High lipoprotein(a) (Lp(a)) levels are a major risk factor for the development of atherosclerosis. The risk of elevated Lp(a) concentration is increased significantly in patients who also have high levels of low density lipoprotein (LDL) cholesterol. To test the hypothesis that increased plasma levels of Lp(a) may enhance the development of atherosclerosis in the setting of hypercholesterolemia, we generated Watanabe heritable hyperlipidemic (WHHL) transgenic (Tg) rabbits expressing human apolipoprotein(a) (apo(a)). We report here that Tg WHHL rabbits developed more extensive advanced atherosclerotic lesions than did non-Tg WHHL rabbits. In particular, the advanced atherosclerotic lesions in Tg WHHL rabbits were frequently associated with calcification, which was barely evident in non-Tg WHHL rabbits. To investigate the molecular mechanism of Lp(a)-induced vascular calcification, we examined the effect of human Lp(a) on cultured rabbit aortic smooth muscle cells and found that smooth muscle cells treated with Lp(a) showed increased alkaline phosphatase activity and enhanced calcium accumulation. These results demonstrate for the first time that Lp(a) accelerates advanced atherosclerotic lesion formation and may play an important role in vascular calcification. High lipoprotein(a) (Lp(a)) levels are a major risk factor for the development of atherosclerosis. The risk of elevated Lp(a) concentration is increased significantly in patients who also have high levels of low density lipoprotein (LDL) cholesterol. To test the hypothesis that increased plasma levels of Lp(a) may enhance the development of atherosclerosis in the setting of hypercholesterolemia, we generated Watanabe heritable hyperlipidemic (WHHL) transgenic (Tg) rabbits expressing human apolipoprotein(a) (apo(a)). We report here that Tg WHHL rabbits developed more extensive advanced atherosclerotic lesions than did non-Tg WHHL rabbits. In particular, the advanced atherosclerotic lesions in Tg WHHL rabbits were frequently associated with calcification, which was barely evident in non-Tg WHHL rabbits. To investigate the molecular mechanism of Lp(a)-induced vascular calcification, we examined the effect of human Lp(a) on cultured rabbit aortic smooth muscle cells and found that smooth muscle cells treated with Lp(a) showed increased alkaline phosphatase activity and enhanced calcium accumulation. These results demonstrate for the first time that Lp(a) accelerates advanced atherosclerotic lesion formation and may play an important role in vascular calcification. Since lipoprotein (a) (Lp(a)) 1The abbreviations used are: Lp(a), lipoprotein(a); Tg, transgenic; apo(a), apolipoprotein(a); LDL, low density lipoprotein; VLDL, very low density lipoprotein; WHHL, Watanabe heritable hyperlipidemic; SMCs, smooth muscle cells; F, fraction; OPN, osteopontin; Osf2, osteoblast-specific factor-2; MGP, matrix Gla protein 1The abbreviations used are: Lp(a), lipoprotein(a); Tg, transgenic; apo(a), apolipoprotein(a); LDL, low density lipoprotein; VLDL, very low density lipoprotein; WHHL, Watanabe heritable hyperlipidemic; SMCs, smooth muscle cells; F, fraction; OPN, osteopontin; Osf2, osteoblast-specific factor-2; MGP, matrix Gla protein was discovered in 1963 by Berg (1Berg K. Acta Pathol. Microbiol. Scand. 1963; 59: 369-382Google Scholar), numerous clinical, epidemiological, and genetic (cross-sectional and prospective) studies have revealed that high plasma levels of Lp(a) are associated with human cardiovascular disease, including coronary heart disease, stroke, and restenosis (2Maher V.M. Brown B.G. Curr. Opin. Lipid. 