SYMPATHETIC NERVOUS SYSTEM REGULATION OF CELL ADHESION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Hypertension affects more than 50 million Americans and comes with enormous annual economic and social costs. Hypertension is associated with significant increased risk for stroke and atherosclerosis. In addition to elevated blood pressure, hypertension is characterized by neuroendocrine and immune activation and cell adhesion molecule activation, including elevated levels of C-reactive protein (CRP), inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), and soluble adhesion molecules intercellular adhesion molecule-1 (sICAM-1) (CD54) and E-selectin (sCD62E), which are predictive of morbidity and mortality outcomes. Pharmacological treatment for hypertension successfully reduces blood pressure, but has limited effectiveness for reducing accompanying inflammation and its associated morbidity and mortality. Exercise and diet interventions have been shown to significantly reduce blood pressure, but few if any studies have examined effects on inflammation in hypertension or potential mechanisms. We will examine the effects of a 12-week exercise intervention and a 12-week exercise plus diet intervention on inflammation and cell adhesion in 150 patients with hypertension (blood pressure 140/90 mm Hg but 120/80 mm Hg but 140/90 mm Hg) who are currently not on anti-hypertensive medication. Prior to and following the interventions, we will assess resting and stress-induced (mental stressor and treadmill exercise testing) changes in circulating levels of CRP, IL-6, TNF-alpha, sICAM-1, sE-selectin, expression of the 2-integrin subunits CD11a and CD11b on leukocytes, leukocyte activation (pseudopod formation), and peripheral blood mononuclear cell (PBMC) chemotaxis. Hypothesis 1. Compared to a 12-week wait-list control group, the 12-week exercise intervention, and especially the 12-week exercise plus diet intervention, will reduce resting and stress-induced inflammation and cell adhesion. 1-1. Intervention groups will exhibit reduced levels of CRP, IL-6, TNF-alpha, sICAM-1, sE-selectin, leukocyte CD11a and CD11b expression, leukocyte activation, chemotaxis at rest pre to post intervention as compared to the wait list control group. 1-2. Intervention groups will exhibit reduced levels of CRP, IL-6, TNF-alpha, sICAM-1, sE-selectin, leukocyte CD11a and CD11b expression, leukocyte activation, and chemotaxis in response to the acute challenges pre to post intervention as compared to the wait list control group. Hypothesis 2. Compared to a 12-week wait-list control group, the 12-week exercise intervention, and especially the 12-week exercise plus diet intervention, will increase fitness levels, reduce urinary catecholamine and cortisol levels, and increase insulin sensitivity. [These hypothesized effects, while relatively straightforward and expected, need to be verified in order the test the mechanisms proposed in Hypothesis 3 below.] 2.1 Both exercise and exercise plus diet groups will show increased fitness levels as compared to the wait list control group. 2.2 Both exercise and exercise plus diet groups will show increased insulin sensitivity and decreased catecholamine and cortisol levels as compared to the wait list control group. 2.3 The exercise plus diet group will show greater weight reduction as compared to the exercise intervention or the wait list control group.