Phosphatidylinositol 3-OH kinase-Akt/protein kinase B pathway mediates Gas6 induction of scavenger receptor A in immortalized human vascular smooth muscle cell line

The growth arrest-specific gene 6 encodes a secreted protein, Gas6, which w as originally identified as the ligand of a receptor, Axl, with tyrosine ki nase activity. The class A scavenger receptor (SRA) mediates lipid uptake i nto cells, leading to the formation of foam cells, an important step in ath erogenesis. Although Gas6 induces SRA expression, the underlying mechanism is not clear. In this report, we show that the Gas6-induced expression of S RA was mediated by the phosphatidylinositol 3-OH kinase (PI3-kinase)-serine /threonine kinase (Akt/protein kinase B [PKB]) pathway involving Akt phosph orylation. This pathway was activated by exposure to Gas6. Furthermore, the effect of Gas6 was abrogated by wortmannin, a specific inhibitor of PI3-ki nase. We also demonstrated that the constitutively active form of Akt enhan ced activity of the SRA promoter but that the dominant-negative mutant of A kt completely abolished the expression of SRA after treatment with Gas6. Th ese results show that the PI3-kinase-Akt/PKB pathway participates in Gas6-i nduced SRA expression and suggests that the activation of Akt/PKB plays an important role in Gas6-induced atherosclerosis and foam cell formation in h uman vascular smooth muscle cells.