Increased pulmonary heme oxygenase-1 and δ-aminolevulinate synthase expression in monocrotaline-induced pulmonary hypertension

Tatsuo Iwasaki, Toru Takahashi, Hiroko Shimizu, Emiko Ohmori, Taro Morimoto, Masahito Kajiya, Mamoru Takeuchi, Kiyoshi Morita, Reiko Akagi, Fumihiko Kajiya

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14 Citations (Scopus)

Abstract

Monocrotaline (MCT), a pyrrolizidine alkaloid plant toxin, is known to cause pulmonary hypertension (PH) in rats. Recent findings suggest that pulmonary inflammation may play a significant role in the pathogenesis in MCT-induced PH. Heme oxygenase-1 (HO-1), the rate-limiting enzyme in heme catabolism, is known to be induced by various oxidative stresses, including inflammation and free heme, and its induction is thought essential in the protection against oxidative tissue injuries. In this study, we examined expression of HO-1 as well as non-specific δ-aminolevulinate synthase (ALAS1), the rate-limiting enzyme in heme catabolism and biosynthesis, respectively, in a rat model of PH produced by subcutaneous injection of MCT (60 mg/kg). MCT treatment caused infiltration of inflammatory cells, fibrosis of the interstitium, and pulmonary arterial wall thickening with marked elevation of right ventricular (RV) pressure, which are characteristics of MCT-induced PH. Gene expression of tumor necrosis factor-α (TNF-α) as well as DNA binding activity of nuclear factor-κB (NF-κB) increased at 1 week after MCT treatment, reached a maximum at 2 weeks, and then decreased to the pretreatment level at 3 weeks. HO-1 expression was markedly increased at 1 week, and continued to increase by 3 weeks following MCT treatment, both at transcriptional and protein levels in the mononuclear cells in the lung. ALAS1 mRNA levels in the lung also significantly increased at 2 weeks after MCT treatment. These findings suggest that pulmonary HO-1 expression was presumably induced by proinflammatory cytokine(s) in MCT-treated rats, resulting in the derepression of heme-repressible ALAS1 expression, and that HO-1 induction plays a significant role as an inflammatory factor in this condition.

Original languageEnglish
Pages (from-to)133-139
Number of pages7
JournalCurrent Neurovascular Research
Volume2
Issue number2
DOIs
Publication statusPublished - Apr 2005

Keywords

  • Heme oxygenase-1
  • Inflammation
  • Monocrotaline
  • Non-specific δ-aminolevulinate synthase
  • Nuclear factor-κB
  • Pulmonary hypertension
  • Tumor necrosis factor-α

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience
  • Cellular and Molecular Neuroscience

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  • Cite this

    Iwasaki, T., Takahashi, T., Shimizu, H., Ohmori, E., Morimoto, T., Kajiya, M., Takeuchi, M., Morita, K., Akagi, R., & Kajiya, F. (2005). Increased pulmonary heme oxygenase-1 and δ-aminolevulinate synthase expression in monocrotaline-induced pulmonary hypertension. Current Neurovascular Research, 2(2), 133-139. https://doi.org/10.2174/1567202053586794