Regulatory effects of 1,25-dihydroxyvitamin D3 on vascular smooth muscle cells
Languages of publication
Inflammatory response has been recognized as a central feature in the development and progression of atherosclerosis, and VSMCs (Vascular Smooth Muscle Cells) - the main cellular component of media, play an important role in this process. Many reports indicate that the biologically active vitamin D metabolite - 1,25-dihydroxyvitamin D3 (1,25(OH)2D3 = calcitriol), besides its well established role in calcium homeostasis, plays an essential role in the regulation of the inflammation process. The aim of this study was to determine the regulatory effects of calcitriol, applied at two supra-physiological doses (10 nM and 100 nM), in VSMC culture. Secretion of the pro-inflammatory cytokines, IL-6 and TNF-α, was significantly attenuated in calcitriol-treated VSMC culture, but the level of anti-inflammatory TGF-β was generally unchanged. Since in advanced atherosclerosis lesions several cell types, including VSMCs, overproduce the HSP70 chaperone protein, we also checked the effects of calcitriol on its synthesis. The presence of 1,25(OH)2D3 did not affect HSP70 synthesis under physiological conditions but the synthesis of HSP70 in VSMCs exposed to heat shock was significantly inhibited by calcitriol (=100 nM). We observed that 1,25(OH)2D3 induced SOD 1 activity, stimulated the expression of IκB-α, and did not influence the level of NF-κB-p65 in VSMCs. The results of our study suggest that 1,25(OH)2D3 may serve as a natural anti-inflammatory agent and may therefore play a beneficial role in the physiology of VSMC in some contexts of atherosclerosis.
- Department of Plant Physiology and Biotechnology, University of Gdańsk, Gdańsk, Poland
- Department of Clinical Immunology & Transplantology, Medical University of Gdańsk, Gdańsk, Poland
- Department of Electron Microscopy, Medical University of Gdańsk, Gdańsk, Poland
- Beauchamp C, Fridovich I (1971) Superoxide dismutase: improved assays and an assay applicable to acrylamide gels. Anal Biochem 44: 276-287.
- Bielecka-Dabrowa A, Barylski M, Mikhailidis DP, Rysz J, Banach M (2009) HSP 70 and atherosclerosis - protector or activator? Expert Opin Ther Targets 13: 307-317.
- Bobryshev YV, Lord RS (2002) Expression of heat shock protein-70 by dendritic cells in the arterial intima and its potential significance in atherogenesis. J Vasc Surg 35: 368-375.
- Bobryshev YV (2010) Vitamin D3 suppresses immune reactions in atherosclerosis, affecting regulatory T cells and dendritic cell function. Arterioscler Thromb Vasc Biol 30: 2317-2319.
- Bonizzi G, Karin M (2004) The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends Immunol 25: 280-288.
- Bradford MM (1976) A rapid and sensitive method for quantitation of microgram quantities of protein utilizing the principle of protein-dye-binding. Anal Biochem 72: 248-254.
- Doran AC, Meller N, McNamara CA (2008) Role of smooth muscle cells in the initiation and early progression of atherosclerosis. Arterioscler Thromb Vasc Biol 28: 812-819.
- Hamel L, Kenney M, Jayyosi Z, Ardati A, Clark K, Spada A, Zilberstein A, Perrone M, Kaplow J, Merkel L, Rojas C (2000) Induction of heat shock protein 70 by herbimycin A and cyclopentenone prostaglandins in smooth muscle cells. Cell Stress Chaperones 5: 121-131.
- Huang CY, Fujimura M, Noshita N, Chang YY, Chan PH (2001) SOD1 down-regulates NF-kappaB and c-Myc expression in mice after transient focal cerebral ischemia. J Cereb Blood Flow Metab 21: 163-173.
- Janjetovic Z, Zmijewski MA, Tuckey RC, DeLeon DA, Nguyen MN, Pfeffer LM, Slominski AT (2009) 20-Hydroxycholecalciferol, product of vitamin D3 hydroxylation by P450scc, decreases NF-kB activity by increasing IkBa levels in human keratinocytes. PLoS One 4: e5988.
- Johnson AD, Berberian PA, Tytell M, Bond MG (1995) Differential distribution of 70-kD heat shock protein in atherosclerosis: Its potential role in arterial SMC survival. Arterioscler Thromb Vasc Biol 15: 27-36.
- Libermann TL, Baltimore D (1990) Activation of interleukin-6 gene expression through the NF-KB transcription factor. Mol Cell Biol 10: 2327-2334.
- Lin SJ, Shyue SK, Hung YY, Chen YH, Ku HH, Chen JW, Tam KB, Chen YL (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.
- Maret A, Clamens S, Delrieu I, Elhage R, Arnal JF, Bayard F (1999) Expression of the interleukin-6 gene is constitutive and not regulated by estrogen in rat vascular smooth muscle cells in culture. Endocrinology 140: 2876-2882.
- Martin-Ventura JL, Leclercq A, Blanco-Colio LM, Egido J, Rossignol P, Meilhac O, Michel JB (2007) Low plasma levels of HSP70 in patients with carotid atherosclerosis are associated with increased levels of proteolytic markers of neutrophil activation. Atherosclerosis 194: 334-341.
