Lipoprotein (a) up-regulates the expression of the plasminogen activator inhibitor 2 in human blood monocytes

Elevated plasma lipoprotein (a) (Lp[a]) and cardiac events show a modest bu t significant association in various clinical studies. However, the influen ce of high L(a) on the gene expression in blood monocytes as a major cell i nvolved in atherogenesis is poorly described. To identify genes influenced by elevated serum Lp(a), the gene expression was analyzed on a complementar y DNA microarray comparing monocytes from a patient with isolated Lp(a) hyp erlipidemia and coronary heart disease with monocytes from a healthy blood donor with low Lp(a), By using this approach, numerous genes were found dif ferentially expressed in patient-versus-control monocytes, Verification of these candidates by Northern blot analysis or semiquantitative polymerase c hain reaction in monocytes from additional patients with Lp(a) hyperlipidem ia and healthy blood donors with elevated Lp(a) confirmed a significant ind uction of plasminogen activator inhibitor type 2 (PAI-2) messenger RNA (mRN A) in monocytes from male, but not from female, individuals with high Lp(a) , indicating that this observation is gender specific. This led also to inc reased intracellular and secreted PAI-2 protein in monocytes from male prob ands with Lp(a) hyperlipidemia. Plasminogen activator inhibitor type 1 (PAI -1) mRNA was found suppressed only in the patients' monocytes and not in he althy probands with high Lp(a) levels. Purified Lp(a) induced PAI-2 mRNA an d protein and reduced PAI-1 expression in monocytes isolated from various c ontrols. 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 o f PAI-2 expression. (C) 2001 by The American Society of Hematology