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J. Biol. Chem., Vol. 277, Issue 49, 47486-47492, December 6, 2002
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From the 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.
Lipoprotein(a) Enhances Advanced Atherosclerosis and Vascular
Calcification in WHHL Transgenic Rabbits Expressing Human
Apolipoprotein(a)*
§¶,§,,,,,
,¶¶
Laboratory of Cardiovascular Disease,
Department of Pathology, Institute of Basic Medical Sciences,
University of Tsukuba, Tsukuba 305-8575, Japan, the Institute
for Experimental Animals, Kobe University School of Medicine, Kobe
650-0017, Japan, the ** Department of Medicine, Northwest
Lipid Research Laboratories, University of Washington, Seattle,
Washington 98103, and the §§ Saga Medical
School, Saga 849-8501, Japan
*
This work was supported by grants-in-aid for scientific
research from the Ministry of Education, Science, and Culture of Japan, by Grant JSPS-RFTF 96I00202 from the Japan Society for the Promotion of
Sciences, and by a grant from the Takeda Science Foundation.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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