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      A Lindera obtusiloba Extract Blocks Calcium-/Phosphate-Induced Transdifferentiation and Calcification of Vascular Smooth Muscle Cells and Interferes with Matrix Metalloproteinase-2 and Metalloproteinase-9 and NF- κB

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          Abstract

          Vascular calcifications bear the risk for cardiovascular complications and have a high prevalence among patients with chronic kidney disease. Central mediators of vascular calcifications are vascular smooth muscle cells (VSMC). They transdifferentiate into a synthetic/osteoblast-like phenotype, which is induced, for example, by elevated levels of calcium and phosphate (Ca/P) due to a disturbed mineral balance. An aqueous extract from Lindera obtusiloba (LOE) is known to exert antifibrotic and antitumor effects or to interfere with the differentiation of preadipocytes. Using murine and rat VSMC cell lines, we here investigated whether LOE also protects VSMC from Ca/P-induced calcification. Indeed, LOE effectively blocked Ca/P-induced calcification of VSMC as shown by decreased VSMC mineralization and secretion of alkaline phosphatase. In parallel, mRNA expression of the calcification markers osterix and osteocalcin was reduced. Vice versa, the Ca/P-induced loss of the VSMC differentiation markers alpha smooth muscle actin and smooth muscle protein 22-alpha was rescued by LOE. Further, LOE blocked Ca/P-induced mRNA expressions and secretions of matrix metalloproteinases-2/-9 and activation of NF- κB, which are known contributors to vascular calcification. In conclusion, LOE interferes with the Ca/P-induced transdifferentiation/calcification of VSMC. Thus, LOE should be further analysed regarding a potential complementary treatment option for cardiovascular diseases including vascular calcifications.

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          Vascular calcification: the killer of patients with chronic kidney disease.

          Cardiovascular complications are the leading cause of death in patients with chronic kidney disease (CKD). Vascular calcification is a common complication in CKD, and investigators have demonstrated that the extent and histoanatomic type of vascular calcification are predictors of subsequent vascular mortality. Although research efforts in the past decade have greatly improved our knowledge of the multiple factors and mechanisms involved in vascular calcification in patients with kidney disease, many questions remain unanswered. No longer can we accept the concept that vascular calcification in CKD is a passive process resulting from an elevated calcium-phosphate product. Rather, as a result of the metabolic insults of diabetes, dyslipidemia, oxidative stress, uremia, and hyperphosphatemia, "osteoblast-like" cells form in the vessel wall. These mineralizing cells as well as the recruitment of undifferentiated progenitors to the osteochondrocyte lineage play a critical role in the calcification process. Important transcription factors such as Msx 2, osterix, and RUNX2 are crucial in the programming of osteogenesis. Thus, the simultaneous increase in arterial osteochondrocytic programs and reduction in active cellular defense mechanisms creates the "perfect storm" of vascular calcification seen in ESRD. Innovative clinical studies addressing the combined use of inhibitors that work on vascular calcification through distinct molecular mechanisms, such as fetuin-A, osteopontin, and bone morphogenic protein 7, among others, will be necessary to reduce significantly the accrual of vascular calcifications and cardiovascular mortality in kidney disease. In addition, the roles of oxidative stress and inflammation on the fate of smooth muscle vascular cells and their function deserve further translational investigation.
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            Osteopontin: a multifunctional molecule regulating chronic inflammation and vascular disease.

            Osteopontin (OPN) is a multifunctional molecule highly expressed in chronic inflammatory and autoimmune diseases, and it is specifically localized in and around inflammatory cells. OPN is a secreted adhesive molecule, and it is thought to aid in the recruitment of monocytes-macrophages and to regulate cytokine production in macrophages, dendritic cells, and T-cells. OPN has been classified as T-helper 1 cytokine and thus believed to exacerbate inflammation in several chronic inflammatory diseases, including atherosclerosis. Besides proinflammatory functions, physiologically OPN is a potent inhibitor of mineralization, it prevents ectopic calcium deposits and is a potent inducible inhibitor of vascular calcification. Clinically, OPN plasma levels have been found associated with various inflammatory diseases, including cardiovascular burden. It is thus imperative to dissect the OPN proinflammatory and anticalcific functions. OPN recruitment functions of inflammatory cells are thought to be mediated through its adhesive domains, especially the arginine-glycine-aspartate (RGD) sequence that interacts with several integrin heterodimers. However, the integrin receptors and intracellular pathways mediating OPN effects on immune cells are not well established. Furthermore, several studies show that OPN is cleaved by at least 2 classes of proteases: thrombin and matrix-metalloproteases (MMPs). Most importantly, at least in vitro, fragments generated by cleavage not only maintain OPN adhesive functions but also expose new active domains that may impart new activities. The role for OPN proteolytic fragments in vivo is almost completely unexplored. We believe that further knowledge of the effects of OPN fragments on cell responses might help in designing therapeutics targeting inflammatory and cardiovascular diseases.
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              Medial localization of mineralization-regulating proteins in association with Mönckeberg's sclerosis: evidence for smooth muscle cell-mediated vascular calcification.

              Calcification of the media of peripheral arteries is referred to as Mönckeberg's sclerosis (MS) and occurs commonly in aged and diabetic individuals. Its pathogenesis is unknown, but its presence predicts risk of cardiovascular events and leg amputation in diabetic patients. Several studies have documented expression of bone-associated genes in association with intimal atherosclerotic calcification, leading to the suggestion that vascular calcification may be a regulated process with similarities to developmental osteogenesis. Therefore, we examined gene expression in vessels with MS to determine whether there was evidence for a regulated calcification process in the vessel media. In situ hybridization, immunohistochemistry, and semiquantitative reverse-transcription polymerase chain reaction were used to examine the expression of mineralization-regulating proteins in human peripheral arteries with and without MS. MS occurred in direct apposition to medial vascular smooth muscle cells (VSMCs) in the absence of macrophages or lipid. These VSMCs expressed the smooth muscle-specific gene SM22alpha and high levels of matrix Gla protein but little osteopontin mRNA. Compared with normal vessels, vessels with MS globally expressed lower levels of matrix Gla protein and osteonectin, whereas alkaline phosphatase, bone sialoprotein, bone Gla protein, and collagen II, all indicators of osteogenesis/chondrogenesis, were upregulated. Furthermore, VSMCs derived from MS lesions exhibited osteoblastic properties and mineralized in vitro. These data indicate that medial calcification in MS lesions is an active process potentially orchestrated by phenotypically modified VSMCs.
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                Author and article information

                Journal
                Evid Based Complement Alternat Med
                Evid Based Complement Alternat Med
                ECAM
                Evidence-based Complementary and Alternative Medicine : eCAM
                Hindawi Publishing Corporation
                1741-427X
                1741-4288
                2015
                30 July 2015
                30 July 2015
                : 2015
                : 679238
                Affiliations
                1Department of Pediatric Nephrology and Center for Cardiovascular Research, Charité-University Medicine, Campus Virchow Clinic, 10115 Berlin, Germany
                2Department of Beauty Design, Human Environmental Sciences College, Wonkwang University, Iksan 570-749, Republic of Korea
                Author notes

                Academic Editor: Roja Rahimi

                Article
                10.1155/2015/679238
                4534752
                26294927
                efd13ba4-7288-46a5-bf3a-92ac4080eba8
                Copyright © 2015 Christian Freise et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 24 March 2015
                : 10 July 2015
                : 13 July 2015
                Categories
                Research Article

                Complementary & Alternative medicine
                Complementary & Alternative medicine

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