Macrophage specific overexpression of the human macrophage scavenger receptor in transgenic mice, using a 180-kb yeast artificial chromosome, leads to enhanced foam cell formation of isolated peritoneal macrophages

Macrophage scavenger receptors class A (MSR) are thought to play an importa nt role in atherogenesis by mediating the unrestricted uptake of modified l ipoproteins by macrophages in the vessel wall leading to foam cell formatio n. To investigate the in vivo role of the MSR in this process, a transgenic mouse model expressing both isoforms of the human MSR was generated. A 180 -kb yeast artificial chromosome (YAC) containing the human MSR gene (MSR1) with 60- and 40-kb flanking sequence at the 5' and 3' end, respectively, wa s obtained by reducing the size of a 1050-kb YAC by homologous recombinatio n. This 180-kb YAC was microinjected into mouse oocytes. In the resulting t ransgenic mice, high levels of mRNA for both type I and type II human MSR1 were detected in peritoneal macrophages and trace levels in other organs, k nown to contain macrophage-derived cells. Using an antibody against the hum an MSR, the Kupffer cells in the liver were shown to contain the MSR protei n. In vivo clearance of acetyl-LDL was not changed in the MSR1-transgenic m ice. However, in vitro studies using peritoneal macrophages from the transg enic mice showed a two-fold increased degradation of acetyl-LDL and cholest erolester accumulation concomitant with a four-fold increase in foam cell f ormation, as compared to wild-type macrophages. Thus, macrophage specific o verexpression of the MSR may lead to increased foam cell formation, which i s one of the initial and crucial steps in atherogenesis. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.