Vascular Calcification
2011; Lippincott Williams & Wilkins; Volume: 31; Issue: 2 Linguagem: Romeno
10.1161/atvbaha.110.220038
ISSN1524-4636
Autores Tópico(s)Microbial metabolism and enzyme function
ResumoHomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 31, No. 2Vascular Calcification Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBVascular CalcificationIt's All the RAGE! Dwight A. Towler Dwight A. TowlerDwight A. Towler From the Department of Medicine, Endocrine Division, Washington University in St Louis, St Louis, MO 63110. Originally published1 Feb 2011https://doi.org/10.1161/ATVBAHA.110.220038Arteriosclerosis, Thrombosis, and Vascular Biology. 2011;31:237–239is companion ofS100A12 in Vascular Smooth Muscle Accelerates Vascular Calcification in Apolipoprotein E–Null Mice by Activating an Osteogenic Gene Regulatory ProgramMacrovascular calcification increasingly afflicts our aging and dysmetabolic population.1 Once considered only a passive process of dead and dying cells, data from multiple laboratories worldwide have converged to reveal that vascular calcification is in great part an actively regulated form of matrix mineral metabolism.2 A uniquely horrendous situation arises in end-stage renal disease.3 Antecedent vasculopathy from diabetes, dyslipidemia, or hypertension interacts with dialysis-modulated uremia—a fluctuating hyperphosphatemic and hyperphosphatemic milieu that increases vascular smooth muscle cell (VSMC) apoptosis, overwhelms defenses against soft tissue mineralization, and promotes low-grade panvascular inflammation.3,4 Elegant genetic studies by Cecil and Terkeltaub,5 coupled with the enlightening work of Festing et al6 and Li et al7 have highlighted the important role of pyrophosphate and phosphate metabolism in the pathobiology of arterial calcification. In addition, oxidative stress signals (reactive oxygen species [ROS]) elaborated in response to key inflammatory cytokines—namely, interleukin6,8 interleukin 1β,9 and tumor necrosis factor10,11—have been shown to participate in vascular activation of the osteochondrogenic gene programs characteristic of bone formation.12 Only recently, however, has signaling via the receptor for advanced glycosylation end products (RAGE) been implicated as a critical contributor to both ROS-regulated13 and pyrophosphate-regulated5 vascular calcification. RAGE is an immunoglobulin superfamily member, initially identified by Yan et al as an endothelial cell surface receptor for glycated proteins that accumulate with hyperglycemia.14 Although membrane-bound RAGE promotes nuclear factor-κB15 and ROS16 signaling, soluble RAGE (sRAGE) functions as a dominant-negative "faux receptor" for RAGE-activating ligands14 (Figure). Indeed, sRAGE levels are reduced in patients with calcific aortic stenosis,17 suggesting that unchecked RAGE-dependent inflammation may contribute to valve calcium load.18 As immediately germane to the pathobiology of diabetic arterial calcification,19 carboxymethyl lysine and other advanced glycation end-products bind RAGE and sRAGE as ligands.15 However, RAGE functions as a crucial signal transducer for HMGB1 and S100A/calgranulin family members, proteins released with cell necrosis and leukocyte activation, respectively.14,20 Seminal studies from Hofmann Bowman et al first identified expression of S100A12—a human RAGE ligand—in aortic aneurysms.21 Furthermore, they showed that transgenic expression of human S100A12 in VSMCs promotes dilating