Abstract
The low-density lipoprotein-related receptor 5 and 6 (Lrp5 and Lrp6) genes were cloned in 1998 based on their homology with the low-density lipoprotein receptor (LDLR) [1–4]. Mutations in either LRP5 or LRP6, proteins have caused a number of disease processed in the field of bone [5, 6], and have been associated with cardiovascular disease [4, 7–9]. The LDL-Density-Pressure theory [10] combines the structure, function analysis of these co-receptors with the results from the genetic studies to provide a unique hypothesis for the role of these receptors in the heart. This chapter provides the genetic mouse evidence to demonstrate that in the presence of experimental hypercholesterolemia, Lrp5/6 receptors, Runx2 genes are up-regulated in the presence of cholesterol and mediate calcification by MicroCT analysis.
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References
Dong Y, Lathrop W, Weaver D, Qiu Q, Cini J, Bertolini D, Chen D. Molecular cloning and characterization of lr3, a novel ldl receptor family protein with mitogenic activity. Biochem Biophys Res Commun. 1998;251:784–90.
Brown SD, Twells RC, Hey PJ, Cox RD, Levy ER, Soderman AR, Metzker ML, Caskey CT, Todd JA, Hess JF. Isolation and characterization of lrp6, a novel member of the low density lipoprotein receptor gene family. Biochem Biophys Res Commun. 1998;248:879–88.
Hey PJ, Twells RC, Phillips MS, Yusuke N, Brown SD, Kawaguchi Y, Cox R, Guochun X, Dugan V, Hammond H, Metzker ML, Todd JA, Hess JF. Cloning of a novel member of the low-density lipoprotein receptor family. Gene. 1998;216:103–11.
Kim DH, Inagaki Y, Suzuki T, Ioka RX, Yoshioka SZ, Magoori K, Kang MJ, Cho Y, Nakano AZ, Liu Q, Fujino T, Suzuki H, Sasano H, Yamamoto TT. A new low density lipoprotein receptor related protein, lrp5, is expressed in hepatocytes and adrenal cortex, and recognizes apolipoprotein e. J Biochem. 1998;124:1072–6.
Gong Y, Slee RB, Fukai N, Rawadi G, Roman-Roman S, Reginato AM, Wang H, Cundy T, Glorieux FH, Lev D, Zacharin M, Oexle K, Marcelino J, Suwairi W, Heeger S, Sabatakos G, Apte S, Adkins WN, Allgrove J, Arslan-Kirchner M, Batch JA, Beighton P, Black GC, Boles RG, Boon LM, Borrone C, Brunner HG, Carle GF, Dallapiccola B, De Paepe A, Floege B, Halfhide ML, Hall B, Hennekam RC, Hirose T, Jans A, Juppner H, Kim CA, Keppler-Noreuil K, Kohlschuetter A, LaCombe D, Lambert M, Lemyre E, Letteboer T, Peltonen L, Ramesar RS, Romanengo M, Somer H, Steichen-Gersdorf E, Steinmann B, Sullivan B, Superti-Furga A, Swoboda W, van den Boogaard MJ, Van Hul W, Vikkula M, Votruba M, Zabel B, Garcia T, Baron R, Olsen BR, Warman ML, Osteoporosis-Pseudoglioma Syndrome Collaborative G. Ldl receptor-related protein 5 (lrp5) affects bone accrual and eye development. Cell. 2001;107:513–23.
Little RD, Carulli JP, Del Mastro RG, Dupuis J, Osborne M, Folz C, Manning SP, Swain PM, Zhao SC, Eustace B, Lappe MM, Spitzer L, Zweier S, Braunschweiger K, Benchekroun Y, Hu X, Adair R, Chee L, FitzGerald MG, Tulig C, Caruso A, Tzellas N, Bawa A, Franklin B, McGuire S, Nogues X, Gong G, Allen KM, Anisowicz A, Morales AJ, Lomedico PT, Recker SM, Van Eerdewegh P, Recker RR, Johnson ML. A mutation in the ldl receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. Am J Hum Genet. 2002;70:11–9.
Fujino T, Asaba H, Kang MJ, Ikeda Y, Sone H, Takada S, Kim DH, Ioka RX, Ono M, Tomoyori H, Okubo M, Murase T, Kamataki A, Yamamoto J, Magoori K, Takahashi S, Miyamoto Y, Oishi H, Nose M, Okazaki M, Usui S, Imaizumi K, Yanagisawa M, Sakai J, Yamamoto TT. Low-density lipoprotein receptor-related protein 5 (lrp5) is essential for normal cholesterol metabolism and glucose-induced insulin secretion. Proc Natl Acad Sci U S A. 2003;100:229–34.
Rajamannan NM, Subramaniam M, Caira F, Stock SR, Spelsberg TC. Atorvastatin inhibits hypercholesterolemia-induced calcification in the aortic valves via the lrp5 receptor pathway. Circulation. 2005;112:I229–34.
