Enhanced Expression of Osteopontin in Human Diabetic Artery and Analysis of Its Functional Role in Accelerated Atherogenesis

Abstract

Abstract-We have previously reported that high glucose stimulates osteopontin (OPN) expression through protein kinase C-dependent pathways as well as hexosamine pathways in cultured rat aortic smooth muscle cells. The finding prompted us to study in vivo expression of OPN in diabetes mellitus. In the present study, we found by immunohistochemistry that medial layers of the carotid arteries of streptozotocin-induced diabetic rats and the forearm arteries of diabetic patients stained positively for OPN antibodies, whereas the staining from arteries of control rats and nondiabetic patients was negative. We also found that OPN stimulated the migration and enhanced platelet-derived growth factor (PDGF)-mediated DNA synthesis of cultured rat aortic smooth muscle cells. OPN and PDGF synergistically activated focal adhesion kinase as well as extracellular signal-regulated kinase; this finding seems to explain the OPN-induced enhancement of PDGF-mediated DNA synthesis. Taken Key Words: diabetic macroangiopathy Ⅲ osteopontin Ⅲ platelet-derived growth factor Ⅲ vascular smooth muscle cells I t is generally accepted that diabetic patients often suffer from atherosclerotic vascular diseases, such as ischemic heart disease and arteriosclerosis obliterans. 1,2 It is also known that diabetic vascular lesions tend to undergo restenosis after angioplasty and that diffuse calcification of the affected arteries is a characteristic feature of diabetic vascular diseases. [3][4][5] However, the reason for the accelerated atherogenesis in diabetes mellitus has not been fully elucidated.Osteopontin (OPN) is a multifunctional phosphoprotein secreted by many cell types, such as osteoclasts, lymphocytes, macrophages, epithelial cells, and vascular smooth muscle cells (SMCs). 6 Overexpression of OPN has been found in several physiological as well as pathological conditions, including immunologic disorders, 7 neoplastic transformation, 8 progression of metastases, 8 formation of urinary stones, 9 and wound healing. 10 It has been reported that OPN protein and mRNA are expressed in the neointima as well as in calcified atheromatous plaque. 11 A neutralizing antibody against OPN has been found to inhibit rat carotid neointimal formation after endothelial denudation. 12 It has also been reported that OPN inhibits the calcification of vascular SMCs in culture. 13 These reports have suggested that OPN contributes not only to the tissue calcification process but also to the development of atherosclerosis, especially in the process of intimal thickening.We have recently reported that high glucose levels stimulate OPN expression through protein kinase C-dependent pathways as well as hexosamine pathways in cultured rat aortic SMCs. 14 The present study was undertaken to gain more insight into the mechanism of diabetic vascular complications. We first demonstrate that OPN protein is highly expressed in the medial layers of the arteries of diabetic rats and patients. Furthermore, OPN stimulates migration and enhances platelet-derived growth factor (PDG...

Plasma osteoprotegerin levels predict cardiovascular and all-cause mortality and deterioration of kidney function in type 1 diabetic patients with nephropathy

“…This accumulation is seen in the tunica media from areas of the tissue with and without atherosclerotic plaques. The accumulation of osteoprotegerin throughout the deeper layers of the vessel wall may reflect generalised changes in the arterial system in diabetes, as part of diffuse arterial changes such as alterations in glycoproteins [31], collagens [32] and glycosaminoglycans [33]. In addition, osteoprotegerin may be related to the development of medial calcification, which is frequently present in patients with diabetes [34,35].…”

Association between osteopontin promoter variants and diastolic dysfunction in hypertensive heart in the Japanese population

“…Taken together, hypertension and DM could synergistically deteriorate diastolic function in human. Kawamura et al 13 previously reported that OPN expression is upregulated in diabetic human and rat vascular walls. In addition, OPN deletion attenuated diastolic dysfunction in heart of streptozotocin-induced diabetic mouse model.…”

“…11,12 More recently, OPN has emerged as an important protein involved in cardiovascular diseases, including post-myocardial infarction (MI) remodeling and atherosclerosis. 13,14 OPN is expressed at low level under physiological condition in heart; however, its expression is markedly increased after MI and cardiac hypertrophy. 14,15 Overexpression of OPN in mouse cardiomyocyte induces cardiac dysfunction, dilation and fibrosis in heart, 16 suggesting its expression is closely related to myocardial function and fibrosis.…”

Teriparatide (Human Parathyroid Hormone (1–34)) Inhibits Osteogenic Vascular Calcification in Diabetic Low Density Lipoprotein Receptor-deficient Mice

“…1A), although nondiabetic animals exhibit a robust skeletal Msx2 induction (in preparation). High fat diets up-regulate aortic expression of osteogenic gene programs, reflected in the levels of OPN and Msx2 expression (15,16,32); however, PTH(1-34) suppressed aortic expression of OPN and Msx2 by ϳ50% (Fig. 1B).…”