Arterial calcification: A review of mechanisms, animal models, and the prospects for therapy

Abstract

Abstract:The causes of arterial calci®cation are beginning to be elucidated. Macrophages, mast cells, and smooth muscle cells are the primary cells implicated in this process. The roles of a variety of bone-related proteins including bone morphogenetic protein-2 (BMP-2), matrix Gla protein (MGP), osteoprotegerin (OPG), osteopontin, and osteonectin in regulating arterial calci®cation are reviewed. Animals lacking MGP, OPG, smad6, carbonic anhydrase isoenzyme II, ®brillin-1, and klotho gene product develop varying extents of arterial calci®cation. Hyperlipidemia, vitamin D, nicotine, and warfarin, alone or in various combinations, produce arterial calci®cation in animal models. MGP has recently been discovered to be an inhibitor of bone morphogenetic protein-2, the principal osteogenic growth factor. Many of the forces that induce arterial calci®cation may act by disrupting the essential post-translational modi®cation of MGP, allowing BMP-2 to induce mineralization. MGP requires gamma-carboxylation before it is functional, and this process uses vitamin K as an essential cofactor. Vitamin K de®ciency, drugs that act as vitamin K antagonists, and oxidant stress are forces that could prevent the formation of GLA residues on MGP. The potential role of arterial apoptosis in calci®cation is discussed. Potential therapeutic options to limit the rate of arterial calci®cation are summarized.

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.…”

Repression of osteocyte Wnt/β-catenin signaling is an early event in the progression of renal osteodystrophy

“…(16)(17)(18)(19)(20)(21)(22)(23) Additionally, soft-tissue calcification including vascular calcification is a common feature of genetic mouse and rat models harboring defects associated with bone mineralization. (24)(25)(26) Clinical improvements in bone health, regardless of the initial bone defect, ameliorate progression of cardiovascular disease. (23) Taken together, these observations support a mechanistic link between bone health and cardiovascular disease and have prompted the Kidney Disease: Improving Global Outcomes (KDIGO) organization to describe characteristics in mineral dysregulation as CKD-mineral bone disorder (CKD-MBD).…”

Effects of the blood coagulation vitamin K as an inhibitor of arterial calcification

“…the cellular and molecular mechanisms leading to arterial calcification has provided strong support for the idea that the mechanisms are similar to the mechanisms underlying bone formation (4). Several proteins suspected to be involved have been identified (1)(2)(3)(4)(5).…”

“…Several proteins suspected to be involved have been identified (1)(2)(3)(4)(5). However the findings that 1) deletion of the gene for the vitamin K-dependent protein matrix Gla protein (MGP) (6) and 2) prevention of vitamin K to work as a cofactor for production of Gla containing proteins in the vessel wall (7) caused massive calcification of the arterial system in rodents led to massive thrombosis and death (6), suggested, for the first time, that vitamin K is an important factor in prevention of arterial calcification.…”