Title page for ETD etd-07022010-132624


Type of Document Dissertation
Author Sriramula, Srinivas
URN etd-07022010-132624
Title Interaction of Tumor Necrosis Factor-Alpha and the Renin Angiotensin System in the Pathogenesis of Hypertension
Degree Doctor of Philosophy (Ph.D.)
Department Comparative Biomedical Sciences (Veterinary Medical Sciences)
Advisory Committee
Advisor Name Title
Francis, Joseph Committee Chair
Li, Shulin Committee Member
Paulsen, Daniel B Committee Member
Sehgal, Inder Committee Member
Foltz, David W Dean's Representative
Keywords
  • Angiotensin II
  • Tumor necrosis factor-alpha
  • Hypertension
  • Cardiac hypertrophy
  • Reactive oxygen species
  • Renin angiotensin system
  • Pro-inflammatory cytokines
Date of Defense 2010-06-25
Availability restricted
Abstract
Hypertension is a major predisposing factor for the development of cardiovascular and renal diseases. The renin-angiotensin system (RAS) plays a pivotal role in the pathogenesis of cardiovascular diseases such as hypertension, myocardial infarction, heart failure, and stroke. Angiotensin II (Ang II), the effector peptide of the RAS, activates a wide spectrum of signaling responses via the Ang II type-I receptor that mediate its physiological control of blood pressure, thirst and sodium balance. For the past two decades, increasing evidence has demonstrated that the circulatory RAS and local/tissue RAS components (heart and brain) may contribute to the development of hypertensive response. Currently, hypertension is considered a low-grade inflammatory condition induced by interaction of the RAS with various pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α). Several in vitro and in vivo studies suggest the existence of a cross-talk between Ang II and TNF-α, implying an important role for TNF-α in blood pressure regulation. However, the functional importance of TNF-α in Ang II-induced response is unclear. In this dissertation, we examined the hypothesis that TNF-α is involved in the Ang II-induced hypertensive response and explored the interaction of Ang II and TNF-α in the heart and brain in the pathogenesis of hypertension. To examine this interaction, the effects of chronic administration of Ang II was evaluated in TNF-α knockout mice to dissect out the role played by TNF-α in the Ang II-induced effects. Additionally, the role of reactive oxygen species and the transcription factor nuclear factor-kappaB (NF-κB), were examined in this interaction between Ang II and TNF-α. Furthermore, to understand the role of central control of blood pressure via the hypothalamic paraventricular nucleus, an important cardiovascular regulatory center in the brain, we studied the effect of TNF-α blockade and Angiotensin Converting Enzyme 2 overexpression within the brain on blood pressure control. Overall, these studies demonstrate a functional interaction between the RAS and TNF-α in hypertension and the possible roles of oxidative stress and NF-κB in mediating the Ang II-induced hypertensive response. These findings provide an important clue in our quest for understanding the pathophysiology of hypertension and other cardiovascular diseases.
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