis shows that the transfer of chromosome 2 from normotensive to hypertensive rats reduces plasma levels of pro-inflammatory cytokines, expression of adhesion molecules and infiltration of T cells in aorta as well as resulting in lower blood pressure levels. These effects are accompanied by increased regulatory T cell mediators. We discovered that regulatory T cells are regulated by chromosome 2 and may be responsible for reducing inflammatory responses in hypertensive rats. / The second study of this thesis demonstrates in DOCA-salt hypertensive rats that superoxide (·O2-) production originates in part from xanthine oxidase activity induced by the ET-1 system and from mitochondrial sources, particularly complex II of the respiratory chain. We thus have uncovered two sources of reactive oxygen species (ROS) that can stimulate inflammatory responses in hypertension, since vascular ·O 2- production in this model was shown to induce vascular inflammation. / The third study of the thesis shows that activators of PPAR-gamma reduce blood pressure levels and signaling pathways including Akt/PKB, SHIP2, ERK1/2, 4E-BP1 in aorta and resistance arteries in Ang II-induced hypertension. PPARy acts as an anti-inflammatory transcription factor, and the present study suggests that Ang II down-regulates PPAR-gamma activity to exert its pro-inflammatory effects. / In conclusion, by targeting inflammatory mediators, it may be possible to reduce blood pressure levels in hypertensive animals. This suggests that inflammatory responses may play a crucial role in development of high blood pressure.

No description available.