Date of Award

Spring 1-1-2010

Document Type

Thesis

Degree Name

Doctor of Philosophy (PhD)

Department

Integrative Physiology

First Advisor

Douglas R. Seals

Second Advisor

David Allen

Third Advisor

Robert Eckel

Abstract

Information and communication technologies (ICT) have come to impact nearly all aspects of modern life, including the development, function and operation of urban and rural landscapes. Impaired vascular endothelium-dependent dilation (EDD), a bio-marker of vascular endothelial dysfunction, is an independent predictor of future cardiovascular events. EDD is reduced with age, but is preserved in middle-aged and older (MA/O) adults who habitually perform aerobic exercise. The purpose of these studies was to determine the role of chronic low-grade inflammation, as assessed by white blood cell (WBC) count and endothelial nuclear factor-kappaB (NF-kappaB) signaling, in the modulation of EDD in sedentary and aerobic exercise-trained MA/O adults.

EDD was 34% less in MA/O sedentary adults with higher compared with lower WBC count. Vascular smooth muscle responsiveness to nitric oxide (NO) was 18% less in subjects with higher vs. lower WBC count, but did not fully explain the differences with EDD. Inhibition of NO reduced EDD in subjects with lower, but not higher WBC count. Tetrahydrobiopterin selectively improved EDD in subjects with higher WBC count by increasing NO bioavailability. Thus, among healthy sedentary MA/O adults, a higher WBC count is related to impaired EDD and this is mediated by reduced responsiveness to NO and reductions in tetrahydrobiopterin and NO bioavailability.

MA/O sedentary adults had a greater expression of NF-kappaB, a key pro-inflammatory transcription factor, in their vascular endothelial cells compared with young sedentary and MA/O aerobic exercise-trained adults. In a sub-group of MA/O subjects, oral salsalate was used to inhibit NF-kappaB signaling. Salsalate treatment reduced endothelial NF-kappaB expression in sedentary subjects, but had no effect in exercise-trained subjects. EDD improved by 76% with salsalate in the sedentary adults, whereas there was no improvement in the exercise-trained adults. In sedentary subjects, antioxidant vitamin C infusion improved EDD by 32% during the placebo condition, but had no effect during salsalate. In exercise-trained subjects, vitamin C infusion did not change EDD during either treatment. Therefore, in sedentary MA/O adults, increased NF-kappaB signaling suppresses EDD, in part, by increased oxidative stress. Reduced NF-kappaB signaling is a key mechanism for preserved EDD in exercise-trained MA/O adults.

Included in

Physiology Commons

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