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Blood, 15 February 2001, Vol. 97, No. 4, pp. 981-986
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Lipoprotein (a) up-regulates the expression of the plasminogen
activator inhibitor 2 in human blood monocytes
Christa Buechler,
Heidrun Ullrich,
Mirko Ritter,
Mustafa Porsch-Oezcueruemez,
Karl J. Lackner,
Stefan Barlage,
Sven Olaf Friedrich,
Gert M. Kostner, and
Gerd Schmitz
From the Institute for Clinical Chemistry and
Laboratory Medicine, University of Regensburg, Germany; and the
Institute of Medical Biochemistry, University of Graz, Austria.
Elevated plasma lipoprotein (a) (Lp[a]) and cardiac events
show a modest but significant association in various clinical studies. However, the influence of high Lp(a) on the gene expression in blood
monocytes as a major cell involved in atherogenesis is poorly described. To identify genes influenced by elevated serum Lp(a), the
gene expression was analyzed on a complementary DNA microarray comparing monocytes from a patient with isolated Lp(a) hyperlipidemia and coronary heart disease with monocytes from a healthy blood donor
with low Lp(a). By using this approach, numerous genes were found
differentially expressed in patient-versus-control monocytes. Verification of these candidates by Northern blot analysis or semiquantitative polymerase chain reaction in monocytes from additional patients with Lp(a) hyperlipidemia and healthy blood donors with elevated Lp(a) confirmed a significant induction of plasminogen activator inhibitor type 2 (PAI-2) messenger RNA (mRNA) in monocytes from male, but not from female, individuals with high Lp(a), indicating that this observation is gender specific. This led also to increased intracellular and secreted PAI-2 protein in monocytes from male probands with Lp(a) hyperlipidemia. Plasminogen activator inhibitor type 1 (PAI-1) mRNA was found suppressed only in the patients' monocytes and not in healthy probands with high Lp(a) levels. Purified
Lp(a) induced PAI-2 mRNA and protein and reduced PAI-1 expression in
monocytes isolated from various controls. The finding that PAI-2 is
elevated in monocytes from male patients with isolated Lp(a)
hyperlipidemia and male healthy probands with high Lp(a) and that
purified Lp(a) up-regulates PAI-2 in control monocytes in vitro
indicate a direct, but gender-specific, effect of Lp(a) for the
induction of PAI-2 expression.
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