Doctor of Philosophy (PhD)


Biomedical and Veterinary Medical Sciences - Comparative Biomedical Sciences

Document Type



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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Committee Chair

Francis, Joseph