- Pockley AG, Calderwood SK, Multhoff G (2009) The atheroprotective properties of Hsp70: a role for Hsp70-endothelial interactions? Cell Stress Chaperones 14: 545-553.
- Pockley AG, Georgiades A, Thulin T, de Faire U, Frostegård J (2003) Serum heat shock protein 70 levels predict the development of atherosclerosis in subjects with established hypertension. Hypertension 42: 235-238.
- Pockley AG, Multhoff G (2010) Circulating HSP70 as an endogenous cytoprotector? Heat shock proteins and whole body physiology. Heat Shock Proteins 5: 317-326.
- Raines EW, Ferri N (2005) Thematic review series: The immune system and atherogenesis. Cytokines affecting endothelial and smooth muscle cells in vascular disease. J. Lipid Res 46: 1081-1092.
- Ross R (1999) Atherosclerosis - an inflammatory disease. N Engl J Med 340: 115-126.
- Sun J, Kong J, Duan Y, Szeto FL, Liao A, Madara JL, Li YC (2006) Increased NF-kappaB activity in fibroblasts lacking the vitamin D receptor. Am J Physiol Endocrinol Metab 291: E315-E322.
- Svensson PA, Asea A, Englund MC, Bausero MA, Jernås M, Wiklund O, Ohlsson BG, Carlsson LM, Carlsson B (2006) Major role of HSP70 as a paracrine inducer of cytokine production in human oxidized LDL treated macrophages. Atherosclerosis 185: 32-38.
- Szeto FL, Sun J, Kong J, Duan Y, Liao A, Madara JL, Li YC (2007) Involvement of the vitamin D receptor in the regulation of NF-κB activity in fibroblasts. J Steroid Biochem Mol Biol 103: 563-566.
- Takeda M, Yamashita T, Sasaki N, Nakajima K, Kita T, Shinohara M, Ishida T, Hirata K (2010) Oral administration of an active form of vitamin D3 (calcitriol) decreases atherosclerosis in mice by inducing regulatory T cells and immature dendritic cells with tolerogenic functions. Arterioscler Thromb Vasc Biol 30: 2495-2503.
- Tang F, Wu X, Wang T, Wang P, Li R, Zhang H, Gao J, Chen S, Bao L, Huang H, Liu P (2007) Tanshinone II A attenuates atherosclerotic calcification in rat model by inhibition of oxidative stress. Vascul Pharmacol 46: 427-438.
- Tedgui A, Mallat Z (2006) Cytokines in atherosclerosis: Pathogenic and regulatory pathways. Physiol Rev 86: 515-581.
- Tukaj C, Trzonkowski P, Kubasik-Juraniec J, Myśliwski A (2007) Quantifying division of aortal smooth muscle cells in culture stimulated by 1,25(OH)2D3. J Steroid Biochem Mol Biol 103: 525-528.
- Tukaj C, Trzonkowski P, Pikuła M, Hallmann A, Tukaj S (2010) Increased migratory properties of aortal smooth muscle cells exposed to calcitriol in culture. J Steroid Biochem Mol Biol 121: 208-211.
- Tukaj C (2008) Enhanced proliferation of aortal smooth muscle cells treated by 1,25(OH)2D3 in vitro coincides with impaired formation of elastic Fibres. Int J Exp Pathol 89: 117-124.
- Vallabhapurapu S, Karin M (2009) Regulation and function of NF-kappaB transcription factors in the immune system. Annu Rev Immunol 27: 693-733.
- van Eden W, van der Zee R, Prakken B (2005) Heat-shock proteins induce T-cell regulation of chronic inflammation. Nat Rev Immunol 5: 318-330.
- Viedt C, Vogel J, Athanasiou T, Shen W, Orth SR, Kübler W, Kreuzer J (2002) Monocyte chemoattractant protein-1 induces proliferation and interleukin-6 production in human smooth muscle cells by differential activation of nuclear factor-kappaB and activator protein-1. Arterioscler Thromb Vasc Biol 22: 914-920.
- Wilson SH, Best PJ, Edwards WD, Holmes DR Jr, Carlson PJ, Celermajer DS, Lerman A (2002) Nuclear factor-kappaB immunoreactivity is present in human coronary plaque and enhanced in patients with unstable angina pectoris. Atherosclerosis 160: 147-153.
- Wu S, Xia Y, Liu X, Sun J (2010) Vitamin D receptor deletion leads to reduced level of IkappaBalpha protein through protein translation, protein-protein interaction, and post-translational modification. Int J Biochem Cell Biol 42: 329-336.
- Wu-Wong JR, Nakane M, Ma J, Dixon D, Gagne G (2006) Vitamin D receptor (VDR) localization in human promyelocytic leukemia cells. Leuk Lymphoma 47: 727-732.
- Yang H, Roberts LJ, Shi MJ, Zhou LC, Ballard BR, Richardson A, Guo ZM (2004) Retardation of atherosclerosis by overexpression of catalase or both Cu/Zn-superoxide dismutase and catalase in mice lacking apolipoprotein E. Circ Res 95: 1075-1081.
- Zampetaki A, Zhang Z, Hu Y, Xu Q (2005) Biomechanical stress induces IL-6 expression in smooth muscle cells via ras/rac1-p38 MAPK-NFkB signaling pathways. Am J Physiol Heart Circ Physiol 288: H2946-H2954.
Publication order reference