The mechanisms responsible for the vascular growth and hypertrophy that accompanies hypertension are unclear. Our recent observations suggest that reactive oxygen species may serve as a hypertrophic signal in cultured vascular smooth muscle cells. In many other systems, most notably tumor cells, oxygen-derived free radicals stimulate growth, implying that the redox state of the cell may be a common step at which growth control can be achieved. Therefore, the proteins and enzymes that produce reactive oxygen species or serve as the antioxidant defense system are critical determinants of the course of vascular disease. In cultured vascular smooth muscle cells, we have shown that vasoactive agents such as angiotensin II cause a delayed generation of superoxide anion by activating a NADH/NADPH oxidase located in the cell membrane. The pathways leading to oxidase activation and the pathways linking oxidase activation to hypertrophy will be examined in this project. In the first specific aim, we will determine the role of arachidonic acid metabolites and tyrosine kinases in activation of the NADH/NADPH oxidase.
In Specific Aim 2, we plan to use p22phox, a key component of the vascular oxidase, to identify other subunits, and to began to examine regulation of oxidase expression. Since the superoxide that is produced by this enzyme system is rapidly dismuted to H202, it is unclear which reactive oxygen species mediate the hypertrophic response to angiotensin II. This question will be addressed in Specific Aim 3, using cells over- and under-expressing catalase. Finally, in Specific Aim 4, we will determine the role of the NADH/NADPH oxidase system in hypertrophy in vivo, using rats made hypertensive by angiotensin II infusion and transgenic mice that over- or under-express p22phox (made by Dr. Harrison in Project 2). These studies will provide insight into the mechanisms responsible for vascular hypertrophy in hypertension. We hypothesize that modification of NADH/NADPH oxidase activity and therefore the oxidative state of the smooth muscle cells may be central to controlling the expression of a subset of genes involved in the development of hypertension. Understanding the cellular events involved in controlling the oxidative environment of VSMC may thus lead to a more in depth understanding of vascular disease processes and the development of specific therapeutic strategies.
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| 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 |
| Yanes, Rolando E; Gustafson, Claire E; Weyand, Cornelia M et al. (2017) Lymphocyte generation and population homeostasis throughout life. Semin Hematol 54:33-38 |
| Weyand, Cornelia M; Goronzy, Jörg J (2016) Aging of the Immune System. Mechanisms and Therapeutic Targets. Ann Am Thorac Soc 13 Suppl 5:S422-S428 |
| Wu, Jing; Montaniel, Kim Ramil C; Saleh, Mohamed A et al. (2016) Origin of Matrix-Producing Cells That Contribute to Aortic Fibrosis in Hypertension. Hypertension 67:461-8 |
| 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 |
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