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Resistin-like molecule-beta in scleroderma-associated pulmonary hypertension.

ABSTRACT: Scleroderma is a systemic, mixed connective tissue disease that can impact the lungs through pulmonary fibrosis, vascular remodeling, and the development of pulmonary hypertension and right heart failure. Currently, little is known about the molecular mechanisms that drive this condition, but we have recently identified a novel gene product that is up-regulated in a murine model of hypoxia-induced pulmonary hypertension. This molecule, known as hypoxia-induced mitogenic factor (HIMF), is a member of the newly described resistin gene family. We have demonstrated that HIMF has mitogenic, angiogenic, vasoconstrictive, inflammatory, and chemokine-like properties, all of which are associated with vascular remodeling in the lung. Here, we demonstrate that the human homolog of HIMF, resistin-like molecule (RELM)-beta, is expressed in the lung tissue of patients with scleroderma-associated pulmonary hypertension and is up-regulated compared with normal control subjects. Immunofluorescence colocalization revealed that RELM-beta is expressed in the endothelium and vascular smooth muscle of remodeled vessels, as well as in plexiform lesions, macrophages, T cells, and myofibroblast-like cells. We also show that addition of recombinant RELM-beta induces proliferation and activation of ERK1/2 in primary cultured human pulmonary endothelial and smooth muscle cells. These results suggest that RELM-beta may be involved in the development of scleroderma-associated pulmonary hypertension.

SUBMITTER: Angelini DJ

PROVIDER: S-EPMC2778162 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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Resistin-like molecule-beta in scleroderma-associated pulmonary hypertension.

Angelini Daniel J DJ Su Qingning Q Yamaji-Kegan Kazuyo K Fan Chunling C Teng Xingwu X Hassoun Paul M PM Yang Stephen C SC Champion Hunter C HC Tuder Rubin M RM Johns Roger A RA

American journal of respiratory cell and molecular biology 20090227 5

Scleroderma is a systemic, mixed connective tissue disease that can impact the lungs through pulmonary fibrosis, vascular remodeling, and the development of pulmonary hypertension and right heart failure. Currently, little is known about the molecular mechanisms that drive this condition, but we have recently identified a novel gene product that is up-regulated in a murine model of hypoxia-induced pulmonary hypertension. This molecule, known as hypoxia-induced mitogenic factor (HIMF), is a membe ...[more]

PMID: 19251945

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Project description:BackgroundScleroderma-associated pulmonary arterial hypertension (SSc-PAH) is a rare disease characterized by a very dismal response to therapy and poor survival. We assessed the effects of up-front combination PAH therapy in patients with SSc-PAH.MethodsIn this prospective, multicenter, open-label trial, 24 treatment-naive patients with SSc-PAH received ambrisentan 10 mg and tadalafil 40 mg daily for 36 weeks. Functional, hemodynamic, and imaging (cardiac magnetic resonance imaging and echocardiography) assessments at baseline and 36 weeks included changes in right ventricular (RV) mass and pulmonary vascular resistance as co-primary endpoints and stroke volume/pulmonary pulse pressure ratio, tricuspid annular plane systolic excursion, 6-minute walk distance, and N-terminal pro-brain natriuretic peptide as secondary endpoints.ResultsAt 36 weeks, we found that treatment had resulted in significant reductions in median (interquartile range [IQR]) RV mass (28.0 g [IQR, 20.6-32.9] vs. 32.5 g [IQR, 23.2-41.4]; P < 0.05) and median pulmonary vascular resistance (3.1 Wood units [IQR, 2.0-5.7] vs. 6.9 Wood units [IQR, 4.0-12.9]; P < 0.0001) and in improvements in median stroke volume/pulmonary pulse pressure ratio (2.6 ml/mm Hg [IQR, 1.8-3.5] vs. 1.4 ml/mm Hg [IQR 8.9-2.4]; P < 0.0001) and mean ( ± SD) tricuspid annular plane systolic excursion (2.2 ± 0.12 cm vs. 1.65 ± 0.11 cm; P < 0.0001), 6-minute walk distance (395 ± 99 m vs. 343 ± 131 m; P = 0.001), and serum N-terminal pro-brain natriuretic peptide (647 ± 1,127 pg/ml vs. 1,578 ± 2,647 pg/ml; P < 0.05).ConclusionsUp-front combination therapy with ambrisentan and tadalafil significantly improved hemodynamics, RV structure and function, and functional status in treatment-naive patients with SSc-PAH and may represent a very effective therapy for this patient population. In addition, we identified novel hemodynamic and imaging biomarkers that could have potential value in future clinical trials. Clinical trial registered with www.clinicaltrials.gov (NCT01042158).

