Involvement of the p38 pathway in the differential induction of heme oxygenase-1 by statins in Neuro-2A cells exposed to lipopolysaccharide

Abstract

Heme oxygenase-1 (HO-1) expression, in response to various stimuli, has been generally reported to protect against cellular stress. However, we previously demonstrated simvastatin-induced HO-1-exaggerated nuclear factor kappa beta (NF-κβ) activation and superoxide production on exposure to lipopolysaccharide (LPS). The addition of the iron chelator, desferrioxamine, to reduce the accumulation of ferric iron from heme by HO-1 resulted in a blockade of aggravated superoxide production. In this study, we demonstrated that, unlike simvastatin, neither atorvastatin- nor rosuvastatin-induced HO-1 upregulation resulted in increased NF-κβ activation and superoxide production of Neuro-2A cells against LPS. Moreover, increased superoxide formation by either atorvastatin or rosuvastatin, in the presence or absence of LPS, could not be reduced by the addition of desferrioxamine, unlike simvastatin. In contrast to our previous experiment, in which simvastatin activated ERK and p38, but not JNK or Akt, both atorvastatin and rosuvastatin phosphorylated ERK, but not p38. Inhibition of p38 activation by 5 μM of SB203580 effectively reduced exaggerated HO-1 upregulation in cells pretreated with simvastatin, but not atorvastatin or rosuvastatin, plus exposure to LPS. The addition of an ERK inhibitor (50 μM of PD98059) did not decrease HO-1 upregulation in cells following any statin pretreatment. Further, the effect of simvastatin on primary cultures of cortical neurons was also different from that on Neuro-2A cells, as HO-1 upregulation did not result in exaggerated NF-κβ activation and superoxide production. This study demonstrated the involvement of p38 in the differential induction of HO-1 by different statins and showed the different physiological relevance of experiments on different cell types.

Keywords::

• Simvastatin
• atorvastatin
• rosuvastatin
• heme oxygenase-1 (HO-1)
• lipopolysaccharide (LPS)
• nuclear factor kappa B (NF-κβ);
• superoxide
• zinc protoprophyrin (ZnPP)
• desferrioxamine (DFO)
• p38