Identifier

etd-03232012-154906

Degree

Doctor of Philosophy (PhD)

Department

Biomedical and Veterinary Medical Sciences - Comparative Biomedical Sciences

Document Type

Dissertation

Abstract

Hypertension is a chronic multifactorial condition with high morbidity and mortality rates, currently affecting about one billion people worldwide. Currently available anti-hypertensive medications 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. Although hypertension has multiple etiologies, physical inactivity has been found to have strong correlation with the disease, so exercise has recently been recommended as a part of lifestyle modifications for all hypertensive patients. Therefore, the present series of in vivo and in vitro studies were undertaken to gain more insight into the effects of regular long-term exercise training (ExT) within the heart and brain of hypertensive animals with the specific aim of investigating the molecular mechanisms underlying the exercise-induced beneficial effects. In the first study, we subjected young spontaneously hypertensive rats (SHRs) to moderate-intensity exercise for 16 weeks. Regular exercise delayed progression of hypertension and improved cardiac function in SHRs, and these effects were mediated by reduced myocardial pro-inflammatory cytokines (PICs), NFêB activity, and improved redox homeostasis. In the second study, we found that chronic exercise not only reduces PICs and vasoconstrictor components of the renin-angiotensin system (RAS) but also improved anti-inflammatory cytokines (AIC) and vasodilatory axis of the RAS within the brain of SHRs. In the third study, we explored the effects of cessation of exercise (physical detraining) on these parameters. Next, we examined the role of GSK-3â in dysregulation of PICs and AIC in vitro using neuronal cell culture and in vivo using angiotensin II-induced hypertensive rat model. Finally, we investigated the effects of ExT on brain GSK-3â in hypertension and whether central GSK-3â mediates exercise-induced beneficial effects in hypertension. Collectively, these studies demonstrate that unlike pharmacological therapies, chronic regular exercise is a non-pharmacological cost-effective tool that has the capability to positively modulate several components of signaling pathways involved in pathogenesis of hypertension. These findings provide greater insight into the molecular mechanisms underlying the exercise-induced beneficial effects and will ultimately lead us to refine the current guidelines for the treatment of hypertension on the basis of scientific evidence.

Date

2012

Document Availability at the Time of Submission

Release the entire work immediately for access worldwide.

Committee Chair

Francis, Joseph

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