Caira FC, Stock SR, Gleason TG, McGee EC, Huang J, Bonow RO, Spelsberg TC, McCarthy PM, Rahimtoola SH, Rajamannan NM. Human degenerative valve disease is associated with up-regulation of low-density lipoprotein receptor-related protein 5 receptor-mediated bone formation. J Am Coll Cardiol. 2006;47:1707–12.
Rajamannan NM, Subramaniam M, Springett M, Sebo TC, Niekrasz M, McConnell JP, Singh RJ, Stone NJ, Bonow RO, Spelsberg TC. Atorvastatin inhibits hypercholesterolemia-induced cellular proliferation and bone matrix production in the rabbit aortic valve. Circulation. 2002;105:2260–5.
Rajamannan NM, Subramaniam M, Stock SR, Stone NJ, Springett M, Ignatiev KI, McConnell JP, Singh RJ, Bonow RO, Spelsberg TC. Atorvastatin inhibits calcification and enhances nitric oxide synthase production in the hypercholesterolaemic aortic valve. Heart. 2005;91:806–10.
Adler Y, Fink N, Spector D, Wiser I, Sagie A. Mitral annulus calcification–a window to diffuse atherosclerosis of the vascular system. Atherosclerosis. 2001;155:1–8.
Rajamannan NM, Subramaniam M, Rickard D, Stock SR, Donovan J, Springett M, Orszulak T, Fullerton DA, Tajik AJ, Bonow RO, Spelsberg T. Human aortic valve calcification is associated with an osteoblast phenotype. Circulation. 2003;107:2181–4.
Rajamannan NM. The role of lrp5/6 in cardiac valve disease: Ldl-density-pressure theory. J Cell Biochem. 2011;112(9):2222–9.
Boyden LM, Mao J, Belsky J, Mitzner L, Farhi A, Mitnick MA, Wu D, Insogna K, Lifton RP. High bone density due to a mutation in ldl-receptor-related protein 5. N Engl J Med. 2002;346:1513–21.
Babij P, Zhao W, Small C, Kharode Y, Yaworsky PJ, Bouxsein ML, Reddy PS, Bodine PV, Robinson JA, Bhat B, Marzolf J, Moran RA, Bex F. High bone mass in mice expressing a mutant lrp5 gene. J Bone Miner Res. 2003;18:960–74.
Westendorf JJ, Kahler RA, Schroeder TM. Wnt signaling in osteoblasts and bone diseases. Gene. 2004;341:19–39.
Holmen SL, Giambernardi TA, Zylstra CR, Buckner-Berghuis BD, Resau JH, Hess JF, Glatt V, Bouxsein ML, Ai M, Warman ML, Williams BO. Decreased bmd and limb deformities in mice carrying mutations in both lrp5 and lrp6. J Bone Miner Res. 2004;19:2033–40.
Shao JS, Cheng SL, Pingsterhaus JM, Charlton-Kachigian N, Loewy AP, Towler DA. Msx2 promotes cardiovascular calcification by activating paracrine wnt signals. J Clin Invest. 2005;115:1210–20.
Akhter MP, Wells DJ, Short SJ, Cullen DM, Johnson ML, Haynatzki GR, Babij P, Allen KM, Yaworsky PJ, Bex F, Recker RR. Bone biomechanical properties in lrp5 mutant mice. Bone. 2004;35:162–9.
Johnson ML, Harnish K, Nusse R, Van Hul W. Lrp5 and wnt signaling: a union made for bone. J Bone Miner Res. 2004;19:1749–57.
Johnson ML, Summerfield DT. Parameters of lrp5 from a structural and molecular perspective. Crit Rev Eukaryot Gene Expr. 2005;15:229–42.
Mani A, Radhakrishnan J, Wang H, Mani A, Mani MA, Nelson-Williams C, Carew KS, Mane S, Najmabadi H, Wu D, Lifton RP. Lrp6 mutation in a family with early coronary disease and metabolic risk factors. Science (New York, NY). 2007;315:1278–82.
Magoori K, Kang MJ, Ito MR, Kakuuchi H, Ioka RX, Kamataki A, Kim DH, Asaba H, Iwasaki S, Takei YA, Sasaki M, Usui S, Okazaki M, Takahashi S, Ono M, Nose M, Sakai J, Fujino T, Yamamoto TT. Severe hypercholesterolemia, impaired fat tolerance, and advanced atherosclerosis in mice lacking both low density lipoprotein receptor-related protein 5 and apolipoprotein e. J Biol Chem. 2003;278:11331–6.
Ishibashi S, Goldstein JL, Brown MS, Herz J, Burns DK. Massive xanthomatosis and atherosclerosis in cholesterol-fed low density lipoprotein receptor-negative mice. J Clin Invest. 1994;93:1885–93.
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Rajamannan, N.M. (2014). Experimental Hypercholesterolemia in Genetic ApoE−/−/Lrp5−/− Mice: Proof of Principle. In: Rajamannan, N. (eds) Molecular Biology of Valvular Heart Disease. Springer, London. https://doi.org/10.1007/978-1-4471-6350-3_8
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DOI: https://doi.org/10.1007/978-1-4471-6350-3_8
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