1995; 6: 229-235Google Scholar, 3Djurovic S. Berg K. Clin. Genet. 1997; 52: 281-292Google Scholar, 4Marcovina S.M. Koschinsky M.L. Am. J. Cardiol. 1998; 82: 57U-66UGoogle Scholar), although several studies have failed to demonstrate such an association (5Ridker P.M. Hennekens C.H. Stampfer M.J. JAMA. 1993; 270: 2195-2199Google Scholar, 6Gurewich V. Mittleman M. JAMA. 1994; 271: 1025-1026Google Scholar). The involvement of Lp(a) in the pathogenesis of atherosclerosis was suggested initially by the presence of Lp(a) in human atherosclerotic lesions (7Rath M. Niendorf A. Reblin T. Dietel M. Krebber H.J. Beisiegel U. Arteriosclerosis. 1989; 9: 579-592Google Scholar, 8Jurgens G. Chen Q. Esterbauer H. Mair S. Ledinski G. Dinges H.P. Arterioscler. Thromb. 1993; 13: 1689-1699Google Scholar), and accumulating evidence indicates that Lp(a) deposition in atherosclerotic plaques is associated with the severity of unstable coronary syndrome (9Dangas G. Mehran R. Harpel P.C. Sharma S.K. Marcovina S.M. Dube G. Ambrose J.A. Fallon J.T. J. Am. Coll. Cardiol. 1998; 32: 2035-2042Google Scholar). Nevertheless, the mechanism(s) by which Lp(a) increases the risk of atherosclerotic vascular disease are largely unknown.The major difficulties in defining the functional roles of Lp(a)in vivo are attributed to the lack of appropriate experimental animals; Lp(a) is naturally present exclusively in Old World monkeys and humans, although one nonprimate species, the hedgehog, has independently evolved an Lp(a)-like protein (10Laplaud P.M. Beaubatie L. Rall Jr., S.C. Luc G. Saboureau M. J. Lipid Res. 1988; 29: 1157-1170Google Scholar). Four reports using Tg mice showed that apolipoprotein (a) (apo(a)) may increase aortic fatty streak formation when the apo(a) Tg mice are fed a high fat diet (11Lawn R.M. Wade D.P. Hammer R.E. Chiesa G. Verstuyft J.G. Rubin E.M. Nature. 1992; 360: 670-672Google Scholar, 12Liu A.C. Lawn R.M. Verstuyft J.G. Rubin E.M. J. Lipid Res. 1994; 35: 2263-2267Google Scholar, 13Lawn R.M. Pearle A.D. Kunz L.L. Rubin E.M. Reckless J. Metcalfe J.C. Grainger D.J. J. Biol. Chem. 1996; 271: 31367-31371Google Scholar, 14Boonmark N.W. Lou X.J. Yang Z.J. Schwartz K. Zhang J.L. Rubin E.M. Lawn R.M. J. Clin. Invest. 1997; 100: 558-564Google Scholar); however, two other studies failed to detect an atherogenic effect of apo(a) in Tg mice expressing either apo(a) alone or human apo(a) and apoB (15Mancini F.P. Newland D.L. Mooser V. Murata J. Marcovina S. Young Hammer R.E. Arterioscler. Thromb. Biol. 1995; Scholar, Newland D.L. R. Marcovina S. J. Mooser V. Hammer R.E. U. S. A. 1998; J. M. L. M. H. Lawn H. H. Watanabe T. Res. with Rubin E.M. J. Biol. Chem. 1998; generated Tg rabbits expressing human apo(a) and showed that human apo(a) is Lp(a) in rabbit is to human apo(a) Tg in which human apo(a) is associated with G. Koschinsky M.L. Lawn R.M. Hammer R.E. J. Biol. Chem. 1992; Scholar). we that Lp(a) increases the development of aortic and coronary atherosclerosis in Tg rabbits fed a diet J. H. H. Marcovina S. K. Watanabe T. Arterioscler. Thromb. Biol. Scholar, T. H. H. H. Marcovina S.M. H. Watanabe T. J. Pathol. Scholar). studies in Tg rabbits or in Tg mice revealed that apo(a), of association with apoB in Tg or the lack of such association in Tg may in the of did an to the of Lp(a) increases the risk of advanced atherosclerotic lesion is a to in the lesions in are fatty streak and in to the lesions in human which are more advanced and associated with and R.E. V. S. Jr., Schwartz