PKC-β activation inhibits IL-18-binding protein causing endothelial dysfunction and diabetic atherosclerosis.

AIMS Clinical observations showed a correlation between accelerated atherosclerosis in diabetes and high plasmatic level of IL-18, a pro-inflammatory cytokine. IL-18 enhances the production of inflammatory cytokines and cellular adhesion molecules contributing to atherosclerotic plaque formation and instability. Previous studies indicated that protein kinase C (PKC)-β inhibition prevented macrophage-induced cytokine expression involved in diabetic (DM) atherosclerotic plaque development. However, the role of PKC-β activation on IL-18/IL-18-binding protein (IL-18BP) pathway causing endothelial dysfunction and monocyte adhesion in diabetes has never been explored. METHODS AND RESULTS Apoe(-/-) mice were rendered DM and fed with western diet containing ruboxistaurin (RBX), a PKC-β inhibitor. After 20 weeks, atherosclerotic plaque composition was quantified. Compared with non-diabetic, DM mice exhibited elevated atherosclerotic plaque formation, cholestoryl ester content and macrophage infiltration, as well as reduced IL-18BP expression in the aorta which was prevented with RBX treatment. Endothelial cells (ECs) and macrophages were exposed to normal or high glucose (HG) levels with or without palmitate and recombinant IL-18 for 24 h. The combined HG and palmitate condition was required to increase IL-18 expression and secretion in macrophages, while it reduced IL-18BP expression in EC causing up-regulation of the vascular cell adhesion molecule (VCAM)-1 and monocyte adhesion. Elevated VCAM-1 expression and monocyte adherence were prevented by siRNA, RBX, and IL-18 neutralizing antibody. CONCLUSION Our study unrevealed a new mechanism by which PKC-β activation promotes EC dysfunction caused by the de-regulation of the IL-18/IL-18BP pathway, leading to increased VCAM-1 expression, monocyte/macrophage adhesion, and accelerated atherosclerotic plaque formation in diabetes.

[1]  K. Natarajan,et al.  High glucose driven expression of pro-inflammatory cytokine and chemokine genes in lymphocytes: molecular mechanisms of IL-17 family gene expression. , 2014, Cellular signalling.

[2]  C. Dinarello,et al.  Interleukin-18 and IL-18 Binding Protein , 2013, Front. Immunol..

[3]  G. King,et al.  Induction of Vascular Insulin Resistance and Endothelin-1 Expression and Acceleration of Atherosclerosis by the Overexpression of Protein Kinase C-&bgr; Isoform in the Endothelium , 2013, Circulation research.

[4]  Y. Zou,et al.  PKC&bgr; Promotes Vascular Inflammation and Acceleration of Atherosclerosis in Diabetic ApoE Null Mice , 2013, Arteriosclerosis, thrombosis, and vascular biology.

[5]  A. Mantovani,et al.  M‐CSF induces the expression of a membrane‐bound form of IL‐18 in a subset of human monocytes differentiating in vitro toward macrophages , 2012, European journal of immunology.

[6]  A. J. Valente,et al.  Interleukin‐18/WNT1‐inducible signaling pathway protein‐1 signaling mediates human saphenous vein smooth muscle cell proliferation , 2011, Journal of cellular physiology.

[7]  H. Brenner,et al.  Interleukin-6 in the prediction of primary cardiovascular events in diabetes patients: results from the ESTHER study. , 2011, Atherosclerosis.

[8]  P. Libby,et al.  Progress and challenges in translating the biology of atherosclerosis , 2011, Nature.

[9]  H. Vargas-Robles,et al.  Correlation Between the Levels of Circulating Adhesion Molecules and Atherosclerosis in Hypertensive Type-2 Diabetic Patients , 2010, Clinical and experimental hypertension.

[10]  Isabel Azevedo,et al.  Chronic Inflammation in Obesity and the Metabolic Syndrome , 2010, Mediators of inflammation.

[11]  B. Gustafson.  Adipose tissue, inflammation and atherosclerosis. , 2010, Journal of atherosclerosis and thrombosis.

[12]  P. Geraldes,et al.  Activation of protein kinase C isoforms and its impact on diabetic complications. , 2010, Circulation research.

[13]  Li Li,et al.  IL-18 overexpression promotes vascular inflammation and remodeling in a rat model of metabolic syndrome. , 2010, Atherosclerosis.

[14]  F. Hu,et al.  Circulating IL-18 and the risk of type 2 diabetes in women , 2009, Diabetologia.

[15]  Y. Zou,et al.  Mice deficient in PKC β and apolipoprotein E display decreased atherosclerosis , 2009, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[16]  S. Baker,et al.  Interleukin 18 binding protein (IL18-BP) inhibits neointimal hyperplasia after balloon injury in an atherosclerotic rabbit model. , 2008, Journal of vascular surgery.

[17]  J. Helge,et al.  Interleukin-18 in plasma and adipose tissue: effects of obesity, insulin resistance, and weight loss. , 2007, European journal of endocrinology.

