Endothelin-1 Levels in Scleroderma Patients: A Pilot Study

Abstract

Endothelin-1 (ET-1) is a potent endogenous vasoconstrictor, which mediates vascular wall cells proliferation, fibrosis, and inflammation through two types of ET-1 receptors (ET-A and ET-B). In our retrospective study the serum levels of ET-1 in 18 systemic sclerosis (SSc) patients with and without digital ulcers (DUs) were assessed to observe possible correlation between the levels of ET-1, the evolution of SSc, and the therapy with an ET-1 antagonist (bosentan). In all our patients, the levels of ET-1 were found higher than normal range and correlate with the severity of the disease. Furthermore we also observed that in patients without DUs the levels of ET-1 were higher and did not correlate with new DUs development. In conclusion, the levels of ET-1 in our studied patients do not correlate with the possible development of DUs. The reduction of ET-1 levels in DUs patients in therapy with bosentan confirms the efficacy of this molecule both for treatment and prevention of digital ulcers. The inhibition of ET-A receptor by its antagonist may activate the opposite ET-B receptors, with well-known function ET-1 degradation and reducing of ET-1 serum level as confirmed in our pilot study.

Current Trends in Vascular Biomarkers for Systemic Sclerosis: A Narrative Review

“…ET-1 exerts its biological activities by interacting with two different cell membrane receptors called ET receptor A (ETAR) and B (ETBR). The former is expressed by vascular smooth muscle cells and mediates vasoconstriction, while the latter is mainly expressed on ECs and mediates vasodilation [ 66 , 67 ]. Increased ET-1 levels have been demonstrated in the circulation of SSc patients [ 41 , 66 , 68 ], particularly in those with pitting scars and DUs [ 69 , 70 , 71 ].…”

“…Increased ET-1 levels have been demonstrated in the circulation of SSc patients [ 41 , 66 , 68 ], particularly in those with pitting scars and DUs [ 69 , 70 , 71 ]. However, in another pilot study, ET-1 values were demonstrated to be higher in SSc patients without DUs with respect to those with, with no association with development of new DUs [ 67 ]. Significant correlations were observed between ET-1 and single NVC measures, such as capillary number/dimension and ramified/enlarged capillaries, suggesting that this protein can be involved in the progression of SSc microvasculopathy [ 70 ].…”

Endothelin Receptor Antagonists: Status Quo and Future Perspectives for Targeted Therapy

“…In SSc patients and patients with Raynaud's phenomenon, plasma ET-1 concentrations are elevated and correlate with the severity of the disease [187][188][189][190]. In addition to its role as a biomarker of vascular disease, ET-1 itself might contribute to the fibrotic and vasculopathic aspects of SSc because it has been shown to stimulate fibroblast and smooth muscle cell proliferation as well as proinflammatory effects [191,192].…”

Potential beneficial role for endothelin in scleroderma vasculopathy: inhibition of endothelial apoptosis by type B endothelin-receptor signaling

“…Endothelin-1 (ET1) is a powerful dose-dependent vasoconstrictor that is believed to be a major contributor to vascular dysfunction and tissue fibrosis in SSc through direct effects on vessels leading to vasoconstriction, hypoxia and ischemia of tissues, and by promoting fibroblast differentiation to myofibroblast (5), leading to enhanced collagen synthesis (6). ET1 is overexpressed in SSc as illustrated by elevated circulating levels and increased tissue expression in the lungs, kidneys, liver and skin (7–8–9–10).…”