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Clinical and Experimental Circulation

Attenuation of monocrotaline-induced pulmonary hypertension by heme oxygenase-1 involves toll-like receptor 4 signaling


Kawakami, H.; Mizuno, Y.; Koga, M.; Goto, T.

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European Journal of Anaesthesiology (EJA): June 12th, 2010 - Volume 27 - Issue 47 - p 78
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Background and Goal of Study: Heme oxygenase-1 (HO-1) is known to have protective role against many vascular diseases such as pulmonary hypertension (PH) in human and experimental models. Although inflammatory processes including Toll-like receptors (TLRs) signalings are involved in the disorders, the underling mechanism of HO-1 to attenuate them is not fully understood. It is reported that HO-1 and TLR4 pathways may have crosstalk via caveolin-1 which regulates multiple proteins in plasma membrane. We hypothesized that the protective role of HO-1 against vascular diseases may involve TLRs signalings. In this study, we investigated whether induction of HO-1 improves monocrotaline(MCT)-induced PH through interaction of caveolin-1 with TLR4 signaling.

Materials and Methods: Sprague Dawley rats were divided into four groups: Group M was given 60mg/kg of MCT 4 weeks before following measurement. Group MH was given 60mg/kg of MCT and hemin, HO-1 inducer 30 mg/kg twice a week for 4 weeks. Group H was given hemin 30mg/kg twice a week for 4 weeks. Group C was control. Systemic and right ventricular pressure (RVP) was measured. The amount of HO-1, caveolin-1, 3 and TLR4 in lung tissue were measured by western blot analysis. Coimmunoprecipitation and immunoblot using lung were performed to analyse the interaction among caveolin-1, TLR4 and HO-1. Immunofluorescence analysis of lung was done against HO-1, caveolin-1 and TLR4. The sections were observed under confocal microscope.

Results and Discussion: RVP was significantly higher in group M than group C, while the increase was attenuated by adding hemin in group MH. Likewise, increased TLR4 expression in lung in group M compared to in group C also reduced in group MH. HO-1 was significantly higher in group M than in group C and further increased in group MH. Caveolin-1 did not differ in group M and MH, and localized in only plasma membrane of alveolar epithelium. Coimmunoprecipitation showed that the both HO-1 and TLR4 biding to caveolin-1 were increased in group MH than in group M. Attenuation of RVP with enhanced HO-1 by hemin was associated with decreased TLR4 expression and increased interaction between caveolin-1 and TLR4. These suggest that HO-1 expression with hemin may not only decrease TLR4 expression but affect TLR4 signaling because caveolin-1 negatively regulates membrane protein activity mostly by binding them.

Conclusion(s): Inhibitory effect of HO-1 with hemin on MCT-induced PH was associated with decreased TLR4 expression and increased interaction between TLR4 and caveolin-1.

© 2010 European Society of Anaesthesiology