Heme oxygenase-1 in cholecystokinin-octapeptipe attenuated injury of pulmonary artery smooth muscle cells induced by lipopolysaccharide and its signal transduction mechanism

World J Gastroenterol. 2004 Jun 15;10(12):1789-94. doi: 10.3748/wjg.v10.i12.1789.


Aim: To study the effect of cholecystokinin-octapeptide (CCK-8) on lipopolysaccharide (LPS) -induced pulmonary artery smooth muscle cell (PASMCs) injury and the role of heme oxygenase-1 (HO-1), and to explore the regulation mechanism of c-Jun N-terminal kinase (JNK) and activator protein-1 (AP-1) signal transduction pathway in inducing HO-1 expression further.

Methods: Cultured PASMCs were randomly divided into 4 or 6 groups: normal culture group, LPS (10 mg/L), CCK-8 (10(-6) mol/L) plus LPS (10 mg/L) group, CCK-8 (10(-6) mol/L) group, zinc protoporphyrin 9 (ZnPPIX) (10(-6) mol/L) plus LPS (10 mg/L) group, CCK-8 (10(-6) mol/L) plus ZnPPIX and LPS (10 mg/L) group. Seven hours after LPS administration, ultrastructural changes and content of malondialdehyde (MDA) of PASMCs in each group were investigated by electron microscopy and biochemical assay respectively. HO-1 mRNA and protein of PASMCs in the former 4 groups were examined by reverse transcriptase polymerase chain reaction (RT-PCR) and immunocytochemistry staining. Changes of c-fos expression and activation of JNK of PASMCs in the former 4 groups were detected with immunocytochemistry staining and Western blot 30 min after LPS administration.

Results: The injuries of PASMCs and the increases of MDA content induced by LPS were alleviated and significantly reduced by CCK-8 (P<0.05). The specific HO-1 inhibitor- ZnPPIX could worsen LPS-induced injuries and weaken the protective effect of CCK-8. The expressions of c-fos, p-JNK protein and HO-1 mRNA and protein were all slightly increased in LPS group, and significantly enhanced by CCK-8 further (P<0.05).

Conclusion: HO-1 may be a key factor in CCK-8 attenuated injuries of PASMCs induced by LPS, and HO-1 expression may be related to the activation of JNK and activator protein (AP-1).

MeSH terms

  • Animals
  • Blotting, Western
  • Cells, Cultured
  • Heme Oxygenase (Decyclizing) / genetics
  • Heme Oxygenase (Decyclizing) / metabolism*
  • Heme Oxygenase-1
  • JNK Mitogen-Activated Protein Kinases
  • Lipopolysaccharides / pharmacology
  • Male
  • Malondialdehyde / metabolism
  • Microscopy, Electron
  • Mitochondria / ultrastructure
  • Mitogen-Activated Protein Kinases / metabolism
  • Muscle, Smooth, Vascular / cytology
  • Muscle, Smooth, Vascular / drug effects
  • Muscle, Smooth, Vascular / enzymology*
  • Proto-Oncogene Proteins c-fos / metabolism
  • Pulmonary Artery / cytology*
  • RNA, Messenger / analysis
  • Rats
  • Rats, Sprague-Dawley
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects*
  • Signal Transduction / physiology
  • Sincalide / pharmacology*


  • Lipopolysaccharides
  • Proto-Oncogene Proteins c-fos
  • RNA, Messenger
  • Malondialdehyde
  • Heme Oxygenase (Decyclizing)
  • Heme Oxygenase-1
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinases
  • Sincalide