[18]  P. Libby,et al.  Interleukin-18, the Metabolic Syndrome, and Subclinical Atherosclerosis: Results From the Dallas Heart Study , 2007, Arteriosclerosis, thrombosis, and vascular biology.

[19]  A. Fürnkranz,et al.  Specific monocyte adhesion to endothelial cells induced by oxidized phospholipids involves activation of cPLA2 and lipoxygenase Published, JLR Papers in Press, February 5, 2006. , 2006, Journal of Lipid Research.

[20]  A. Goldfine,et al.  Activation of vascular protein kinase C-beta inhibits Akt-dependent endothelial nitric oxide synthase function in obesity-associated insulin resistance. , 2006, Diabetes.

[21]  B. Zinman,et al.  Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. , 2005, The New England journal of medicine.

[22]  H. Makino,et al.  Serum interleukin-18 levels are associated with nephropathy and atherosclerosis in Japanese patients with type 2 diabetes. , 2005, Diabetes care.

[23]  J. McGill,et al.  The effect of ruboxistaurin on nephropathy in type 2 diabetes. , 2005, Diabetes care.

[24]  B. K. Pedersen,et al.  Elevated plasma interleukin-18 is a marker of insulin-resistance in type 2 diabetic and non-diabetic humans. , 2005, Clinical immunology.

[25]  Srilaxmi Bearelly,et al.  Ruboxistaurin, a Protein Kinase C β Inhibitor, as an Emerging Treatment for Diabetes Microvascular Complications , 2005, The Annals of pharmacotherapy.

[26]  Seng-Lai Tan,et al.  Emerging and diverse roles of protein kinase C in immune cell signalling. , 2003, The Biochemical journal.

[27]  Y. Aso,et al.  Relationships of plasma interleukin-18 concentrations to hyperhomocysteinemia and carotid intimal-media wall thickness in patients with type 2 diabetes. , 2003, Diabetes care.

[28]  M. Hall,et al.  Up-regulation of IL-18BP, but not IL-18 mRNA in rat liver by LPS. , 2003, Cytokine.

[29]  C. Dinarello,et al.  Interleukin-18 binding protein reduces b16 melanoma hepatic metastasis by neutralizing adhesiveness and growth factors of sinusoidal endothelium. , 2003, Cancer research.

[30]  M. Goldman,et al.  Critical role of protein kinase C ϵ for lipopolysaccharide‐induced IL‐12 synthesis in monocyte‐derived dendritic cells , 2002, European journal of immunology.

[31]  R. Frey,et al.  PKCzeta regulates TNF-alpha-induced activation of NADPH oxidase in endothelial cells. , 2002, Circulation research.

[32]  Peter Libby,et al.  Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. , 2002, JAMA.

[33]  A. M. Lefer,et al.  Mechanisms of amelioration of glucose-induced endothelial dysfunction following inhibition of protein kinase C in vivo. , 2002, Diabetes.

[34]  A. Tedgui,et al.  Expression of Interleukin-18 in Human Atherosclerotic Plaques and Relation to Plaque Instability , 2001, Circulation.

[35]  A. Tedgui,et al.  Interleukin-18/Interleukin-18 Binding Protein Signaling Modulates Atherosclerotic Lesion Development and Stability , 2001, Circulation research.

[36]  M. Cybulsky,et al.  A major role for VCAM-1, but not ICAM-1, in early atherosclerosis. , 2001, The Journal of clinical investigation.

[37]  W. Maśliński,et al.  Protein kinase c-dependent pathway is critical for the production of pro-inflammatory cytokines (TNF-alpha, IL-1beta, IL-6). , 1999, Cytokine.

[38]  A. Meager.  Cytokine regulation of cellular adhesion molecule expression in inflammation. , 1999, Cytokine & growth factor reviews.

[39]  V. Kamanna,et al.  Activation of mesangial cells with TNF-alpha stimulates M-CSF gene expression and monocyte proliferation: evidence for involvement of protein kinase C and protein tyrosine kinase. , 1996, Biochimica et biophysica acta.

[40]  S. Bursell,et al.  Amelioration of Vascular Dysfunctions in Diabetic Rats by an Oral PKC β Inhibitor , 1996, Science.

[41]  I. Jialal,et al.  Free fatty acids in the presence of high glucose amplify monocyte inflammation via Toll-like receptors. , 2011, American journal of physiology. Endocrinology and metabolism.

[42]  C. Dinarello,et al.  Interleukin-18 Binding Protein in the Sera of Patients with Wegener’s Granulomatosis , 2008, Journal of Clinical Immunology.

[43]  Grupa badawcza Pkc-Drs.  The effect of ruboxistaurin on visual loss in patients with moderately severe to very severe nonproliferative diabetic retinopathy. Initial results of the Protein Kinase C beta Inhibitor Diabetic Retinopathy Study (PKC-DRS) Multicenter Randomized Clinical Trial , 2005 .

[44]  E. B. Smith,et al.  The relationship between plasma and tissue lipids in human atherosclerosis. , 1974, Advances in lipid research.