Induction of HO-1 by Mevastatin Mediated via a Nox/ROS-Dependent c-Src/PDGFRα/PI3K/Akt/Nrf2/ARE Cascade Suppresses TNF-α-Induced Lung Inflammation

Abstract

Background: Mevastatin (MVS), a 3-hydroxy-3-methylglutaryl coenzyme, a reductase (HMG-CoA) inhibitor, has anti-inflammatory effects potentially via up-regulation of heme oxygenase-1 (HO-1). However, the mechanisms underlying MVS-induced HO-1 expression remain largely unknown in human pulmonary alveolar epithelial cells (HPAEpiCs). Methods: HO-1 and intercellular adhesion molecule (ICAM)-1 expression were determined using real-time PCR, Western blotting, and promoter reporter analyses. The signaling components were investigated using pharmacological inhibitors or specific small interfering RNA (siRNA)s. Interaction between Nrf2 and the antioxidant response element (ARE) binding site for the HO-1 promoter was determined by chromatin immunoprecipitation (ChIP) assay. Results: Upregulation of HO-1 by MVS attenuated the tumor necrosis factor (TNF)-α-stimulated ICAM-1 expression associated with THP-1 adhesion to HPAEpiCs. These inhibitory effects of HO-1 were reversed by tin protoporphyrin (SnPP)IX or by transfection with HO-1 siRNA. MVS-induced HO-1 expression was mediated via NADPH oxidase (Nox)-derived reactive oxygen species (ROS) generation. Activation of Nox2/ROS further stimulated the phosphorylation of p47phox, proto-oncogene tyrosine-protein kinase (c-Src), platelet-derived growth factor receptor (PDFGR)α, protein kinase B (Akt), and Nrf2, which were inhibited by siRNAs. Pretreatment with pharmacological inhibitors, including diphenyleneiodonium (DPI), apocynin (APO), N-acetyl-L-cysteine (NAC), PP1, AG1296, or LY294002, reduced the MVS-activated Nrf2 nuclear-translocation binding to the ARE on the HO-1 promoter. Conclusions: MVS-induced HO-1 is, at least in part, mediated through a p47phox/Nox2/ROS-dependent activation of c-Src/PDGFRα/PI3K/Akt-regulated Nrf2/ARE axis and suppresses the TNF-α-mediated inflammatory responses in HPAEpiCs.

Pro-Resolving FPR2 Agonists Regulate NADPH Oxidase-Dependent Phosphorylation of HSP27, OSR1, and MARCKS and Activation of the Respective Upstream Kinases

“…NAC and apocynin have prevented PI3K activation in several experimental systems [ 153 , 154 , 155 , 156 ]. NAC increases cellular synthesis of glutathione and can reduce superoxide generation [ 157 ].…”

Mevastatin-Induced AP-1-Dependent HO-1 Expression Suppresses Vascular Cell Adhesion Molecule-1 Expression and Monocyte Adhesion on Human Pulmonary Alveolar Epithelial Cells Challenged with TNF-α

“…Our previous study shows that up-regulation of HO-1 protects against lung inflammatory responses induced by LPS [21]. In addition, MVS has been shown to time-dependently induce the expression of HO-1 expression in HPAEpiCs [23]. Here, we evaluated the effect of HO-1 expression by MVS on the TNF-α-induced VCAM-1 expression in HPAEpiCs.…”

Chinese Herbs and Repurposing Old Drugs as Therapeutic Agents in the Regulation of Oxidative Stress and Inflammation in Pulmonary Diseases

“…A previous study using the zymosan-injected air pouch to trigger inflammation found that pretreatment with atorvastatin attenuated cell influx and the expression of proinflammatory cytokines and chemokines along with induction of HO-1 in the cells of the exudate of the air pouch, effects which were reversed by exposure to tin protoporphyrin IX (SnPPIX), an heme oxygenase inhibitor. 217 Our recent study also revealed that HO-1 induction by mevastatin through the Nrf2/ARE axis was regulated by the p47 phox /Nox2/ROS-dependent activation of c-Src/PDGFR/PI3K/Akt 112 or by c-Jun activation activated by the PKC/Pyk2/p38 MAPK- or JNK1/2-dependent pathways and led to AP-1-binding on the HO-1 promoter region 113 using HPAEpiCs and animal studies. Further, mevastatin can suppress inflammatory responses mediated by TNFα.…”

“… 86 Our recent studies have demonstrated that HO-1 is induced by mevastatin mediated via a Nox/ROS-dependent c-Src/PDGFRα/PI3K/Akt/Nrf2/ARE cascade or via c-Jun activation of PKCα/Pyk2/p38α MAPK or JNK1/2 to suppress proinflammatory mediators-mediated inflammatory responses in human pulmonary alveolar epithelial cells (HPAEpiCs). 112 , 113 Carbon monoxide-releasing molecule (CORM-2) induces HO-1 expression via Src, epidermal growth factor receptor (EGFR), and PI3K/Akt to increase the formation of the Nrf2 and AREs complex in HPAEpiCs to suppress TNF-α-mediated inflammatory responses. 114 CORM-2 also activates a PYK2/PKCα/ERK1/2/AP-1 pathway leading to HO-1 expression in HPAEpiCs.…”

“…Further, mevastatin can suppress inflammatory responses mediated by TNFα. 112 , 113 Chemotaxis is also attenuated by statins, as demonstrated by the rosuvastatin-induced decrease in the number of macrophages, lymphocytes, neutrophils, eosinophils, and total inflammatory cells recruited into BALF, as well as the lower levels of TNF-α, IL-4, IL-5, and IL-13 in BALF. 218 Treatment with another statin, simvastatin, also prevented the recruitment of leukocytes to the lung, abrogated pulmonary endothelial injury, attenuated pulmonary hyperpermeability, 219 , 220 reduced pulmonary cytokine levels such as IL-13 and TGF-β1 in patients with lung fibrosis, 221 , 222 and improved oxygenation in mechanically ventilated mice.…”