Heme oxygenase-1 induction by rosiglitazone via PKC alpha/AMPK alpha/p38 MAPK alpha/SIRT1/PPAR gamma pathway suppresses lipopolysaccharide-mediated pulmonary inflammation

HO-1 (heme oxygenase-1), an antioxidant enzyme, induced by rosiglitazone (PPAR ligands) can be a potential treatment of inflammation. However, the mechanisms of rosiglitazone-induced HO-1 expression in human pulmonary alveolar epithelial cells (HPAEpiCs) remain largely unknown. In this study, we found that upregulation of HO-1 in vitro or in vivo by rosiglitazone attenuated VCAM-1 gene expression and monocyte adhesion to HPAEpiCs challenged with lipopolysaccharide (LPS). The inhibitory effects of rosiglitazone on LPS-mediated responses were reversed by transfection with HO-1 siRNA. LPS-induced VCAM-1 expression was mediated through NF-kappa B activation which was attenuated by rosiglitazone via suppressing p65 activation and translocation into the nucleus. Moreover, pretreatment with the inhibitor of PKCs (H7), PKC alpha (Go6976), AMPK alpha (Compound C), p38 MAPK alpha (p38i VIII), SIRT1 (Sirtinol), or PPAR gamma (T0070907) and transfection with siRNA of PKC alpha, AMPK alpha, p38 MAPK alpha, SIRT1, or PPAR gamma abolished the rosiglitazone-induced HO-1 expression in HPAEpiCs. Further studies indicated that rosiglitazone stimulated SIRT1 deacetylase leading to PGClatranslocation from the cytosol into the nucleus, promoting fragmentation of NCoR and phosphorylation of PPARy. Subsequently, PPAR gamma was activated by phosphorylation of PKC alpha, AMPK alpha, p38 MAPK alpha, and SIRT1, which turned on transcription of HO-1 gene by binding to PPAR gamma response element (PPRE) and enhancing PPAR gamma promoter activity. These results suggested that rosiglitazone-induced HO-1 expression is mediated through PKC alpha/AMPK alpha/p38 MAPKct/ SIRT1-dependent deacetylation of Ac-PGC1 alpha and fragmentation of NCoR/PPAR gamma activation in HPAEpiCs. Up-regulation of HO-1 protected against the inflammatory responses triggered by LPS, at least in part, through attenuation of NF-kappa B. (C) 2018 Elsevier Inc. All rights reserved.