Role of Toll-Like Receptor 4 in Pathophysiology of Hypertension




Doctor of Philosophy (PhD)


Biomedical and Veterinary Medical Sciences - Comparative Biomedical Sciences

Document Type



Hypertension is a chronic multifactorial condition with high morbidity and mortality rates, cur-rently affecting about 1 billion people worldwide. Currently available anti-hypertensive medica-tions are found to be effective in reducing blood pressure (BP), but still more than 50% of those diagnosed with hypertension fail to respond to these anti-hypertensive regimens. Very recently, role of toll-like receptors (TLRs), particularly TLR4 in pathogenesis of several inflammatory conditions including cardiovascular diseases are becoming evident. However, the functional im-portance of the brain TLR4 and its interaction with other molecules involved in the pathogenesis of hypertension has never been explored yet. Therefore, the present series of in vivo studies were undertaken to gain more insight into the role of central TLR4 in the pathophysiology of hyper-tension and to delineate the underlying molecular mechanisms of effects of TLR4 in the disease process. In the first study, we centrally blocked TLR4 expression with viral inhibitory peptide (VIPER; a specific TLR4 blocker) via intracerebroventricular infusion in Ang II-induced hyper-tensive rats. Central TLR4 blockade delayed progression of hypertension and improved cardiac function in hypertensive rats and these effects were mediated by reduced myocardial pro-inflammatory cytokines (PICs), NFκB activity, and plasma norepinephrine (NE) levels. In the second study, we found that spontaneously hypertensive rats (SHR) had significantly higher lev-els of TLR4 in the paraventricular nucleus of hypothalamus (PVN), particularly in the neurons and microglia but not so much in astrocytes. TLR4 blockade specifically in the PVN not only reduces PICs, NE and HMGB1 (an endogenous ligand for TLR4) but also improved anti-inflammatory cytokines within the PVN of SHRs. In the third study, we examined the hyperten-sive and inflammatory responses of Angiotensin II (Ang II; an effector molecule of renin angio-tensin system) in mice lacking the gene for the TLR4. Next, we confirmed the role of TLR4 in the PVN in pathophysiology of hypertension by investigating the effects of PVN-specific shRNA-mediated suppression of TLR4 receptor function in a genetic rat model of human essen-tial hypertension. Collectively, these studies demonstrate that cross-talk between central TLR4 and RAS plays an important role in the pathophysiology of hypertension and inhibition of TLR4 within the PVN has ability to positively modulate several components of signaling pathways in-volved in pathogenesis of hypertension. These findings provide greater insight into the molecular mechanisms underlying the role of TLR4 in hypertension and will ultimately lead us to develop newer and more effective treatment interventions for hypertension.



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Committee Chair

Francis, Joseph

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