In this project, we shall examine the central hypothesis that there is a functional linkage between hypertension, physical forces and vascular inflammation. Based on substantial preliminary and published data showing that a) mechanical forces are a necessary factor for the evolution of vascular hypertrophy in hypertension; b) mechanical forces are capable of altering the oxidative state of vascular cells; and ) expression of many key pro-inflammatory molecules is induced by oxidative stress, we propose that hypertension induces a pro-inflammatory states that shares many common pathogenic mechanisms with atherosclerosis. Furthermore, we propose that mechanical forces exerted upon the arterial wall in hypertension function via mechanistically defined molecular signaling pathways that result in the development of a predictable inflammatory response and subsequent vascular hypertrophy. The following Specific Aims are proposed: I. Determine the mechanistic deformation; II. Explore the potential role of activation of the tissue renin-angiotensin system as a mechanisms of deformation-induced MCP-1 expression; III. Examine the potential role of NADH/NADPH oxidase-driven p38 kinase activation of AP-1 and NF-kappaB regulation of MCP-1 expression in response to mechanical deformation; and IV. Using an animal model of hypertension, determine the physiologic significance of increased MCP-1 expression on monocyte recruitment and hypertensive vascular pathology. These studies will provide insight into the molecular mechanisms underlying mechanical regulation of the inflammatory response that accompanies hypertension, and may thus lead to improved therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL058000-03
Application #
6316706
Study Section
Project Start
2000-05-25
Project End
2001-04-30
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
3
Fiscal Year
2000
Total Cost
$418,286
Indirect Cost
Name
Emory University
Department
Type
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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