Doctor of Philosophy (PhD)


Biomedical and Veterinary Medical Sciences - Veterinary Clinical Sciences

Document Type



Hypertension is a serious condition with high morbidity and mortality rates, as well as a major predisposing factor for multiple cardiovascular and renal diseases. Angiotensin II (Ang II) of the renin-angiotensin system (RAS) plays a pivotal role in propagating the hypertensive response. Moreover, hypertension is considered a chronic low-grade inflammatory condition that intimately involves the actions of proinflammatory cytokines (PICs) such as tumor necrosis factor-alpha (TNF). Recent evidence highlights the role that inflammation, specifically TNF, plays in hypertension and in regulating the RAS, but the understanding as to how inflammation is regulated following Ang II or TNF activation, as well as the resultant consequences, is currently unclear. Based upon the literature and work from our laboratory, we hypothesize that inflammatory regulation in local tissues alters the systemic hypertensive response, possibly through an inflammatory-driven reactive oxygen species (ROS) mechanism. Therefore, we examined the role of inflammatory mediators in the heart and brain in regulating the hypertensive response through the modulation of ROS, the transcription factor Nuclear Factor-kappaB (NFêB) and the dysregulation of components of the RAS. To examine this interaction, we conducted a series of in vivo experiments designed to better understand these mechanisms. First, we evaluated the effects of TNF infusion on blood pressure response and RAS component expression in the heart. We further explored these inflammatory mechanisms in spontaneously hypertensive rats through the actions of histone deacetylases in maintaining the hypertensive state through inflammatory modulation. Next, we examined the interaction of TNF in the brain in regulating the RAS in the Ang II-induced hypertensive drive. Finally, we examined how NFêB in the hypothalamic paraventricular nucleus contributed to the dysregulation of the RAS and adverse pressure responses in Ang II-induced hypertension. Combined, these studies demonstrate a functional and signaling dependence between PICs and the RAS in hypertension, potentially through a ROS-mediated mechanism. These findings provide insight into the important signaling pathways involved in hypertension, as well as outline potential future therapeutic targets for the continued fight against this debilitating disease.



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Committee Chair

Francis, Joseph