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 |
| Wenzel, Ulrich; Turner, Jan Eric; Krebs, Christian et al. (2016) Immune Mechanisms in Arterial Hypertension. J Am Soc Nephrol 27:677-86 |
| Montaniel, Kim Ramil C; Harrison, David G (2016) Is Hypertension a Bone Marrow Disease? Circulation 134:1369-1372 |
| Wen, Zhenke; Shimojima, Yasuhiro; Shirai, Tsuyoshi et al. (2016) NADPH oxidase deficiency underlies dysfunction of aged CD8+ Tregs. J Clin Invest 126:1953-67 |
| Watanabe, Ryu; Goronzy, Jörg J; Berry, Gerald et al. (2016) Giant Cell Arteritis: From Pathogenesis to Therapeutic Management. Curr Treatm Opt Rheumatol 2:126-137 |
| Qi, Qian; Cavanagh, Mary M; Le Saux, Sabine et al. (2016) Diversification of the antigen-specific T cell receptor repertoire after varicella zoster vaccination. Sci Transl Med 8:332ra46 |
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