Project description:Rationale: Pulmonary arterial hypertension is a common and potentially fatal complication of scleroderma that may involve inflammatory and autoimmune mechanisms. Alterations in the gene expression of peripheral blood mononuclear cells have been previously described in patients with pulmonary arterial hypertension. The ability to identify patients at risk for developing pulmonary hypertension would be clinically beneficial. Objective: To identify genes that are differentially expressed in peripheral blood mononuclear cells in scleroderma patients with and without pulmonary hypertension which could be used as biomarkers of disease for early diagnosis and provide insight into pathogenesis of pulmonary hypertension in at-risk populations. Methods and Results: Gene expression analysis was performed on a carefully characterized Microarray Cohort of scleroderma patients with (n=10) and without (n=10) pulmonary hypertension. Differentially expressed genes were confirmed in the Microarray Cohort and validated in a separate Validation Cohort of scleroderma patients with (n=15) and without (n=19) pulmonary hypertension by RT-qPCR. We identified inflammatory and immune-related genes including interleukin-7 receptor (IL-7R) and chemokine receptor 7 (CCR7) as differentially expressed in patients with scleroderma-associated pulmonary hypertension. Flow cytometry confirmed decreased expression of IL-7R on circulating CD4+ T cells from scleroderma patients with pulmonary hypertension. Conclusions: Differences exist in the expression of inflammatory and immune-related genes in peripheral blood cells derived from patients with scleroderma-related pulmonary hypertension compared to those with normal pulmonary artery pressures. These findings may have implications as biomarkers to screen at-risk populations to facilitate early diagnosis and provide insight into inflammatory and autoimmune mechanisms of scleroderma-related pulmonary hypertension. Gene expression analysis was performed on a carefully characterized Microarray Cohort of scleroderma patients with (n=10) and without (n=10) pulmonary hypertension. Differentially expressed genes were confirmed in the Microarray Cohort by RT-qPCR.

Project description:Scleroderma-associated pulmonary arterial hypertension (SSc-PAH) is associated with worse outcome than idiopathic pulmonary arterial hypertension (IPAH), potentially due to worse right ventricular adaptation to load as suggested by pressure-volume loop analysis. The value of non-invasive load-adaptability metrics has not been fully explored in SSc-PAH. This study sought to assess whether patients with incident SSc-PAH have worse echocardiographic load-adaptability metrics than patients with IPAH. Twenty-two patients with incident SSc-PAH were matched 1:1 with IPAH based on pulmonary vascular resistance. Echocardiographic load-adaptability indices were divided into: surrogates of ventriculo-arterial coupling (e.g. right ventricular area change/end-systolic area), indices reflecting the proportionality of load adaptation (e.g. tricuspid regurgitation velocity-time integral normalized for average right ventricular radius), and simple ratios (e.g. tricuspid annular plane systolic excursion/right ventricular systolic pressure). The prognostic value of these indices for clinical worsening (i.e. death, transplant, or hospitalization for heart failure) at one year was explored. The two groups were comprised of patients of similar age, with similar cardiac index, pulmonary resistance, capacitance and NT-proBNP levels ( p > 0.10). There was no difference in baseline right ventricular dimension, function or load-adaptability indices. At one year, eight (36.4%) SSc-PAH patients had experienced clinical worsening (eight hospitalizations and two deaths) versus one hospitalization in the IPAH group. Load adaptation at one year in survivors was not worse in SSc-PAH ( p > 0.33). Patients with IPAH responded better to therapy than SSc-PAH in terms of reduction of right ventricular areas at one year ( p < 0.05). Right ventricular load-adaptability echocardiographic indices do not appear to capture the increased risk of negative outcomes at one year associated with SSc-PAH.

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Resistin-like molecule-beta in scleroderma-associated pulmonary hypertension.

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Resistin-like molecule-beta in scleroderma-associated pulmonary hypertension.

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