Arterioscler. Thromb. Biol. 1995; Scholar). is advanced atherosclerotic lesions that increase the risk of and coronary heart disease and factor is that the major atherogenic present in are and than in Lp(a) we human apo(a) Tg rabbits with WHHL an for human hypercholesterolemia, to apo(a) Tg WHHL rabbits. WHHL rabbits have T. Brown J.L. Scholar). The apo(a) Tg WHHL an for the of Lp(a) rabbits have high plasma levels of on a diet and atherosclerosis that of Scholar). Tg WHHL rabbits have levels of Lp(a) in plasma than apo(a) Tg rabbits to an J. M. H. M. Marcovina S. Watanabe T. J. Lipid Res. Scholar). accumulating evidence studies that patients have levels of Lp(a) than and the risk of elevated Lp(a) concentration is increased significantly in the presence of high levels of A. H. H. M. S. G. J. Scholar). have suggested that elevated Lp(a) may a risk factor for coronary heart disease in patients with elevated levels S. J. Am. Coll. Cardiol. 1998; Scholar). is also to the apo(a) Tg WHHL to elevated plasma levels of Lp(a) and and the increased risk for atherosclerosis. In we the atherosclerotic lesions in Tg WHHL rabbits and found that Tg WHHL rabbits developed more extensive advanced lesions than did non-Tg WHHL rabbits. To the of is the first report to that Lp(a) may enhance the development of atherosclerotic lesions with we for the first time that Lp(a) advanced lesion development in Tg WHHL rabbits. Tg WHHL rabbits have high levels of plasma non-Tg WHHL also have high levels of human In one that the two Tg and non-Tg to the of one risk two risk high alone and high and Lp(a) Tg WHHL rabbits showed increased atherosclerotic lesions in the aortic and in to non-Tg WHHL and lesions of advanced including and calcification. The of more extensive advanced atherosclerotic lesions in Tg WHHL rabbits the that Lp(a) is a risk factor for the development of atherosclerosis also the that the risk of for atherosclerosis is increased significantly in the setting of elevated is that Lp(a) to a increase in the of lesions in Tg WHHL which is we found in apo(a) Tg rabbits J. H. H. Marcovina S. K. Watanabe T. Arterioscler. Thromb. Biol. Scholar). We that and WHHL Tg rabbits may to in atherogenic S.K. A. L.L. Young J. Clin. Invest. Scholar), or is that the very high plasma levels of in WHHL rabbits may the effect of Lp(a) on the lesion In humans, Lp(a) levels are to atherogenic G. The and of Scholar). the plasma Lp(a) levels in Tg WHHL rabbits are than is significantly in which have The lipoprotein of Tg and non-Tg WHHL rabbits were and the of and apoB in to the of increased advanced atherosclerosis in Tg WHHL rabbits. is that the presence of plasma Lp(a) was the major factor the of the lesions in Tg WHHL rabbits. The presence of and a of in advanced lesions in Tg WHHL the in human atherosclerosis R.E. V. S. Jr., Schwartz Arterioscler. Thromb. Biol. 1995; Scholar). important of the was the of vascular in Tg WHHL which was barely in non-Tg WHHL rabbits. We have the that in Tg WHHL rabbits may by increased plasma or calcium increased alkaline phosphatase activity is that vascular has in either human apo(a) Tg mice (11Lawn R.M. Wade D.P. Hammer R.E. Chiesa G. Verstuyft J.G. Rubin E.M. Nature. 