Increased pulmonary heme oxygenase-1 and delta-aminolevulinate synthase expression in monocrotaline-induced pulmonary hypertension.
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 delta-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-alpha (TNF-alpha) as well as DNA binding activity of nuclear factor-kappaB (NF-kappaB) 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.
Iwasaki
Tatsuo
T
Department of Cardiovascular Physiology, Okayama University Graduate School of Medicine and Dentistry, 2-5-1 Shikata-cho, Okayama, 700-8558, Japan.
Takahashi
Toru
T
Shimizu
Hiroko
H
Ohmori
Emiko
E
Morimoto
Taro
T
Kajiya
Masahito
M
Takeuchi
Mamoru
M
Morita
Kiyoshi
K
Akagi
Reiko
R
Kajiya
Fumihiko
F
D000624:5-Aminolevulinate Synthetase / Q000378:metabolism*; D000818:Animals; D004247:DNA / Q000378:metabolism; D015870:Gene Expression; D006419:Heme Oxygenase (Decyclizing) / Q000378:metabolism*; D051547:Heme Oxygenase-1; D006863:Hydrogen-Ion Concentration; D006976:Hypertension, Pulmonary / Q000139:chemically induced* / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000201:enzymology*; D008297:Male; D016686:Monocrotaline; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D016686:Monocrotaline; D004247:DNA; D006419:Heme Oxygenase (Decyclizing); D051547:Heme Oxygenase-1; D000624:5-Aminolevulinate Synthetase