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.
Yanes, Rolando E; Gustafson, Claire E; Weyand, Cornelia M et al. (2017) Lymphocyte generation and population homeostasis throughout life. Semin Hematol 54:33-38 |
Kim, C; Fang, F; Weyand, C M et al. (2017) The life cycle of a T cell after vaccination - where does immune ageing strike? Clin Exp Immunol 187:71-81 |
Foss, Jason D; Kirabo, Annet; Harrison, David G (2017) Do high-salt microenvironments drive hypertensive inflammation? Am J Physiol Regul Integr Comp Physiol 312:R1-R4 |
Loperena, Roxana; Harrison, David G (2017) Oxidative Stress and Hypertensive Diseases. Med Clin North Am 101:169-193 |
Weyand, Cornelia M; Zeisbrich, Markus; Goronzy, Jörg J (2017) Metabolic signatures of T-cells and macrophages in rheumatoid arthritis. Curr Opin Immunol 46:112-120 |
Wu, Jing; Saleh, Mohamed A; Kirabo, Annet et al. (2016) Immune activation caused by vascular oxidation promotes fibrosis and hypertension. J Clin Invest 126:50-67 |
Li, Yinyin; Shen, Yi; Hohensinner, Philipp et al. (2016) Deficient Activity of the Nuclease MRE11A Induces T Cell Aging and Promotes Arthritogenic Effector Functions in Patients with Rheumatoid Arthritis. Immunity 45:903-916 |
Shirai, Tsuyoshi; Nazarewicz, Rafal R; Wallis, Barbara B et al. (2016) The glycolytic enzyme PKM2 bridges metabolic and inflammatory dysfunction in coronary artery disease. J Exp Med 213:337-54 |
Itani, Hana A; McMaster Jr, William G; Saleh, Mohamed A et al. (2016) Activation of Human T Cells in Hypertension: Studies of Humanized Mice and Hypertensive Humans. Hypertension 68:123-32 |
Jeong, Euy-Myoung; Chung, Jaehoon; Liu, Hong et al. (2016) Role of Mitochondrial Oxidative Stress in Glucose Tolerance, Insulin Resistance, and Cardiac Diastolic Dysfunction. J Am Heart Assoc 5: |
Showing the most recent 10 out of 241 publications