TY - JOUR
T1 - Increased pulmonary heme oxygenase-1 and δ-aminolevulinate synthase expression in monocrotaline-induced pulmonary hypertension
AU - Iwasaki, Tatsuo
AU - Takahashi, Toru
AU - Shimizu, Hiroko
AU - Ohmori, Emiko
AU - Morimoto, Taro
AU - Kajiya, Masahito
AU - Takeuchi, Mamoru
AU - Morita, Kiyoshi
AU - Akagi, Reiko
AU - Kajiya, Fumihiko
PY - 2005/4
Y1 - 2005/4
N2 - 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.
AB - 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.
KW - Heme oxygenase-1
KW - Inflammation
KW - Monocrotaline
KW - Non-specific δ-aminolevulinate synthase
KW - Nuclear factor-κB
KW - Pulmonary hypertension
KW - Tumor necrosis factor-α
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U2 - 10.2174/1567202053586794
DO - 10.2174/1567202053586794
M3 - Article
C2 - 16181105
AN - SCOPUS:21044436875
VL - 2
SP - 133
EP - 139
JO - Current Neurovascular Research
JF - Current Neurovascular Research
SN - 1567-2026
IS - 2
ER -