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      Is Inflammation the Link between Atherosclerosis and Vascular Calcification in Chronic Kidney Disease?

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          Atherosclerosis and vascular calcification often co-exist in chronic kidney disease (CKD) patients. Although the former has been recently recognized as an active inflammatory process, atherosclerosis-related calcification of the intima is still viewed as a passive epiphenomenon. Recent experimental data showed that ossification of the internal vascular wall might also be an active inflammatory process interrelated to atherosclerosis. Factors like RANKL (receptor activator of nuclear factor ĸB ligand), RANK and osteoprotegerin modulate vascular calcification and at the same time are involved in the process of atherosclerosis. Moreover, basic calcium phosphate crystals could interact with and activate monocytes-macrophages that produce proinflammatory cytokines capable of initiating – via endothelial activation and leukocyte adhesion – the atherosclerotic process. Thus, vascular calcification might be an active player and not simply an epiphenomenon in atherosclerosis. Should the above-mentioned data be confirmed in future studies, calcification of the internal vascular wall and atherosclerosis might be viewed and treated as tightly interconnected and linked by inflammation processes in CKD patients.

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          Most cited references 14

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          Regulation of vascular calcification by osteoclast regulatory factors RANKL and osteoprotegerin.

          Vascular calcification often occurs with advancing age, atherosclerosis, various metabolic disorders such as diabetes mellitus and end-stage renal disease, or in rare genetic diseases, leading to serious clinical consequences. Such mineralization can occur at various sites (cardiac valves, arterial intima or media, capillaries), involve localized or diffuse widespread calcification, and result from numerous causes that provoke active inflammatory and osteogenic processes or disordered mineral homeostasis. Although valuable research has defined many key factors and cell types involved, surprising new insights continue to arise that deepen our understanding and suggest novel research directions or strategies for clinical intervention in calcific vasculopathies. One emerging area in vascular biology involves the RANKL/RANK/OPG system, molecules of the tumor necrosis factor-related family recently discovered to be critical regulators of immune and skeletal biology. Evidence is accumulating that such signals may be expressed, regulated, and function in vascular physiology and pathology in unique ways to promote endothelial cell survival, angiogenesis, monocyte or endothelial cell recruitment, and smooth muscle cell osteogenesis and calcification. Concerted research efforts are greatly needed to understand these potential roles, clarify whether RANKL (receptor activator of nuclear factor kappaB ligand) promotes and osteoprotegerin (OPG) protects against vascular calcification, define how OPG genetic polymorphisms relate to cardiovascular disease, and learn whether elevated serum OPG levels reflect endothelial dysfunction in patients. Overall, the RANKL/RANK/OPG system may mediate important and complex links between the vascular, skeletal, and immune systems. Thus, these molecules may play a central role in regulating the development of vascular calcification coincident with declines in skeletal mineralization with age, osteoporosis, or disease.
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            Osteoprotegerin inactivation accelerates advanced atherosclerotic lesion progression and calcification in older ApoE-/- mice.

            Osteoprotegerin (OPG), a member of the tumor necrosis factor (TNF) superfamily of proteins, plays an important role in bone remodeling and is expressed in both mouse and human atherosclerotic lesions. The current study was designed to assess whether OPG plays a role in the progression and calcification of advanced atherosclerotic lesions in apoE(-/-) mice. Atherosclerotic lesion area and composition and aortic calcium content were examined in mice deficient in both OPG and apolipoprotein E (OPG(-/-).apoE(-/-) mice) at 20, 40, and 60 weeks of age. Littermate OPG(+/+).apoE(-/-) mice were used as controls. The average cross-sectional area of lesions in the innominate arteries was increased in OPG(-/-).apoE(-/-) mice at 40 and 60 weeks of age. The increase in lesion area was coupled with a reduced cellularity and an increase in connective tissue including laminated layers of elastin. Sixty-week-old OPG(-/-).apoE(-/-) mice also had an increase in the area of calcification of the lesions. There were no differences in markers of plaque stability. In vitro, OPG induced matrix metalloproteinase-9 (MMP-9) activity in macrophages and smooth muscle cells and acted as a survival factor for serum-deprived smooth muscle cells. OPG inhibits advanced plaque progression by preventing an increase in lesion size and lesion calcification. OPG may act as a survival factor and may modulate MMP9 production in vascular cells.
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              Multifunctional roles for serum protein fetuin-a in inhibition of human vascular smooth muscle cell calcification.

              Vascular calcification predicts an increased risk for cardiovascular events/mortality in atherosclerosis, diabetes, and ESRD. Serum concentrations of alpha(2)-Heremens-Schmid glycoprotein, commonly referred to as fetuin-A, are reduced in ESRD, a condition associated with an elevated circulating calcium x phosphate product. Mice that lack fetuin-A exhibit extensive soft tissue calcification, which is accelerated on a mineral-rich diet, suggesting that fetuin-A acts to inhibit calcification systemically. Western blot and immunohistochemistry demonstrated that serum-derived fetuin-A co-localized with calcified human vascular smooth muscle cells (VSMC) in vitro and in calcified arteries in vivo. Fetuin-A inhibited in vitro VSMC calcification, induced by elevated concentrations of extracellular mineral ions, in a concentration-dependent manner. This was achieved in part through inhibition of apoptosis and caspase cleavage. Confocal microscopy and electron microscopy-immunogold demonstrated that fetuin-A was internalized by VSMC and concentrated in intracellular vesicles. Subsequently, fetuin-A was secreted via vesicle release from apoptotic and viable VSMC. Vesicles have previously been identified as the nidus for mineral nucleation. The presence of fetuin-A in vesicles abrogated their ability to nucleate basic calcium phosphate. In addition, fetuin-A enhanced phagocytosis of vesicles by VSMC. These observations provide evidence that the uptake of the serum protein fetuin-A by VSMC is a key event in the inhibition of vesicle-mediated VSMC calcification. Strategies aimed at maintaining normal circulating levels of fetuin-A may prove beneficial in patients with ESRD.

                Author and article information

                Blood Purif
                Blood Purification
                S. Karger AG
                March 2007
                26 January 2007
                : 25
                : 2
                : 179-182
                Department of Nephrology, General Hospital of Athens, Athens, Greece
                99011 Blood Purif 2007;25:179–182
                © 2007 S. Karger AG, Basel

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                Figures: 1, References: 19, Pages: 4
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