Expression of TGF-β1 and its receptor genes (TβR I, TβR II, and TβR III-betaglycan) in peripheral blood leucocytes in patients with idiopathic pulmonary arterial hypertension and Eisenmenger's syndrome

Abstract

Abstract. Idiopathic pulmonary arterial hypertension (IPAH)is characterized by smooth muscle cell, endothelial cell, and fibroblast hypertrophy and an increase in extracellular matrix volume in pulmonary precapillary arterioles. These features lead to a gradual increase of pulmonary vascular resistance, right-heart failure, and premature death. Bone morphogenetic protein receptor type 2 (BMPR-2) gene mutations have been identified to cause IPAH. BMPR-2 receptor mutation results in BMP signalling pathway termination and leads to disturbed growth and differentiation of pulmonary circulation cells. Transforming growth factor (TGF)-ß1 inhibits the migration and proliferation of endothelial and smooth muscle cells, and stimulates their differentiation, thus it has antiinflammatory and immunosuppressive properties, inhibiting vascular remodeling and is responsible for extracellular matrix production. The aim of this study was to analyse the profile of TGF-ß1 and the expression of its receptor (TßR I, TßR II and TßR III-betaglycan) genes in IPAH and in secondary forms of pulmonary arterial hypertension [Eisenmenger's syndrome (ES) patients]. Twenty-one patients with IPAH (2 men), 12 ES patients, and 10 healthy controls were enrolled in the study. QRT-PCR analysis of the transcriptive activity of TGF-ß1 and its receptor genes was performed with each patient. There were differences in receptor gene expression among the patient groups. The highest expression was observed in Eisenmenger syndrome patients (approximately 5-to 8-fold increase). There was a negative correlation between the gene expression of TGF-ß1 and that of its receptors, and a positive correlation between TßR II and TßR III in healthy controls. In IPAH patients a positive correlation between TGF-ß1 and TßR I was found. There was a difference in expression of TGF-ß1/receptor gene ratios and expression of receptor gene ratios between the examined groups. The differences in expression between IPAH and ES patients might suggest the role of these cytokines in IPAH pathogenesis. A disturbed proportion of expression of TGF-ß1 and receptor genes in IPAH patients might be one of the pathogenetic factors of the disease.

Transforming Growth Factor-Beta (TGF-β) Signaling in Paravertebral Muscles in Juvenile and Adolescent Idiopathic Scoliosis

“…A standard curve was constructed for standards of ACTB (TaqMan DNA Template Reagents Kit, Applied Biosystems) and mRNA abundance in all tissue specimens was expressed as mRNA copy number per 1 μ g of total RNA. Details of the qRT-PCR method and the sequence of PCR primers were described in previous studies [ 49 , 50 ].…”

TGF-β and BMPR2 Signaling in PAH: Two Black Sheep in One Family

“…TGF-β-single nucleotide polymorphisms (SNP) on top of heterozygous BMPR2 mutation modulate the age of diagnosis and penetrance of familial PAH [ 45 ]. Other circulating ligands, such as activins and GDFs, are increased in PAH, as well, possibly stimulating cell growth and thereby contributing to pulmonary vascular remodeling [ 18 , 19 , 31 , 32 , 33 , 38 ]. The different animal models for pulmonary hypertension (PH) confirm the human pathology harboring more TGF-β and activins in the serum, pulmonary arteries and the RV in hypoxia or monocrotaline (MCT)-induced PH in rats [ 12 , 22 , 23 , 26 ].…”

Activin-Like Kinase 5 (ALK5) Mediates Abnormal Proliferation of Vascular Smooth Muscle Cells from Patients with Familial Pulmonary Arterial Hypertension and Is Involved in the Progression of Experimental Pulmonary Arterial Hypertension Induced by Monocrotaline

“…4 Furthermore, analysis of the expression levels of TGF-␤1, ALK5 and transforming growth factor-␤ receptor II (TGF-␤RII) in leukocytes from patients with iPAH also reveals that the ratio of ALK5 expression to TGF-␤RII is significantly higher in iPAH patients compared with normal controls, pointing toward an imbalance in expression patterns of components of the TGF-␤ pathway in circulating immune cells. 5 Taken together, this evidence suggests that abnormal TGF-␤/ ALK5 signaling may be important in mediating the development and progression of iPAH.…”