ABSTRACT
Aim To determine the feasibility of transforming growth factor-a ( TGF-a ) as a diagnostic bio-marker for systemic-to-pulmonary shunts induced pulmonary arterial hypertension ( PAH ). Methods Systemic-to-pulmonary shunts induced PAH was built by combined surgery ( right pulmonary artery was ligated and a cervical shunt was established one week later). A total of 49 patients with congenital heart diseases were recruited, including 24 congenital heart disease patients without PAH(CHD) and 25 congenital heart disease patients with pulmonary arterial hypertension (CIID-PAH). Moreover, 20 healthy volunteers matched by age and sex were also included. Enzyme linked immunosorbent assay (EL1SA) was used to test TGF-a concentrations in plasma of systemic-to-pulmonary shunts induced PAH rats and CHD-PAH patients. Results ELISA results showed that TGF-a levels in plasma of systemic-to-pulmonary shunts induced PAH rats were significantly higher than those of sham operated group. Spearman correlation analysis showed that plasma TGF-a concentrations were positively associated with right ventricular systolic pressure, pulmonary arterial systolic pressure, mean pulmonary arterial pressure and right ventricular hypertrophy index. The plasma concentration of TGF-a in CHD-PAH patients was much higher than that of CHD patients and healthy vol- unteers ( CON); however, there was no significant difference between CHD group and CON group; Using 314 ng • L"1 as cutoff value of TGF-a for the diagnosis of CHD-PAH, the sensitivity, specificity and area under the cure was 0. 760, 0. 750 and 0. 895, respectively. Conclusions Plasma concentration of TGF-a increases with the progression of systemic-to-pulmonary shunt induced PAH; the level of TGF-a in plasma may be a potential biomarker for the diagnosis of systemic- to-pulmonary shunt induced PAII.
ABSTRACT
Gap junction connexin-43 (Cx43) molecules are responsible for electrical impulse conduction in the heart and are affected by transforming growth factor-â (TGF-â). This cytokine increases during Trypanosoma cruzi infection, modulating fibrosis and the parasite cell cycle. We studied Cx43 expression in cardiomyocytes exposed or not to TGF-â T. cruzi, or SB-431542, an inhibitor of TGF-â receptor type I (ALK-5). Cx43 expression was also examined in hearts with dilated cardiopathy from chronic Chagas disease patients, in which TGF-â signalling had been shown previously to be highly activated. We demonstrated that TGF-â treatment induced disorganised gap junctions in non-infected cardiomyocytes, leading to a punctate, diffuse and non-uniform Cx43 staining. A similar pattern was detected in T. cruzi-infected cardiomyocytes concomitant with high TGF-â secretion. Both results were reversed if the cells were incubated with SB-431542. Similar tests were performed using human chronic chagasic patients and we confirmed a down-regulation of Cx43 expression, an altered distribution of plaques in the heart and a significant reduction in the number and length of Cx43 plaques, which correlated negatively with cardiomegaly. We conclude that elevated TGF-â levels during T. cruzi infection promote heart fibrosis and disorganise gap junctions, possibly contributing to abnormal impulse conduction and arrhythmia that characterise severe cardiopathy in Chagas disease.
Subject(s)
Adult , Animals , Female , Humans , Male , Mice , Middle Aged , Benzamides/therapeutic use , Chagas Disease/metabolism , /metabolism , Dioxoles/therapeutic use , Gap Junctions/metabolism , Myocytes, Cardiac/chemistry , Receptors, Transforming Growth Factor beta/antagonists & inhibitors , Transforming Growth Factor beta/therapeutic use , Chagas Disease/drug therapy , Fluorescent Antibody Technique , Gap Junctions/drug effects , Immunohistochemistry , Microscopy, Confocal , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolismABSTRACT
OBJECTIVE: We studied the expression of epidermal growh factor(EGF) and transforming growth factor(TGF)-a and epidermal growth factor receptor(EGFR) in human trophoblast and decidua at the first and third trimester. METHODS: To confirm the expression of EGF, TGF-a and EGFR immunohisochemically in human trophoblast and decidua, we used monoclonal antibodies to EGF, TGF-a and EGFR. RESULTS: Immunohistochemical stainings using anti-EGF, anti-TGF- a and anti-EGFR antibodies showed a specific stainings in human trophoblast and decidua at the first and third trimester. The staining intensity of EGF in the trophoblast was light to moderate at the first trimester and moderate at the third trimester, and that in the decidua was light to moderate at the first trimester and light at the third trimester. The patterns of expression of TGF- a in the trophoblast and decidua were similar to that seen with EGF in the trophoblast and that of EGFR in trophoblast and decidua were similar to that seen with EGF in decidua. CONCLUSION: These findings suggest that EGF, TGF-a and EGFR may play an important role in human trophoblast and decidua during gestation.