aortic matrix remodeling in mice.21 Although elastinolysis and oxidative stress—stimuli for vascular calcification22—were concomitantly upregulated by the S100A12 transgene, the impact on arteriosclerotic calcium accrual was not previously addressed.21Download figureDownload PowerPointFigure. Integration of Nox and RAGE signaling by S100A12. Hofmann Bowman et al13 provide evidence that the RAGE ligand S100A12 interacts with Nox1 NAD(P)H oxidase to promote osteochondrogenic differentiation VSMCs via oxidative stress signaling. The inhibitory "faux receptor" sRAGE inhibits S100A12-dependent ROS generation and osteogenic mineralization. Robust elaboration of VSMC osteogenic potential requires monocyte/macrophage-derived signals, as first demonstrated by Tintut et al.10 Although S100A12 binds both RAGE14 and Nox1,13 induction of the putative Nox1-RAGE heterodimeric complex by S100A12 has yet to be directly demonstrated. Whether other RAGE ligands also interact with Nox1 is unknown.See accompanying article on page 337In the current issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Hofmann Bowman et al directly examine the role and regulation of the S100A12/RAGE axis in vascular calcification.13 Implementing the apolipoprotein E−/− murine model, they show that selective VSMC expression of S100A12 increased medial calcium accrual by ≈2- to 6-fold in proximal aorta and innominate arteries, respectively.13 Concomitant increases in bone morphogenetic protein-2 and Runx2—master regulators of osteogenic mineralization23—were also elicited by the S100A12 transgene. Robust responses were observed in apolipoprotein E–null mice, a permissive background for time-dependent medial osteochondral metaplasia even on standard rodent chow diets.24 Ex vivo, S100A12 upregulated osteogenic gene expression and mineralization of cultured transgenic VSMCs.13 Interestingly, the proosteogenic propensity elicited by the S100A12 transgene required conditioned media from lipid-challenged apolipoprotein E–null macrophages13; this presumably reflects contributions of oxysterols, tumor necrosis factor, or other signals elaborated by the monocytic/macrophage lineage that augment the osteogenic milieu.9,10 Of note, similar cross-talk occurs between the osteoclast (monocyte lineage) and the bone-forming osteoblast in the skeleton.25 Importantly, the actions of S100A12 were dependent on RAGE and oxidative stress signaling because both recombinant sRAGE and NAD(P)H oxidase (Nox) inhibition reduced osteogenic programming and calcification.13Why is this study so enlightening? There are several important reasons. First, it provides compelling, independent yet convergent evidence for the crucial role of oxidative stress and NAD(P)H oxidase signaling in arterial calcification.12,26 Intriguingly, downregulation of VSMC Nox1 has also been implicated in the inhibition of medial calcification in other settings.27 Second, RAGE ligands, such as S100/calgranulins, are not normally expressed in VSMCs in the absence of injury.14,28 Thus, the capacity of a uniquely human RAGE agonist, S100A12, to promote VSMC osteochondrogenic mineralization in transgenic mice provides strong evidence that the paracrine S100/RAGE axis enhances vascular calcium accrual.14 Apolipoprotein E deficiency24 likely affords the elaboration of macrophage-derived humoral signals that synergize with S100A12,13 as well as osteogenic morphogens,29 to drive arteriosclerotic medial calcification (Figure). Third, the report introduces a new view of the mechanisms whereby S100/calgranulins upregulate ROS production by VSMCs—namely, via direct cell surface Nox1 activation13 (Figure). Hoffman Bowman et al demonstrate protein-protein interactions between Nox1 and S100A12,13 and similar interactions may occur with other Nox members in other contexts.16 Given the prior evidence that RAGE agonists, such as S100/calgranulin, increase ROS production,14 a heterodimeric RAGE-Nox1 signaling complex may mediate ROS generation and osteogenic mineralization in VSMCs (Figure). This model is supported by data demonstrating that sRAGE inhibits S100A12-induced osteogenic gene expression and calcium deposition in cultured VSMCs.13 Finally, when taken together with very recent data from Cecil and Terkeltaub5—data demonstrating that RAGE conveys arterial osteochondrogenic signals activated by pyrophosphate deficiency5—the work of Hofmann Bowman et al highlights RAGE as a nodal point in the pathobiology of arterial calcification.13 Hyperglycemia, inflammation, abnormal pyrophosphate/phosphate metabolism, hypercholesterolemia, and oxidative stress signaling now converge on the RAGE axis as a mediator of arterial osteochondrogenic mineralization. Vascular calcification? Perhaps it's all the RAGE. At a minimum, a better understanding of RAGE signaling will engender innovative strategies for the prevention and treatment of arteriosclerotic calcification.Sources of FundingDr Towler is supported by grants HL69229, HL81138, and HL88651 from the National Institutes of Health and by the Barnes-Jewish Hospital Foundation.DisclosuresNone.FootnotesCorrespondence to Dwight A. Towler, MD, PhD, Washington University in St Louis, Internal Medicine, Endocrine/Metabolism, Campus Box 8127, 660 S Euclid Ave, St Louis, MO 63110. E-mail [email protected]wustl.eduReferences1. Demer LL, Tintut Y. Vascular calcification: pathobiology of a multifaceted disease. Circulation. 2008; 117:2938–2948.LinkGoogle Scholar2. Sage AP, Tintut Y, Demer LL. Regulatory mechanisms in vascular calcification. Nat Rev Cardiol. 2010; 7:528–536.CrossrefMedlineGoogle Scholar3. Moe SM. Vascular calcification: the three-hit model. J Am Soc Nephrol. 2009; 20:1162–1164.CrossrefMedlineGoogle Scholar4. Shroff RC, McNair R, Figg N, Skepper JN, Schurgers L, Gupta A, Hiorns M, Donald AE, Deanfield J, Rees L, Shanahan CM. Dialysis accelerates medial vascular calcification in part by triggering smooth muscle cell apoptosis. Circulation. 2008; 118:1748–1757.LinkGoogle Scholar5. Cecil DL, Terkeltaub RA. Arterial calcification is driven by RAGE in Enpp1-/- mice. J Vasc Res. 2010; 48:227–235.CrossrefMedlineGoogle Scholar6. Festing MH, Speer MY, Yang HY, Giachelli CM. Generation of mouse conditional and null alleles of the type III sodium-dependent phosphate cotransporter PiT-1. Genesis. 2009; 47:858–863.MedlineGoogle Scholar7. Li X, Yang HY, Giachelli CM. Role of the sodium-dependent phosphate cotransporter, Pit-1, in vascular smooth muscle cell calcification. Circ Res. 2006; 98:905–912.LinkGoogle Scholar8. Yao Y, Watson AD, Ji S, Bostrom KI. Heat shock protein 70 enhances vascular bone morphogenetic protein-4 signaling by binding matrix Gla protein. Circ Res. 2009; 105:575–584.LinkGoogle Scholar9. Parhami F, Basseri B, Hwang J, Tintut Y, Demer LL. High-density lipoprotein regulates calcification of vascular cells. Circ Res. 2002; 91:570–576.LinkGoogle Scholar10. Tintut Y, Patel J, Territo M, Saini T, Parhami F, Demer LL. Monocyte/macrophage regulation of vascular calcification in vitro. Circulation. 