Pulmonary arterial hypertension (PAH) is a complex, multifactorial disease characterised by endothelial cells (EC) dysfunction and subsequent uncontrolled proliferation of vascular smooth muscle cells (VSMC), leading to a progressive increase in pulmonary vascular resistance and ultimately right heart failure. PAH is frequently associated with connective tissue diseases (CTD). The most common cause of CTD associated PAH is Systemic Sclerosis or Scleroderma (SSc), an autoimmune condition characterised by tissue fibrosis and endothelial cell dysfunction. While tissue fibrosis is the hallmark of SSc, EC dysfunction is a very early pathological manifestation and it causes PAH in 40% of patients during the course of the disease.
The most important profibrotic growth factor involved in SSc is transforming growth factor (TGF)-β, however the putative link between aberrant TGF-β signalling and EC dysfunction is still not clear. Heme oxygenase 1 (HO-1) is an inducible enzyme (under hypoxia) with important antioxidant, anti-proliferative, and anti-inflammatory properties in VSMC and ECand its expression can be supressed by TGF-β.
Here we explored whether inhibitory effect of TGF-β on HO-1 expression could be the link between aberrant TGF-β signalling and the endothelial dysfunction associated with the pathogenesis of PAH.
Using immunohistochemistry we examined the expression of HO-1 in both skin and lung biopsies from healthy controls and patients with SSc. HO-1 expression was less dominant in the skin of SSc patients. By contrast, HO-1 was only detected in the infiltrated areas of SSc lung biopsies. Expression of HO-1 was assessed by western blotting (n = 4) and quantitative PCR (n = 3) in skin fibroblasts isolated from SSc patients and healthy subjects under Normoxia (control),chronic hypoxia (CH, in vitro model of PAH), TGF-β (5 ng/mL), and the combination of CH + TGF-β. Basal HO-1 expression was downregulated in SSc fibroblasts compared with healthy controls. HO-1 expression was upregulated by CH and not significantly affected by TGF-β. By contrast, TGF-β reversed the CH-dependent upregulation of HO-1 expression under CH.
Importantly our results show that aberrant TGF-β signalling within SSc is responsible for the downregulation of HO-1, and might be responsible for the endothelial dysfunction associated with the pathogenesis of PAH.
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