This Article Full Text Full Text (PDF) Data Supplement Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Madamanchi, N. R. Articles by Runge, M. S. Search for Related Content PubMed PubMed Citation Articles by Madamanchi, N. R. Articles by Runge, M. S.

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2001;21:321.)
© 2001 American Heart Association, Inc.

Vascular Biology

Reactive Oxygen Species Regulate Heat-Shock Protein 70 via the JAK/STAT Pathway

Nageswara R. Madamanchi; Suzhen Li; Cam Patterson; Marschall S. Runge

From the Program in Molecular Cardiology, University of North Carolina, Chapel Hill.

Correspondence to Marschall S. Runge, MD, PhD, Department of Medicine, 3033 Old Clinic Building, CB# 7005, University of North Carolina, Chapel Hill, NC 27599-7005. E-mail mrunge{at}med.unc.edu

Abstract—Reactive oxygen species (ROS) such as hydrogen peroxide (H₂O₂) activate intracellular signal transduction pathways implicated in the pathogenesis of cardiovascular disease. H₂O₂ is a mitogen for rat vascular smooth muscle cells (VSMCs), and protein tyrosine phosphorylation is a critical event in VSMC mitogenesis. Therefore, we investigated whether the mitogenic effects of H₂O₂, such as stimulation of extracellular signal–regulated kinase (ERK)2, are mediated via activation of cytoplasmic Janus tyrosine kinases (JAKs). JAK2 was activated rapidly in VSMCs treated with H₂O₂, and signal transducers and activators of transcription (STAT) STAT1 and STAT3 were tyrosine-phosphorylated and translocated to the nucleus in a JAK2-dependent manner. Inhibition of JAK2 activity with AG-490 partially inhibited H₂O₂-induced ERK2 activity, suggesting that JAK2 is upstream of the Ras/Raf/mitogen-activated protein kinase–ERK/ERK mitogenic pathway. Because heat-shock proteins (HSPs) can protect cells from ROS, we investigated the effect of H₂O₂ on HSP expression. H₂O₂ stimulated HSP70 expression in a time-dependent manner, and AG-490 abolished H₂O₂-induced HSP70 expression. H₂O₂ activated the HSP70 promoter via enhanced binding of STATs to cognate binding sites in the promoter. Regulation of chaperones such as HSP70 via activation of the JAK/STAT pathway suggests that in addition to its growth-promoting effects, this pathway may help VSMCs adapt to oxidative stress.

Key Words: vascular smooth muscle cells • JAK2 • reactive oxygen species • STAT • AG-490

This article has been cited by other articles:

				T. Araki, J. Langenick, M. Gamper, R. A. Firtel, and J. G. Williams Evidence that DIF-1 and hyper-osmotic stress activate a Dictyostelium STAT by inhibiting a specific protein tyrosine phosphatase Development, April 1, 2008; 135(7): 1347 - 1353. [Abstract] [Full Text] [PDF]

				Y. Yokomaku, T. Sugimoto, S. Kume, S.-i. Araki, K. Isshiki, M. Chin-Kanasaki, M. Sakaguchi, N. Nitta, M. Haneda, D. Koya, et al. Asialoerythropoietin Prevents Contrast-Induced Nephropathy J. Am. Soc. Nephrol., February 1, 2008; 19(2): 321 - 328. [Abstract] [Full Text] [PDF]

				E. M. Hurt, S. B. Thomas, B. Peng, and W. L. Farrar Integrated molecular profiling of SOD2 expression in multiple myeloma Blood, May 1, 2007; 109(9): 3953 - 3962. [Abstract] [Full Text] [PDF]

				P. K. Mehta and K. K. Griendling Angiotensin II cell signaling: physiological and pathological effects in the cardiovascular system Am J Physiol Cell Physiol, January 1, 2007; 292(1): C82 - C97. [Abstract] [Full Text] [PDF]

