Abstract
Proteasome inhibitors are considered to have anti-inflammatory therapeutic potential. However, recent reports addressing proteasome inhibition in the vascular system are controversial, ranging from beneficial anti-inflammatory and anti-oxidative effects to potentiation of inflammation and oxidative stress. This study was based on the hypothesis that the divergent effects might be a result of a differential and dose-dependent responsiveness of vascular cells to proteasome inhibitors. We tested whether low doses of proteasome inhibitors would favor anti-inflammatory effects in vascular cells in vitro and in vivo. Human umbilical vein endothelial cells (HUVEC) were preincubated with proteasome inhibitors MG132 and MG262 at concentrations that did not affect cell viability during a 24-h treatment. Upon addition of tumor necrosis factor alpha (TNF-α) the induced expression of adhesion molecules and the adhesion of monocytic THP-1 cells to HUVECs was significantly lowered. However, nuclear translocation of NF-κB was only slightly diminished. Low-dose pretreatment with proteasome inhibitors decreased TNF-α-induced generation of reactive oxygen species in HUVEC. Bortezomib was administered at a dose of 50 µg/kg body weight to Dahl salt-sensitive rats (DSSR) on high-salt diet. This low-dose proteasome inhibition led to decreased hypertension-induced oxidative stress and reduced expression of vascular cell adhesion molecule 1 (VCAM-1) in the aortae.
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References
Kisselev AF, Goldberg AL (2001) Proteasome inhibitors: from research tools to drug candidates. Chem Biol 8:739–758
Meiners S, Ludwig A, Stangl V, Stangl K (2008) Proteasome inhibitors: poisons and remedies. Med Res Rev 28:309–327
Coux O, Tanaka K, Goldberg AL (1996) Annu Rev Biochem 65:801–847
Elliott PJ, Zollner TM, Boehncke WH (2003) Proteasome inhibition: a new anti-inflammatory strategy. J Mol Med 81:235–245
Karin M, Ben-Neriah Y (2000) Phosphorylation meets ubiquitination: the control of NF-kappaB activity. Annu Rev Immunol 18:621–663
Galkina E, Ley K (2007) Vascular adhesion molecules in atherosclerosis. Arterioscler Thromb Vasc Biol 27:2292–2301
Harrison D, Griendling KK, Landmesser U et al (2003) Role of oxidative stress in atherosclerosis. Am J Cardiol 91(3A):7–11
Read MA, Neish AS, Luscinskas FW et al (1995) The proteasome pathway is required for cytokine-induced endothelial-leukocyte adhesion molecule expression. Immunity 2:493–506
Kalogeris TJ, Laroux FS, Cockrell A et al (1999) Effect of selective proteasome inhibitors on TNF-induced activation of primary and transformed endothelial cells. Am J Physiol 276:C856–C864
Dagia NM, Goetz DJ (2003) A proteasome inhibitor reduces concurrent, sequential, and long-term IL-1 beta- and TNF-alpha-induced ECAM expression and adhesion. Am J Physiol Cell Physiol 285:C813–C822
Conner EM, Brand S, Davis JM et al (1997) Proteasome inhibition attenuates nitric oxide synthase expression, VCAM-1 transcription and the development of chronic colitis. J Pharmacol Exp Ther 282:1615–1622
Berti R, Williams AJ, Velarde LC et al (2003) Effect of the proteasome inhibitor MLN519 on the expression of inflammatory molecules following middle cerebral artery occlusion and reperfusion in the rat. Neurotox Res 5:505–514
Herrmann J, Saguner AM, Versari D et al (2007) Chronic proteasome inhibition contributes to coronary atherosclerosis. Circ Res 101:865–874
Ludwig A, Meiners S (2008) Targeting of the proteasome worsens atherosclerosis? Circ Res 102:e37
Meiners S, Ludwig A, Lorenz M et al (2006) Nontoxic proteasome inhibition activates a protective antioxidant defense response in endothelial cells. Free Radic Biol Med 40:2232–2241