2002; 105:650–655.LinkGoogle Scholar11. Al-Aly Z, Shao JS, Lai CF, Huang E, Cai J, Behrmann A, Cheng SL, Towler DA. Aortic Msx2-Wnt calcification cascade is regulated by TNF-α-dependent signals in diabetic Ldlr-/- mice. Arterioscler Thromb Vasc Biol. 2007; 27:2589–2596.LinkGoogle Scholar12. Byon CH, Javed A, Dai Q, Kappes JC, Clemens TL, Darley-Usmar VM, McDonald JM, Chen Y. Oxidative stress induces vascular calcification through modulation of the osteogenic transcription factor Runx2 by AKT signaling. J Biol Chem. 2008; 283:15319–15327.CrossrefMedlineGoogle Scholar13. Hofmann Bowman MA, Gawdzik J, Bukhari U, Husain AN, Toth PT, Kim G, Earley J, McNally EM. S100A12 in vascular smooth muscle accelerates vascular calcification in apolipoprotein E-null mice by activating an osteogenic gene regulatory program. Arterioscler Thromb Vasc Biol. 2011; 31:337–344.LinkGoogle Scholar14. Yan SF, Ramasamy R, Schmidt AM. The RAGE axis: a fundamental mechanism signaling danger to the vulnerable vasculature. Circ Res. 2010; 106:842–853.LinkGoogle Scholar15. Kislinger T, Fu C, Huber B, Qu W, Taguchi A, Du Yan S, Hofmann M, Yan SF, Pischetsrieder M, Stern D, Schmidt AM. N(ε)-(Carboxymethyl)lysine adducts of proteins are ligands for receptor for advanced glycation end products that activate cell signaling pathways and modulate gene expression. J Biol Chem. 1999; 274:31740–31749.CrossrefMedlineGoogle Scholar16. Wautier MP, Chappey O, Corda S, Stern DM, Schmidt AM, Wautier JL. Activation of NADPH oxidase by AGE links oxidant stress to altered gene expression via RAGE. Am J Physiol Endocrinol Metab. 2001; 280:E685–E694.CrossrefMedlineGoogle Scholar17. Basta G, Corciu AI, Vianello A, Del Turco S, Foffa I, Navarra T, Chiappino D, Berti S, Mazzone A. Circulating soluble receptor for advanced glycation end-product levels are decreased in patients with calcific aortic valve stenosis. Atherosclerosis. 2010; 210:614–618.CrossrefMedlineGoogle Scholar18. Rajamannan NM. Calcific aortic stenosis: lessons learned from experimental and clinical studies. Arterioscler Thromb Vasc Biol. 2009; 29:162–168.LinkGoogle Scholar19. Tanikawa T, Okada Y, Tanikawa R, Tanaka Y. Advanced glycation end products induce calcification of vascular smooth muscle cells through RAGE/p38 MAPK. J Vasc Res. 2009; 46:572–580.CrossrefMedlineGoogle Scholar20. Kim W, Hudson BI, Moser B, Guo J, Rong LL, Lu Y, Qu W, Lalla E, Lerner S, Chen Y, Yan SS, D'Agati V, Naka Y, Ramasamy R, Herold K, Yan SF, Schmidt AM. Receptor for advanced glycation end products and its ligands: a journey from the complications of diabetes to its pathogenesis. Ann N Y Acad Sci. 2005; 1043:553–561.CrossrefMedlineGoogle Scholar21. Hofmann Bowman M, Wilk J, Heydemann A, Kim G, Rehman J, Lodato JA, Raman J, McNally EM. S100A12 mediates aortic wall remodeling and aortic aneurysm. Circ Res. 2010; 106:145–154.LinkGoogle Scholar22. Shao JS, Cheng SL, Sadhu J, Towler DA. Inflammation and the osteogenic regulation of vascular calcification: a review and perspective. Hypertension. 2010; 55:579–592.LinkGoogle Scholar23. Lian JB, Stein GS, Javed A, van Wijnen AJ, Stein JL, Montecino M, Hassan MQ, Gaur T, Lengner CJ, Young DW. Networks and hubs for the transcriptional control of osteoblastogenesis. Rev Endocr Metab Disord. 