Role of Vascular Oxidative Stress in Hypertension
| dc.contributor.advisor | Lokhandwala, Mustafa F. | |
| dc.contributor.committeeMember | Banday, Anees Ahmad | |
| dc.contributor.committeeMember | Marwaha, Aditi | |
| dc.contributor.committeeMember | Majid, Dewan S. A. | |
| dc.contributor.committeeMember | Lewis, Russell E. | |
| dc.creator | Bhatt, Siddhartha | |
| dc.date.accessioned | 2012-04-19T14:27:21Z | |
| dc.date.accessioned | 2012-04-19T14:27:23Z | |
| dc.date.available | 2012-04-19T14:27:21Z | |
| dc.date.available | 2012-04-19T14:27:23Z | |
| dc.date.created | August 2011 | |
| dc.date.issued | 2011-08 | |
| dc.date.updated | 2012-04-19T14:27:23Z | |
| dc.description.abstract | Hypertension affects 1 in 3 adult Americans and is a primary risk factor for cardiovascular diseases. Better understanding of hypertension pathogenesis is important for development of effective therapeutic agents. An important underlying factor present during hypertension is oxidative stress (OS). However, causal role of OS in hypertension is unclear. Increased vascular resistance resulting from enhanced vasoconstriction and impaired vasodilation is a hallmark of hypertension. Enhanced vasoconstriction is associated with increased reactivity to vasoconstrictors such as angiotensin (Ang) II. Ang II-induced vasoconstriction is exaggerated during hypertension and is associated with Ang II type 1 receptors (AT1R) upregulation, the cause of which is unknown. OS modulates redox sensitive transcription factors including nuclear factor kappa B (NFκB), which has been associated with AT1R upregulation. Thus, OS via NFκB can transcriptionally upregulate AT1R. The impaired vasodilation in hypertension is attributed to endothelial dysfunction resulting from attenuated nitric oxide (NO) availability. OS can also contribute to endothelial dysfunction by reducing NO production and increasing NO scavenging. Our objective was to study the role of OS in hypertension development. The first part of the study investigates whether OS is a cause or consequence of hypertension. Studies in 3-4 week old spontaneously hypertensive rats (SHR) revealed that OS precedes hypertension development and is associated with NFκB activation and AT1R upregulation. Treatment of young SHR with pyrrolidine dithiocarbamate, an antioxidant with NFκB inhibitory action, attenuated hypertension development and normalized NFκB and AT1R expression. Experiments in human aortic smooth muscle cells also exhibited OS-induced AT1R upregulation through mechanisms involving NFκB. The second part of the study investigates the role of early oxidative stress in endothelial dysfunction with focus on elucidating role of resveratrol, an antioxidant polyphenol. Our results demonstrate, early resveratrol treatment lowers oxidative stress and reduces NO scavenging and eNOS uncoupling thereby preventing endothelial dysfunction and attenuating hypertension development. In conclusion, early vascular OS in SHR could contribute to hypertension by modulating AT1 receptor upregulation, possibly via NFκB. Additionally, vascular OS could also contribute to endothelial dysfunction by increasing NO scavenging and eNOS uncoupling. Resveratrol treatment lowered oxidative stress, prevented endothelial dysfunction and attenuated hypertension development in SHR. | |
| dc.description.department | Pharmacological and Pharmaceutical Sciences, Department of | |
| dc.format.digitalOrigin | born digital | |
| dc.format.mimetype | application/pdf | |
| dc.identifier.uri | http://hdl.handle.net/10657/271 | |
| dc.language.iso | eng | |
| dc.rights | The author of this work is the copyright owner. UH Libraries and the Texas Digital Library have their permission to store and provide access to this work. Further transmission, reproduction, or presentation of this work is prohibited except with permission of the author(s). | |
| dc.subject | Oxidative stress | |
| dc.subject | AT1 receptors | |
| dc.subject | Endothelial Dysfunction | |
| dc.subject | Vascular | |
| dc.subject.lcsh | Pharmacology | |
| dc.title | Role of Vascular Oxidative Stress in Hypertension | |
| dc.type.dcmi | Text | |
| dc.type.genre | Thesis | |
| thesis.degree.college | College of Pharmacy | |
| thesis.degree.department | Pharmacological and Pharmaceutical Sciences, Department of | |
| thesis.degree.discipline | Pharmacology | |
| thesis.degree.grantor | University of Houston | |
| thesis.degree.level | Doctoral | |
| thesis.degree.name | Doctor of Philosophy |