Homocysteine induces protein kinase C activation and stimulates c-fos and lipoprotein lipase expression in macrophages

Hyperhomocysteinemia is an independent risk factor for cardiovascular disease in human diabetes. Among the multiple factors that may account for the atherogenicity of homocysteine (Hcys) in patients with diabetes, macrophage (Mo) lipoprotein lipase (LPL) has unique features in that it is increased in human diabetes and acts as a proatherogenic factor in the arterial wall. In the present study, we determined the direct regulatory effect of Hcys on Mo LPL gene expression and secretion. Incubation of J774 Mo with Hcys increased, in a time- and dose-dependent manner, LPL mRNA expression and secretion. Induction of LPL gene expression was biphasic, peaking at I and 6 h. Whereas Hcys treatment increased protein kinase C (PKC) activity in Mo, pretreatment of Mo with PKC inhibitors totally suppressed Hcys-induced LPL mRNA expression. Hcys also increases the levels of c-fos mRNA in Mo and enhanced nuclear protein binding to the AP-1 sequence of the LPL gene promoter. Overall, these results demonstrate that Hcys stimulates Mo LPL at both the gene and protein levels and that Hcys-induced LPL mRNA expression requires PKC activation. They also suggest a possible role of c-fos in the stimulatory effect of Hcys on Mo LPL mRNA expression. These observations suggest a new mechanism by which Hcys may exert its proatherogenic effects in human diabetes.