1992; 360: 670-672Google or Tg rabbits J. H. H. Marcovina S. K. Watanabe T. Arterioscler. Thromb. Biol. Scholar). In rabbits fed a diet high matrix than were in H. Scholar), WHHL rabbits were found to vascular when fed a diet high and calcium L.L. or of is a of human atherosclerotic lesions and to a of such coronary heart disease and aortic 1994; Scholar). In the lesions of Tg WHHL rabbits of the in human advanced and may an for vascular associated with atherosclerosis. The presence of and the association Lp(a) and in the lesions of Tg WHHL rabbits to a hypothesis that Lp(a) is a of the of vascular calcification. a the we also found that Lp(a) deposition is in the of atherosclerotic is important to that that Lp(a) is frequently in atherosclerotic lesions by The Lp(a) The of vascular has an than an or of A. L.L. Scholar, L.L. Curr. Opin. is Lp(a) in vascular cells such To we have several to the effect of Lp(a) on of cultured in of with Lp(a) in an enhanced calcium in a and Lp(a) significantly of of protein and is with the that of is associated with high levels of and low levels of in human vascular Arterioscler. Thromb. Biol. 1998; Scholar). Lp(a) may enhance by the of to was and alkaline phosphatase activity was increased in treated with results that Lp(a) may in the of vascular calcification. In Tg WHHL of Lp(a) was with and Lp(a) was which is with the studies Rubin E.M. J. Biol. Chem. 1998; Scholar, J. H. H. Marcovina S. K. Watanabe T. Arterioscler. Thromb. Biol. Scholar). may that although rabbit apoB a which is for with apo(a) in may in rabbit apoB for such is apo(a) to associated with apoB either in or to such calcification. In a we have found that Lp(a) Tg rabbits showed a effect on calcium to human studies are to apo(a) associated Lp(a) associated Lp(a), and Lp(a) Lp(a) the effect on the mechanism(s) of the increased formation of advanced atherosclerotic lesions by Lp(a) in Tg WHHL rabbits the presence of or in the lesions indicates that either or which an to Lp(a) may or such or is also or in the studies showed that Lp(a) increases the of in A. M. J. Clin. Invest. 1994; and in human cells and rabbit J. R. A. S. K. Scholar). mechanism is in may the in Tg WHHL rabbits. with studies using cultured showed that and are of vascular L. Res. evidence that Lp(a) is a risk factor for the of atherosclerosis is also an of the of the of lesion we have that Lp(a) is a in the vascular associated with atherosclerosis. the molecular mechanism(s) of Lp(a) and are the of advanced atherosclerosis in Tg WHHL rabbits for the of human atherosclerosis and such and In to Tg WHHL rabbits have increased of We that the Tg WHHL with high levels of Lp(a) and advanced atherosclerosis may an for the of in the of atherosclerosis in patients with high levels of Since lipoprotein (a) (Lp(a)) 1The abbreviations used are: Lp(a), lipoprotein(a); Tg, transgenic; apo(a), apolipoprotein(a); LDL, low density lipoprotein; VLDL, very low density lipoprotein; WHHL, Watanabe heritable hyperlipidemic; SMCs, smooth muscle cells; F, fraction; OPN, osteopontin; Osf2, osteoblast-specific factor-2; MGP, matrix Gla protein 1The abbreviations used are: Lp(a), lipoprotein(a); Tg, transgenic; apo(a), apolipoprotein(a); LDL, low density lipoprotein; VLDL, very low density lipoprotein; WHHL, Watanabe heritable hyperlipidemic; SMCs, smooth muscle cells; F, fraction; OPN, osteopontin; Osf2, osteoblast-specific factor-2; MGP, matrix Gla protein was discovered in 1963 by Berg (1Berg K. Acta Pathol. Microbiol. Scand. 1963; 59: 369-382Google Scholar), numerous clinical, epidemiological, and genetic (cross-sectional and prospective) studies have revealed that high plasma levels of Lp(a) are associated with human cardiovascular disease, including coronary heart disease, stroke, and restenosis (2Maher V.M. Brown B.G. Curr. Opin. Lipid. 1995; 6: 229-235Google Scholar, 3Djurovic S. Berg K. Clin. Genet. 