Tanshinone IIA-induced attenuation of lung injury in endotoxemic mice is associated with reduction of hypoxia-inducible factor 1α expression.

Abstract

Inhibiting hypoxia-inducible factor (HIF)-1α activity has been proposed as a novel therapeutic target in LPS-induced sepsis syndrome. We have reported that tanshinone IIA (TIIA) can reduce LPS-induced lethality and lung injury in mice, but the precise mechanisms have not been fully described. Therefore, the present study investigated whether the protective effect of TIIA was related to the inhibition of LPS-induced HIF-1α expression and what mechanisms accounted for it. This study showed that TIIA pretreatment improved LPS-induced biochemical and cellular changes and reduced the production of inflammatory cytokines. Pretreatment with TIIA decreased LPS-induced HIF-1α expression in vivo and in vitro. TIIA did not affect the LPS-induced HIF-1α mRNA level but inhibited HIF-1α protein translation by the inhibition of the PI3K/AKT and MAPK pathways and related protein translational regulators, such as p70S6K1, S6 ribosomal protein, 4E-BP1, and eIF4E, and promoted HIF-1α protein degradation via the proteasomal pathway in LPS-stimulated macrophages. These observations partially explain the antiinflammatory effects of TIIA, which provides scientific basis for its application for the treatment of acute lung injury/acute respiratory distress syndrome or sepsis.

• Authors: Min Xu, Fale Cao, Lili Liu, Bo Zhang, Yanxia Wang, Haiying Dong, Yan Cui, Mingqing Dong, Dunquan Xu, Yi Liu, Pengtao Zhao, Wen Niu, Zhichao Li
• Journal: American journal of respiratory cell and molecular biology (Am J Respir Cell Mol Biol) Vol. 45 Issue 5 Pg. 1028-35 (Nov 2011) ISSN: 1535-4989 [Electronic] United States
• PMID: 21622293 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Abietanes
• Adaptor Proteins, Signal Transducing
• Anti-Inflammatory Agents, Non-Steroidal
• Carrier Proteins
• Cell Cycle Proteins
• DNA-Binding Proteins
• Eif4ebp1 protein, mouse
• Elf5 protein, mouse
• Eukaryotic Initiation Factors
• Hypoxia-Inducible Factor 1, alpha Subunit
• Lipopolysaccharides
• Phosphoproteins
• Ribosomal Protein S6
• Transcription Factors
• tanshinone
• Ribosomal Protein S6 Kinases, 70-kDa
• Proteasome Endopeptidase Complex

Topics

• Abietanes (pharmacology)
• Acute Lung Injury (drug therapy)
• Adaptor Proteins, Signal Transducing
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Carrier Proteins (antagonists & inhibitors)
• Cell Cycle Proteins
• DNA-Binding Proteins (antagonists & inhibitors)
• Endotoxemia (chemically induced, drug therapy)
• Eukaryotic Initiation Factors
• Hypoxia-Inducible Factor 1, alpha Subunit (antagonists & inhibitors, biosynthesis)
• Lipopolysaccharides (toxicity)
• MAP Kinase Signaling System (drug effects)
• Macrophages (drug effects)
• Male
• Mice
• Mice, Inbred BALB C
• Phosphoproteins (antagonists & inhibitors)
• Proteasome Endopeptidase Complex (drug effects)
• Protein Biosynthesis (drug effects)
• Ribosomal Protein S6 (antagonists & inhibitors)
• Ribosomal Protein S6 Kinases, 70-kDa (antagonists & inhibitors)
• Transcription Factors (antagonists & inhibitors)