Stangl V, Lorenz M, Meiners S et al (2004) Long-term up-regulation of eNOS and improvement of endothelial function by inhibition of the ubiquitin-proteasome pathway. FASEB J 18:272–279
Stangl V, Günther C, Jarrin A et al (2001) Homocysteine inhibits TNF-alpha-induced endothelial adhesion molecule expression and monocyte adhesion via nuclear factor-kappaB dependent pathway. Biochem Biophys Res Commun 280:1093–1100
Ludwig A, Lorenz M, Grimbo N, Steinle F, Meiners S, Bartsch C, Stangl K, Baumann G, Stangl V (2004) The tea flavonoid epigallocatechin-3-gallate reduces cytokine-induced VCAM-1 expression and monocyte adhesion to endothelial cells. Biochem Biophys Res Commun 316:659–665
Wong SH, Knight JA, Hopfer SM et al (1987) Lipoperoxides in plasma as measured by liquid-chromatographic separation of malondialdehyde-thiobarbituric acid adduct. Clin Chem 33:214–220
Bross PF, Kane R, Farrell AT et al (2004) Approval summary for bortezomib for injection in the treatment of multiple myeloma. Clin Cancer Res 10:3954–3964
Cavaletti G, Gilardini A, Canta A et al (2007) Bortezomib-induced peripheral neurotoxicity: a neurophysiological and pathological study in the rat. Exp Neurol 204:317–325
Chen JW, Chen YH, Lin FY et al (2003) Ginkgo biloba extract inhibits tumor necrosis factor-alpha-induced reactive oxygen species generation, transcription factor activation, and cell adhesion molecule expression in human aortic endothelial cells. Arterioscler Thromb Vasc Biol 23:1559–1566
Chen JW, Lin FY, Chen YH et al (2004) Carvedilol inhibits tumor necrosis factor-alpha-induced endothelial transcription factor activation, adhesion molecule expression, and adhesiveness to human mononuclear cells. Arterioscler Thromb Vasc Biol 24:2075–2081
Lin SJ, Shyue SK, Hung YY et al (2005) Superoxide dismutase inhibits the expression of vascular cell adhesion molecule-1 and intracellular cell adhesion molecule-1 induced by tumor necrosis factor-alpha in human endothelial cells through the JNK/p38 pathways. Arterioscler Thromb Vasc Biol 25:334–340
Li L, Chu Y, Fink GD, Engelhardt JF et al (2003) Endothelin-1 stimulates arterial VCAM-1 expression via NADPH oxidase-derived superoxide in mineralocorticoid hypertension. Hypertension 42:997–1003
Spiecker M, Peng HB, Liao JK (1997) Inhibition of endothelial vascular cell adhesion molecule-1 expression by nitric oxide involves the induction and nuclear translocation of IkappaBalpha. J Biol Chem 272:30969–30974
Matthews JR, Botting CH, Panico M et al (1996) Inhibition of NF-kappaB DNA binding by nitric oxide. Nucleic Acids Res 24:2236–2242
Marshall HE, Hess DT, Stamler JS (2004) S-nitrosylation: physiological regulation of NF-kappaB. Proc Natl Acad Sci U S A 101:8841–8842
Tian N, Gu JW, Jordan S, Rose RA et al (2007) Immune suppression prevents renal damage and dysfunction and reducesarterial pressure in salt-sensitive hypertension. Am J Physiol Heart Circ Physiol 292:H1018–H1025
Kobayashi N, Hara K, Tojo A et al (2005) Eplerenone shows renoprotective effect by reducing LOX-1-mediated adhesion molecule, PKCepsilon-MAPK-p90RSK, and Rho-kinase pathway. Hypertension 45:538–544
Acknowledgments
We are grateful for the excellent assistance of Susanne Metzkow and Anke Stach. This work was supported by a grant from the foundation Deutsche Stiftung für Herzforschung [F/02/05] to Karl Stangl and Antje Ludwig.
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The authors declare that they have no competing financial interests.
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Ludwig, A., Fechner, M., Wilck, N. et al. Potent anti-inflammatory effects of low-dose proteasome inhibition in the vascular system. J Mol Med 87, 793–802 (2009). https://doi.org/10.1007/s00109-009-0469-9
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DOI: https://doi.org/10.1007/s00109-009-0469-9