1997; 52: 281-292Google Scholar, 4Marcovina S.M. Koschinsky M.L. Am. J. Cardiol. 1998; 82: 57U-66UGoogle Scholar), although several studies have failed to demonstrate such an association (5Ridker P.M. Hennekens C.H. Stampfer M.J. JAMA. 1993; 270: 2195-2199Google Scholar, 6Gurewich V. Mittleman M. JAMA. 1994; 271: 1025-1026Google Scholar). The involvement of Lp(a) in the pathogenesis of atherosclerosis was suggested initially by the presence of Lp(a) in human atherosclerotic lesions (7Rath M. Niendorf A. Reblin T. Dietel M. Krebber H.J. Beisiegel U. Arteriosclerosis. 1989; 9: 579-592Google Scholar, 8Jurgens G. Chen Q. Esterbauer H. Mair S. Ledinski G. Dinges H.P. Arterioscler. Thromb. 1993; 13: 1689-1699Google Scholar), and accumulating evidence indicates that Lp(a) deposition in atherosclerotic plaques is associated with the severity of unstable coronary syndrome (9Dangas G. Mehran R. Harpel P.C. Sharma S.K. Marcovina S.M. Dube G. Ambrose J.A. Fallon J.T. J. Am. Coll. Cardiol. 1998; 32: 2035-2042Google Scholar). Nevertheless, the mechanism(s) by which Lp(a) increases the risk of atherosclerotic vascular disease are largely The major difficulties in defining the functional roles of Lp(a)in vivo are attributed to the lack of appropriate experimental animals; Lp(a) is naturally present exclusively in Old World monkeys and humans, although one nonprimate species, the hedgehog, has independently evolved an Lp(a)-like protein (10Laplaud P.M. Beaubatie L. Rall Jr., S.C. Luc G. Saboureau M. J. Lipid Res. 1988; 29: 1157-1170Google Scholar). Four reports using Tg mice showed that apolipoprotein (a) (apo(a)) may increase aortic fatty streak formation when the apo(a) Tg mice are fed a high fat diet (11Lawn R.M. Wade D.P. Hammer R.E. Chiesa G. Verstuyft J.G. Rubin E.M. Nature. 1992; 360: 670-672Google Scholar, 12Liu A.C. Lawn R.M. Verstuyft J.G. Rubin E.M. J. Lipid Res. 1994; 35: 2263-2267Google Scholar, 13Lawn R.M. Pearle A.D. Kunz L.L. Rubin E.M. Reckless J. Metcalfe J.C. Grainger D.J. J. Biol. Chem. 1996; 271: 31367-31371Google Scholar, 14Boonmark N.W. Lou X.J. Yang Z.J. Schwartz K. Zhang J.L. Rubin E.M. Lawn R.M. J. Clin. Invest. 1997; 100: 558-564Google Scholar); however, two other studies failed to detect an atherogenic effect of apo(a) in Tg mice expressing either apo(a) alone or human apo(a) and apoB (15Mancini F.P. Newland D.L. Mooser V. Murata J. Marcovina S. Young Hammer R.E. Arterioscler. Thromb. Biol. 1995; Scholar, Newland D.L. R. Marcovina S. J. Mooser V. Hammer R.E. U. S. A. 1998; Scholar). J. M. L. M. H. Lawn H. H. Watanabe T. Res. with Rubin E.M. J. Biol. Chem. 1998; generated Tg rabbits expressing human apo(a) and showed that human apo(a) is Lp(a) in rabbit is to human apo(a) Tg in which human apo(a) is associated with G. Koschinsky M.L. Lawn R.M. Hammer R.E. J. Biol. Chem. 1992; Scholar). we that Lp(a) increases the development of aortic and coronary atherosclerosis in Tg rabbits fed a diet J. H. H. Marcovina S. K. Watanabe T. Arterioscler. Thromb. Biol. Scholar, T. H. H. H. Marcovina S.M. H. Watanabe T. J. Pathol. Scholar). studies in Tg rabbits or in Tg mice revealed that apo(a), of association with apoB in Tg or the lack of such association in Tg may in the of did an to the of Lp(a) increases the risk of advanced atherosclerotic lesion is a to in the lesions in are fatty streak and in to the lesions in human which are more advanced and associated with and R.E. V. S. Jr., Schwartz Arterioscler. Thromb. Biol. 1995; Scholar). is advanced atherosclerotic lesions that increase the risk