α-Lipoic Acid Inhibits Endotoxin-stimulated Expression of iNOS and Nitric Oxide Independent of the Heat Shock Response in RAW 264.7 Cells

Abstract

The heat shock response protects against sepsis-induced mortality, organ injury, cardiovascular dysfunction, and apoptosis. Several inducers of the heat shock response, such as hyperthermia, sodium arsenite, and pyrollidine dithiocarbonate, inhibit NF-κB activation and nitric oxide formation. The antioxidant lipoic acid (LA) has recently been found to inhibit NF-κB activation and nitric oxide formation. We therefore tested the hypothesis that LA induces a heat shock response. To test this hypothesis, we determined whether exposure to LA affects expression of both heat shock protein 70 (HSP-70) and nuclear heat shock factor-1 (HSF-1) in lipopolysaccharide (LPS) stimulated macrophages. LA and hyperthermia attenuated LPS-induced increases in nuclear NF-κB, iNOS protein, and media nitrite concentrations. LPS and hyperthermia increased HSP-70 concentrations 8-fold and 20-fold, respectively. No effect of LA treatment alone on HSP-70 protein expression was detected. Likewise, no effect of LA on HSF-1 protein expression was detected. These data suggest that LA inhibits LPS-induced activation of iNOS in macrophages independent of the heat shock response.