2006; 7:1–16.CrossrefMedlineGoogle Scholar24. Qiao JH, Fishbein MC, Demer LL, Lusis AJ. Genetic determination of cartilaginous metaplasia in mouse aorta. Arterioscler Thromb Vasc Biol. 1995; 15:2265–2272.LinkGoogle Scholar25. Pederson L, Ruan M, Westendorf JJ, Khosla S, Oursler MJ. Regulation of bone formation by osteoclasts involves Wnt/BMP signaling and the chemokine sphingosine-1-phosphate. Proc Natl Acad Sci U S A. 2008; 105:20764–20769.CrossrefMedlineGoogle Scholar26. Miller JD, Chu Y, Brooks RM, Richenbacher WE, Pena-Silva R, Heistad DD. Dysregulation of antioxidant mechanisms contributes to increased oxidative stress in calcific aortic valvular stenosis in humans. J Am Coll Cardiol. 2008; 52:843–850.CrossrefMedlineGoogle Scholar27. Cheng SL, Shao JS, Halstead LR, Distelhorst K, Sierra O, Towler DA. Activation of vascular smooth muscle parathyroid hormone receptor inhibits Wnt/β-catenin signaling and aortic fibrosis in diabetic arteriosclerosis. Circ Res. 2010; 107:271–282.LinkGoogle Scholar28. Perera C, McNeil HP, Geczy CL. S100 calgranulins in inflammatory arthritis. Immunol Cell Biol. 2010; 88:41–49.CrossrefMedlineGoogle Scholar29. Kha HT, Basseri B, Shouhed D, Richardson J, Tetradis S, Hahn TJ, Parhami F. Oxysterols regulate differentiation of mesenchymal stem cells: pro-bone and anti-fat. J Bone Miner Res. 2004; 19:830–840.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Ghosh S, Luo D, He W, Chen J, Su X and Huang H (2020) Diabetes and calcification: The potential role of anti-diabetic drugs on vascular calcification regression, Pharmacological Research, 10.1016/j.phrs.2020.104861, 158, (104861), Online publication date: 1-Aug-2020. Beloqui O, Moreno M, San José G, Pejenaute Á, Cortés A, Landecho M, Díez J, Fortuño A and Zalba G (2017) Increased phagocytic NADPH oxidase activity associates with coronary artery calcification in asymptomatic men, Free Radical Research, 10.1080/10715762.2017.1321745, 51:4, (389-396), Online publication date: 3-Apr-2017. Bardeesi A, Gao J, Zhang K, Yu S, Wei M, Liu P and Huang H (2017) A novel role of cellular interactions in vascular calcification, Journal of Translational Medicine, 10.1186/s12967-017-1190-z, 15:1, Online publication date: 1-Dec-2017. Dhar S, Sun Z, Meininger G and Hill M (2017) Nonenzymatic glycation interferes with fibronectin-integrin interactions in vascular smooth muscle cells, Microcirculation, 10.1111/micc.12347, 24:3, (e12347), Online publication date: 1-Apr-2017. Boström K (2016) Where do we stand on vascular calcification?, Vascular Pharmacology, 10.1016/j.vph.2016.05.014, 84, (8-14), Online publication date: 1-Sep-2016. Yang X, Liaw L, Prudovsky I, Brooks P, Vary C, Oxburgh L and Friesel R (2015) Fibroblast Growth Factor Signaling in the Vasculature, Current Atherosclerosis Reports, 10.1007/s11883-015-0509-6, 17:6, Online publication date: 1-Jun-2015. Yan L, Mathew L, Chellan B, Gardner B, Earley J, Puri T and Hofmann Bowman M (2014) S100/Calgranulin-Mediated Inflammation Accelerates Left Ventricular Hypertrophy and Aortic Valve Sclerosis in Chronic Kidney Disease in a Receptor for Advanced Glycation End Products–Dependent Manner, Arteriosclerosis, Thrombosis, and Vascular Biology, 34:7, (1399-1411), Online publication date: 1-Jul-2014. Ndip A, Wilkinson F, Jude E, Boulton A and Alexander M (2014) RANKL–OPG and RAGE modulation in vascular calcification and diabetes: novel targets for therapy, Diabetologia, 10.1007/s00125-014-3348-z, 57:11, (2251-2260), Online publication date: 1-Nov-2014. McCarty M and DiNicolantonio J (2015) The Molecular Biology and Pathophysiology