of and coronary heart disease and factor is that the major atherogenic present in are and than in Scholar). To Lp(a) we human apo(a) Tg rabbits with WHHL an for human hypercholesterolemia, to apo(a) Tg WHHL rabbits. WHHL rabbits have T. Brown J.L. Scholar). The apo(a) Tg WHHL an for the of Lp(a) rabbits have high plasma levels of on a diet and atherosclerosis that of Scholar). Tg WHHL rabbits have levels of Lp(a) in plasma than apo(a) Tg rabbits to an J. M. H. M. Marcovina S. Watanabe T. J. Lipid Res. Scholar). accumulating evidence studies that patients have levels of Lp(a) than and the risk of elevated Lp(a) concentration is increased significantly in the presence of high levels of A. H. H. M. S. G. J. Scholar). have suggested that elevated Lp(a) may a risk factor for coronary heart disease in patients with elevated levels S. J. Am. Coll. Cardiol. 1998; Scholar). is also to the apo(a) Tg WHHL to elevated plasma levels of Lp(a) and and the increased risk for atherosclerosis. In we the atherosclerotic lesions in Tg WHHL rabbits and found that Tg WHHL rabbits developed more extensive advanced lesions than did non-Tg WHHL rabbits. To the of is the first report to that Lp(a) may enhance the development of atherosclerotic lesions with calcification. we for the first time that Lp(a) advanced lesion development in Tg WHHL rabbits. Tg WHHL rabbits have high levels of plasma non-Tg WHHL also have high levels of human In one that the two Tg and non-Tg to the of one risk two risk high alone and high and Lp(a) Tg WHHL rabbits showed increased atherosclerotic lesions in the aortic and in to non-Tg WHHL and lesions of advanced including and calcification. The of more extensive advanced atherosclerotic lesions in Tg WHHL rabbits the that Lp(a) is a risk factor for the development of atherosclerosis also the that the risk of for atherosclerosis is increased significantly in the setting of elevated is that Lp(a) to a increase in the of lesions in Tg WHHL which is we found in apo(a) Tg rabbits J. H. H. Marcovina S. K. Watanabe T. Arterioscler. Thromb. Biol. Scholar). We that and WHHL Tg rabbits may to in atherogenic S.K. A. L.L. Young J. Clin. Invest. Scholar), or is that the very high plasma levels of in WHHL rabbits may the effect of Lp(a) on the lesion In humans, Lp(a) levels are to atherogenic G. The and of Scholar). the plasma Lp(a) levels in Tg WHHL rabbits are than is significantly in which have The lipoprotein of Tg and non-Tg WHHL rabbits were and the of and apoB in to the of increased advanced atherosclerosis in Tg WHHL rabbits. is that the presence of plasma Lp(a) was the major factor the of the lesions in Tg WHHL rabbits. The presence of and a of in advanced lesions in Tg WHHL the in human atherosclerosis R.E. V. S. Jr., Schwartz Arterioscler. Thromb. Biol. 1995; Scholar). important of the was the of vascular in Tg WHHL which was barely in non-Tg WHHL rabbits. We have the that in Tg WHHL rabbits may by increased plasma or calcium increased alkaline phosphatase activity is that vascular has in either human apo(a) Tg mice (11Lawn R.M. Wade D.P. Hammer R.E. Chiesa G. Verstuyft J.G. Rubin E.M. Nature. 