Homocysteine and α-Lipoic Acid Regulate p44/42 MAP Kinase Phosphorylation in NIH/3T3 Cells

Biological thiols can regulate cell signal transduction. The effects of two biothiols, homocysteine (Hcy), a risk factor for cardiovascular disease, and α-lipoic acid (αLA), a therapeutic antioxidant, on p44/42 mitogen-activated protein kinases (MAPK) phosphorylation were examined in NIH/3T3 fibroblasts. Cells grown in serum-containing media had constitutive levels of MAPK phosphorylation as determined by Western blot analysis using the phospho-specific MAPK antibody. Treatment of cells with 20 μM Hcy for 0-60 min resulted in a transient enhancement of MAPK phosphorylation. In contrast, 20 μM αLA inhibited serum-mediated phosphorylation of MAPK. The differential effects of these two thiols are not due to their redox states as oxidized Hcy (Hcy thiolactone) enhanced MAPK phosphorylation. The effect of αLA appears to be serum-dependent because Hcy or αLA treatment of serum-deprived cells activated MAPK phosphorylation. Thus, αLA and Hcy can either induce common signal transduction pathways or differentially modulate MAPK phosphorylation, depending on the state of the cell. This relationship may be important to understand how some biothiols are associated with pathogenic events while others offer potential as therapeutic agents.