				K. R. Brunt, K. K. Fenrich, G. Kiani, M. Yat Tse, S. C. Pang, C. A. Ward, and L. G. Melo Protection of Human Vascular Smooth Muscle Cells From H2O2-Induced Apoptosis Through Functional Codependence Between HO-1 and AKT Arterioscler. Thromb. Vasc. Biol., September 1, 2006; 26(9): 2027 - 2034. [Abstract] [Full Text] [PDF]

				I. Kuwahara, E. P. Lillehoj, W. Lu, I. S. Singh, Y. Isohama, T. Miyata, and K. C. Kim Neutrophil elastase induces IL-8 gene transcription and protein release through p38/NF-{kappa}B activation via EGFR transactivation in a lung epithelial cell line Am J Physiol Lung Cell Mol Physiol, September 1, 2006; 291(3): L407 - L416. [Abstract] [Full Text] [PDF]

				R. E. Clempus and K. K. Griendling Reactive oxygen species signaling in vascular smooth muscle cells Cardiovasc Res, July 15, 2006; 71(2): 216 - 225. [Abstract] [Full Text] [PDF]

				J. I. Mendez, W. J. Nicholson, and W. R. Taylor SOD Isoforms and Signaling in Blood Vessels: Evidence for the Importance of ROS Compartmentalization Arterioscler. Thromb. Vasc. Biol., May 1, 2005; 25(5): 887 - 888. [Full Text] [PDF]

				N. R. Madamanchi, S.-K. Moon, Z. S. Hakim, S. Clark, A. Mehrizi, C. Patterson, and M. S. Runge Differential Activation of Mitogenic Signaling Pathways in Aortic Smooth Muscle Cells Deficient in Superoxide Dismutase Isoforms Arterioscler. Thromb. Vasc. Biol., May 1, 2005; 25(5): 950 - 956. [Abstract] [Full Text] [PDF]

				B. Xu, G.-h. Dong, H. Liu, Y.-q. Wang, H.-w. Wu, and H. Jing Recombinant Human Erythropoietin Pretreatment Attenuates Myocardial Infarct Size: A Possible Mechanism Involves Heat Shock Protein 70 and Attenuation of Nuclear Factor-kappaB Ann. Clin. Lab. Sci., April 1, 2005; 35(2): 161 - 168. [Abstract] [Full Text] [PDF]

				N. Strunnikova, C. Zhang, D. Teichberg, S. W. Cousins, J. Baffi, K. G. Becker, and K. G. Csaky Survival of Retinal Pigment Epithelium after Exposure to Prolonged Oxidative Injury: A Detailed Gene Expression and Cellular Analysis Invest. Ophthalmol. Vis. Sci., October 1, 2004; 45(10): 3767 - 3777. [Abstract] [Full Text] [PDF]

				E. M. Sandberg and P. P. Sayeski Jak2 Tyrosine Kinase Mediates Oxidative Stress-induced Apoptosis in Vascular Smooth Muscle Cells J. Biol. Chem., August 13, 2004; 279(33): 34547 - 34552. [Abstract] [Full Text] [PDF]

				M. Takano, A. Meneshian, E. Sheikh, Y. Yamakawa, K. B. Wilkins, E. A. Hopkins, and G. B. Bulkley Rapid upregulation of endothelial P-selectin expression via reactive oxygen species generation Am J Physiol Heart Circ Physiol, November 1, 2002; 283(5): H2054 - H2061. [Abstract] [Full Text] [PDF]

				Q. Xu Role of Heat Shock Proteins in Atherosclerosis Arterioscler. Thromb. Vasc. Biol., October 1, 2002; 22(10): 1547 - 1559. [Abstract] [Full Text] [PDF]

				J. M. Carcamo, O. Borquez-Ojeda, and D. W. Golde Vitamin C inhibits granulocyte macrophage-colony-stimulating factor-induced signaling pathways Blood, May 1, 2002; 99(9): 3205 - 3212. [Abstract] [Full Text] [PDF]

				C. Patterson, G. A. Stouffer, N. Madamanchi, and M. S. Runge New Tricks for Old Dogs : Nonthrombotic Effects of Thrombin in Vessel Wall Biology Circ. Res., May 25, 2001; 88(10): 987 - 997. [Abstract] [Full Text] [PDF]