of Vascular Calcification, Postgraduate Medicine, 10.3810/pgm.2014.03.2740, 126:2, (54-64), Online publication date: 1-Mar-2014. Greco R, Tassorelli C, Stefania Mangione A, Levandis G, Certo M, Nappi G, Bagetta G, Blandini F and Amantea D (2014) Neuroprotection by the PARP inhibitor PJ34 modulates cerebral and circulating RAGE levels in rats exposed to focal brain ischemia, European Journal of Pharmacology, 10.1016/j.ejphar.2014.10.006, 744, (91-97), Online publication date: 1-Dec-2014. Tang S, Wang Y, Li Y, Lin H, Manzanero S, Hsieh Y, Phipps S, Hu C, Chiou H, Huang Y, Yang W, Mattson M, Arumugam T and Jeng J (2013) Functional Role of Soluble Receptor for Advanced Glycation End Products in Stroke, Arteriosclerosis, Thrombosis, and Vascular Biology, 33:3, (585-594), Online publication date: 1-Mar-2013. Wang Y, Shan J, Yang W, Zheng H and Xue S (2013) High Mobility Group Box 1 (HMGB1) Mediates High-Glucose-Induced Calcification in Vascular Smooth Muscle Cells of Saphenous Veins, Inflammation, 10.1007/s10753-013-9704-1, 36:6, (1592-1604), Online publication date: 1-Dec-2013. Kim J, Park S, Lee M, Song Y, Han S, Kim S, Kang S, Choi K, Kim H and Yoo T (2012) Plasma levels of soluble receptor for advanced glycation end products (sRAGE) and proinflammatory ligand for RAGE (EN-RAGE) are associated with carotid atherosclerosis in patients with peritoneal dialysis, Atherosclerosis, 10.1016/j.atherosclerosis.2011.07.115, 220:1, (208-214), Online publication date: 1-Jan-2012. Basta G, Turco S, Navarra T, Mazzarisi A, Cocci F, Coceani M, Bianchi M, Schlueter M and Marraccini P (2012) Inverse Association between Circulating Levels of Soluble Receptor for Advanced Glycation End-Products and Coronary Plaque Burden, Journal of Atherosclerosis and Thrombosis, 10.5551/jat.10561, . Miller J, Weiss R, Heistad D and Towler D (2011) Calcific Aortic Valve Stenosis: Methods, Models, and Mechanisms, Circulation Research, 108:11, (1392-1412), Online publication date: 27-May-2011.Rutsch F, Nitschke Y, Terkeltaub R and Towler D (2011) Genetics in Arterial Calcification, Circulation Research, 109:5, (578-592), Online publication date: 19-Aug-2011. Choi B, Ro H, Jung E, Kim A, Chang J, Lee H, Chung W, Jung J and Aikawa E (2016) Circulating S100A12 Levels Are Associated with Progression of Abdominal Aortic Calcification in Hemodialysis Patients, PLOS ONE, 10.1371/journal.pone.0150145, 11:2, (e0150145) Chellan B, Sutton N and Hofmann Bowman M (2018) S100/RAGE-Mediated Inflammation and Modified Cholesterol Lipoproteins as Mediators of Osteoblastic Differentiation of Vascular Smooth Muscle Cells, Frontiers in Cardiovascular Medicine, 10.3389/fcvm.2018.00163, 5 Related articlesS100A12 in Vascular Smooth Muscle Accelerates Vascular Calcification in Apolipoprotein E–Null Mice by Activating an Osteogenic Gene Regulatory ProgramMarion A. Hofmann Bowman, et al. Arteriosclerosis, Thrombosis, and Vascular Biology. 2011;31:337-344 February 2011Vol 31, Issue 2 Advertisement Article InformationMetrics © 2011 American Heart Association, Inc.https://doi.org/10.1161/ATVBAHA.110.220038PMID: 21248279 Originally publishedFebruary 1, 2011 Keywordscytokinessuperoxidevascular musclecalcificationreactive oxygen speciesPDF download Advertisement SubjectsAnimal Models of Human DiseaseAtherosclerosisGene Expression and RegulationGenetically Altered and Transgenic ModelsGrowth Factors/CytokinesMetabolismOxidant StressPathophysiologyValvular Heart DiseaseVascular Biology
Referência(s)