1992; 360: 670-672Google or Tg rabbits J. H. H. Marcovina S. K. Watanabe T. Arterioscler. Thromb. Biol. Scholar). In rabbits fed a diet high matrix than were in H. Scholar), WHHL rabbits were found to vascular when fed a diet high and calcium L.L. or of is a of human atherosclerotic lesions and to a of such coronary heart disease and aortic 1994; Scholar). In the lesions of Tg WHHL rabbits of the in human advanced and may an for vascular associated with atherosclerosis. The presence of and the association Lp(a) and in the lesions of Tg WHHL rabbits to a hypothesis that Lp(a) is a of the of vascular calcification. a the we also found that Lp(a) deposition is in the of atherosclerotic is important to that that Lp(a) is frequently in atherosclerotic lesions by The Lp(a) The of vascular has an than an or of A. L.L. Scholar, L.L. Curr. Opin. is Lp(a) in vascular cells such To we have several to the effect of Lp(a) on of cultured in of with Lp(a) in an enhanced calcium in a and Lp(a) significantly of of protein and is with the that of is associated with high levels of and low levels of in human vascular Arterioscler. Thromb. Biol. 1998; Scholar). Lp(a) may enhance by the of to was and alkaline phosphatase activity was increased in treated with results that Lp(a) may in the of vascular calcification. In Tg WHHL of Lp(a) was with and Lp(a) was which is with the studies Rubin E.M. J. Biol. Chem. 1998; Scholar, J. H. H. Marcovina S. K. Watanabe T. Arterioscler. Thromb. Biol. Scholar). may that although rabbit apoB a which is for with apo(a) in may in rabbit apoB for such is apo(a) to associated with apoB either in or to such calcification. In a we have found that Lp(a) Tg rabbits showed a effect on calcium to human studies are to apo(a) associated Lp(a) associated Lp(a), and Lp(a) Lp(a) the effect on the mechanism(s) of the increased formation of advanced atherosclerotic lesions by Lp(a) in Tg WHHL rabbits the presence of or in the lesions indicates that either or which an to Lp(a) may or such or is also or in the studies showed that Lp(a) increases the of in A. M. J. Clin. Invest. 1994; and in human cells and rabbit J. R. A. S. K. Scholar). mechanism is in may the in Tg WHHL rabbits. with studies using cultured showed that and are of vascular L. Res. evidence that Lp(a) is a risk factor for the of atherosclerosis is also an of the of the of lesion we have that Lp(a) is a in the vascular associated with atherosclerosis. the molecular mechanism(s) of Lp(a) and are the of advanced atherosclerosis in Tg WHHL rabbits for the of human atherosclerosis and such and In to Tg WHHL rabbits have increased of We that the Tg WHHL with high levels of Lp(a) and advanced atherosclerosis may an for the of in the of atherosclerosis in patients with high levels of In we for the first time that Lp(a) advanced lesion development in Tg WHHL rabbits. Tg WHHL rabbits have high levels of plasma non-Tg WHHL also have high levels of human In one that the two Tg and non-Tg to the of one risk two risk high alone and high and Lp(a) Tg WHHL rabbits showed increased atherosclerotic lesions in the aortic and in to non-Tg WHHL and lesions of advanced including and calcification. The of more extensive advanced atherosclerotic lesions in Tg WHHL rabbits the that Lp(a) is a risk factor for the development of atherosclerosis also the that the risk of for atherosclerosis is increased significantly in the setting of elevated is that Lp(a) to a increase in the of lesions in Tg WHHL which is we found in apo(a) Tg rabbits J. H. H. Marcovina S. K. Watanabe T. Arterioscler. Thromb. Biol. Scholar). We that and WHHL Tg rabbits may to in atherogenic S.K. A. L.L. Young J. Clin. Invest. Scholar), or is that the very high plasma levels of in WHHL rabbits may the effect of Lp(a) on the lesion In humans, Lp(a) levels are to atherogenic G. The and of Scholar). the plasma Lp(a) levels in Tg WHHL rabbits are than is significantly in which have The lipoprotein of Tg and non-Tg