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High expression of CXCR4 and stem cell markers in a monocrotaline and chronic hypoxia-induced rat model of pulmonary arterial hypertension.

ABSTRACT: Pulmonary arterial hypertension (PAH) is a severe and fatal clinical syndrome. C-X-C chemokine receptor type 4 (CXCR4) is known to serve a key role in recruiting mesenchymal stem cells (MSCs) from the bone marrow. In the present study, a rat model of PAH induced by 5 weeks of chronic hypoxia and treatment with a single injection of monocrotaline (60 mg/kg) was used to investigate the involvement of CXCR4 in PAH. Successful establishment of the PAH model was confirmed by significant differences between the PAH and control groups in right ventricular systolic pressure, Fulton index, wall thickness, vascular occlusion score determined by immunohistochemical staining and the expression of inflammatory markers measured by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). The expression of CXCR4 and other stem cell markers were compared in the PAH and control groups. RT-qPCR showed that the expression of CXCR4, SCF, c-Kit, and CD29, which are expressed in MSCs, was significantly higher in the PAH group. Immunohistochemical staining also showed that the numbers of CXCR4-, c-Kit- and CD90-positive cells were significantly higher in the PAH group. These results suggest that CXCR4 is involved in the pathogenesis of PAH and that stem cells may serve an important role in pulmonary vascular remodeling.

SUBMITTER: Zhang T

PROVIDER: S-EPMC5952071 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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High expression of CXCR4 and stem cell markers in a monocrotaline and chronic hypoxia-induced rat model of pulmonary arterial hypertension.

Zhang Tingting T Kawaguchi Nanako N Hayama Emiko E Furutani Yoshiyuki Y Nakanishi Toshio T

Experimental and therapeutic medicine 20180403 6

Pulmonary arterial hypertension (PAH) is a severe and fatal clinical syndrome. C-X-C chemokine receptor type 4 (CXCR4) is known to serve a key role in recruiting mesenchymal stem cells (MSCs) from the bone marrow. In the present study, a rat model of PAH induced by 5 weeks of chronic hypoxia and treatment with a single injection of monocrotaline (60 mg/kg) was used to investigate the involvement of CXCR4 in PAH. Successful establishment of the PAH model was confirmed by significant differences b ...[more]

PMID: 29805477

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Project description:BackgroundC-X-C chemokine receptor type 4 (CXCR4) may be involved in the development of pulmonary arterial hypertension (PAH). CXCR4 inhibitor AMD3100 was described to have a positive effect on the prevention of pulmonary arterial muscularization in PAH models. Silibinin is a traditional medicine that has an antagonistic effect on CXCR4. We investigated the effect of silibinin using rat models of PAH.MethodsPAH was induced by a single subcutaneous injection of monocrotaline. The rats were maintained in a chronic hypoxic condition (10% O2) with or without silibinin. To evaluate the efficacy of silibinin on PAH, right ventricular systolic pressure (RVSP), Fulton index (weight ratio of right ventricle to the left ventricle and septum), percent medial wall thickness (% MT), and vascular occlusion score (VOS) were measured and calculated. Immunohistochemical analysis was performed targeting CXCR4 and c-Kit. Reverse transcription-quantitative polymerase chain reaction was performed for the stem cell markers CXCR4, stromal cell derived factor-1 (SDF-1), c-Kit, and stem cell factor (SCF), and the inflammatory markers monocyte chemoattractant protein 1 (MCP1), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNFα). Statistical analyses were performed using t-test and one-way analysis of variance with Bonferroni's post hoc test.ResultsSilibinin treatment for 1 week reduced RVSP and Fulton index. Treatment for 2 weeks reduced RVSP, Fulton index, % MT, and VOS, as well as downregulating the expression of CXCR4, SDF-1, and TNFα in pulmonary arteries. In contrast, treatment for 3 weeks failed to ameliorate PAH. The time-course study demonstrated that RVSP, Fulton index, % MT, and VOS gradually increased over time, with a decrease in the expression of CXCR4 and TNFα occurring after 2 weeks of PAH development. After 3 weeks, SDF-1, c-Kit, and SCF began to decrease and, after 5 weeks, MCP1 and IL-6 gradually accumulated.ConclusionsThe CXCR4 inhibitor silibinin can ameliorate PAH, possibly through the suppression of the CXCR4/SDF-1 axis, until the point where PAH becomes a severe and irreversible condition. Silibinin results in reduced pulmonary arterial pressure and delays pulmonary arteriolar occlusion and pulmonary vascular remodeling.

Project description:BackgroundPulmonary hypertension (PH) is a serious disease with poor prognosis. Reports show that cells in remodeled pulmonary arteries of PH patients have similar characteristics to cancer cells, such as exuberant inflammation, increased proliferation, and decreased apoptosis. An ideal strategy for developing PH therapies is to directly target pulmonary vascular remodeling. High levels of histone deacetylase (HDAC) expression and activity are found in certain cancers, and research has shown the potential of HDAC inhibitors in repressing tumor growth via anti-inflammatory and anti-proliferative effects. To date, little is known about the effectiveness of HDAC inhibitors against pulmonary vascular remodeling in severe PH.ObjectiveTo investigate whether class I HDAC inhibitors suppress or reverse the development of severe PH in rats.MethodsMale Sprague-Dawley rats were injected with a single, subcutaneous dose of monocrotaline (60 mg/kg), and were exposed to chronic hypoxia to induce severe PH. Valproic acid, a class I HDAC inhibitor, was administered to rats daily via gastric gavage (300 mg/kg) in a PH prevention study (during the first 3 weeks) or a PH reversal study (from 3 to 5 weeks). At the end of experiment, hemodynamic indices were measured, ventricular hypertrophy indices were calculated and vascular remodeling phenotypes were analyzed.ResultsAfter 3 weeks exposure to a combined stimulation of monocrotaline and chronic hypoxia, rats exhibited a reduced body weight, elevated right ventricular systolic pressure, an increased Fulton index, right ventricle weight ratio, medial wall thickness and muscularized peripheral pulmonary arteries. These parameters for PH evaluation were exacerbated from 3 to 5 weeks. Daily administration of valproic acid therapy prevented and partially reversed the development of severe PH in rats, and decreased inflammation and proliferation in remodeled pulmonary arteries.ConclusionThese data show that class I HDAC inhibitors may be effective for treating severe PH.

Dataset Information

High expression of CXCR4 and stem cell markers in a monocrotaline and chronic hypoxia-induced rat model of pulmonary arterial hypertension.

Publications

High expression of CXCR4 and stem cell markers in a monocrotaline and chronic hypoxia-induced rat model of pulmonary arterial hypertension.

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