High expression of genes for calcification-regulating proteins in human atherosclerotic plaques.

Abstract

Calcification is common in atheromatous plaques and may contribute to plaque rupture and subsequent thrombosis. However, little is known about the mechanisms which regulate the calcification process. Using in situ hybridization and immunohistochemistry we show that two bone-associated proteins, osteopontin (OP) and matrix Gla protein (MGP), are highly expressed in human atheromatous plaques. High levels of OP mRNA and protein were found in association with necrotic lipid cores and areas of calcification. The predominant cell type in these areas was the macrophage-derived foam cell, although some smooth muscle cells could also be identified. MGP was expressed uniformly by smooth muscle cells in the normal media and at high levels in parts of the atheromatous intima. Highest levels of this matrix-associated protein were found in lipid-rich areas of the plaque. The pattern of expression of these two genes contrasted markedly with that of calponin and SM22 alpha, genes expressed predominantly by differentiated smooth muscle cells and whose expression was generally confined to the media of the vessel. The postulated function of OP and MGP as regulators of calcification in bone and the high levels and colocalization of both in atheromatous plaques suggest they have an important role in plaque pathogenesis and stability.

Advanced Oxidation Protein Products Induce Vascular Calcification by Promoting Osteoblastic Trans-Differentiation of Smooth Muscle Cells via Oxidative Stress and ERK Pathway

“…These osteoblastic reactions may then lead to mineralization of the extracellular matrix. [7][8][9][10][11] Witko-Sarsat et al were the first to report that AOPPs were significantly increased in hemodialysis patients and proposed that AOPPs might be formed during oxidative stress by reaction of plasma proteins with chlorinated oxidants. AOPPs have been recognized as markers of oxidant-mediated protein damage.…”

“…[1][2][3][4][5][6] Accumulating evidence suggests that vascular calcification resembles developmental bone mineralization, with the production of "bone" proteins by vascular smooth muscle cells (VSMCs), such as osteopontin (OPN) and type-I collagen. [7][8][9][10][11] Furthermore, a recent study [12] demonstrates that the addition of uremic serum to cultured VSMCs accelerated mineralization and up-regulated the expression of osteopontin and core binding factor-a1 (CBF-a1), a transcription factor that is important for osteoblast differentiation and bone matrix protein expression. [13] This implies that the uremia may lead to dedifferentiation of VSMCs, with subsequent mineralization.…”

Mice lacking smooth muscle calponin display increased bone formation that is associated with enhancement of bone morphogenetic protein responses

“…The ectopic bone formation often occurs in atherosclerotic neointima, where ␣-SMA-positive microvascular pericytes and de-differentiated smooth muscle cells are accumulated (Shanahan et al 1994;Bostrom et al 1995). These cells express low or undetectable levels of basic calponin gene product (Shanahan et al 1994).…”

“…These cells express low or undetectable levels of basic calponin gene product (Shanahan et al 1994). Demer and co-workers suggested that possible mechanisms for bone formation in the artery walls are the developmental retention of pluripotent mesenchymal cells or osteoblastic immigration coupled with a loss of molecular regulatory control that unmasks an osteogenic programme (Bostrom et al 1995).…”

Identification of the Phosphorylated Sites of Metabolically 32P-Labeled Osteopontin from Cultured Chicken Osteoblasts

“…Not only did the decalcified bone samples containing the collagen-phosphoproteins complexes markedly decrease the nucleation induction time, but this property was lost when the phosphate groups alone were removed enzymatically, leaving the dephosphorylated collagen-phosphoprotein completely intact and, hence, pinpointing the role of the phosphate groups in this in vitro crystal nucleation event (27,28). In addition to their postulated role in calcification, these phosphoproteins have been implicated in many other biological functions (13)(14)(15)(16)29).Two major glycosylated phosphoproteins in bone and many other mineralized tissues, osteopontin (OPN) 1 and bone sialo-* This work was supported by National Institutes of Health Grant AR34078, a grant from the Peabody Foundation, and the Milton Fund of the Harvard Medical School. The costs of publication of this article were defrayed in part by the payment of page charges.…”