WHHL rabbits were and the of and apoB in to the of increased advanced atherosclerosis in Tg WHHL rabbits. is that the presence of plasma Lp(a) was the major factor the of the lesions in Tg WHHL rabbits. The presence of and a of in advanced lesions in Tg WHHL the in human atherosclerosis R.E. V. S. Jr., Schwartz Arterioscler. Thromb. Biol. 1995; Scholar). important of the was the of vascular in Tg WHHL which was barely in non-Tg WHHL rabbits. We have the that in Tg WHHL rabbits may by increased plasma or calcium increased alkaline phosphatase activity is that vascular has in either human apo(a) Tg mice (11Lawn R.M. Wade D.P. Hammer R.E. Chiesa G. Verstuyft J.G. Rubin E.M. Nature. 1992; 360: 670-672Google or Tg rabbits J. H. H. Marcovina S. K. Watanabe T. Arterioscler. Thromb. Biol. Scholar). In rabbits fed a diet high matrix than were in H. Scholar), WHHL rabbits were found to vascular when fed a diet high and calcium L.L. or of is a of human atherosclerotic lesions and to a of such coronary heart disease and aortic 1994; Scholar). In the lesions of Tg WHHL rabbits of the in human advanced and may an for vascular associated with atherosclerosis. The presence of and the association Lp(a) and in the lesions of Tg WHHL rabbits to a hypothesis that Lp(a) is a of the of vascular calcification. a the we also found that Lp(a) deposition is in the of atherosclerotic is important to that that Lp(a) is frequently in atherosclerotic lesions by The Lp(a) The of vascular has an than an or of A. L.L. Scholar, L.L. Curr. Opin. Scholar). is Lp(a) in vascular cells such To we have several to the effect of Lp(a) on of cultured in of with Lp(a) in an enhanced calcium in a and Lp(a) significantly of of protein and is with the that of is associated with high levels of and low levels of in human vascular Arterioscler. Thromb. Biol. 1998; Scholar). Lp(a) may enhance by the of to was and alkaline phosphatase activity was increased in treated with results that Lp(a) may in the of vascular calcification. In Tg WHHL of Lp(a) was with and Lp(a) was which is with the studies Rubin E.M. J. Biol. Chem. 1998; Scholar, J. H. H. Marcovina S. K. Watanabe T. Arterioscler. Thromb. Biol. Scholar). may that although rabbit apoB a which is for with apo(a) in may in rabbit apoB for such is apo(a) to associated with apoB either in or to such calcification. In a we have found that Lp(a) Tg rabbits showed a effect on calcium to human studies are to apo(a) associated Lp(a) associated Lp(a), and Lp(a) Lp(a) the effect on calcification. the mechanism(s) of the increased formation of advanced atherosclerotic lesions by Lp(a) in Tg WHHL rabbits the presence of or in the lesions indicates that either or which an to Lp(a) may or such or is also or in the studies showed that Lp(a) increases the of in A. M. J. Clin. Invest. 1994; and in human cells and rabbit J. R. A. S. K. Scholar). mechanism is in may the in Tg WHHL rabbits. with studies using cultured showed that and are of vascular L. Res. Scholar). In evidence that Lp(a) is a risk factor for the of atherosclerosis is also an of the of the of lesion we have that Lp(a) is a in the vascular associated with atherosclerosis. the molecular mechanism(s) of Lp(a) and are the of advanced atherosclerosis in Tg WHHL rabbits for the of human atherosclerosis and such and In to Tg WHHL rabbits have increased of We that the Tg WHHL with high levels of Lp(a) and advanced atherosclerosis may an for the of in the of atherosclerosis in patients with high levels of
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