Abstract
Systemic sclerosis (SSc, scleroderma) is a severe autoimmune connective tissue disease characterized by widespread peripheral microvasculopathy, and progressive cutaneous and visceral fibrosis, leading to significant organ dysfunction. Sirtuins (SIRTs) are a family of NAD-dependent protein deacetylases with pleiotropic effects on a variety of biological processes, including metabolism, cell survival, and aging. In the last decades, increasing studies have explored the contribution of SIRTs to the pathogenesis of SSc, highlighting a significant antifibrotic effect of both SIRT1 and SIRT3. On these bases, the aim of this study was to measure circulating SIRT1 and SIRT3 levels by enzyme-linked immune-sorbent assay in a well-characterized cohort of SSc patients (n = 80) and healthy controls (n = 71), focusing on their possible association with disease clinical features, and their potential as biomarkers reflecting SSc activity and severity. Significantly decreased serum levels of both SIRT1 and SIRT3 were found in SSc patients compared to controls. In SSc, the reduction in circulating SIRT1 and SIRT3 associated with a greater extent of cutaneous fibrosis, presence of interstitial lung disease, and worse pulmonary function. Serum SIRT1 and SIRT3 decrease also correlated with the severity of nailfold microvascular damage, with SIRT3 levels being additionally related to the occurrence of digital ulcers. The levels of these two proteins showed a direct correlation with one another in the circulation of SSc patients. Of the two SIRTs, serum SIRT3 was found to better reflect disease activity and severity in a logistic regression analysis model. Our findings suggest that serum SIRT1 and SIRT3 may represent novel potential biomarkers of increased risk for a more severe, life-threatening SSc disease course.
Highlights
Systemic sclerosis (SSc, scleroderma) is a severe autoimmune disease characterized by widespread microvasculopathy, clinically manifesting with Raynaud’s phenomenon, refractory ischemic digital ulcers (DUs), pulmonary artery hypertension (PAH), and renal crisis, as well as by cutaneous and visceral fibrosis, leading to significant organ dysfunction [1–4]
When we performed receiver operator characteristics (ROC) curve analysis, we found that the area under the curve (AUC) of SIRT1 was 0.68, indicating a low diagnostic accuracy
Since, when comparing SSc subgroup medians, we found significant differences in serum levels of both SIRT1 and SIRT3 according to the cutaneous subset, the presence of interstitial lung disease (ILD), and the severity of the nailfold videocapillaroscopy (NVC) pattern, we carried out multiple logistic regression analysis combining serum SIRT1 and SIRT3 as independent variables, and one of the three abovementioned disease phenotypes as a single dependent variable each time
Summary
Systemic sclerosis (SSc, scleroderma) is a severe autoimmune disease characterized by widespread microvasculopathy, clinically manifesting with Raynaud’s phenomenon, refractory ischemic digital ulcers (DUs), pulmonary artery hypertension (PAH), and renal crisis, as well as by cutaneous and visceral fibrosis, leading to significant organ dysfunction [1–4]. Such a highly heterogeneous spectrum of pathological manifestations associates with a widely variable prognosis, with lung fibrosis that clinically manifests as interstitial lung disease (ILD) representing the principal cause of death [5–7]. Concerning SSc histopathology, skin and internal organ fibrosis is driven by profibrotic myofibroblasts, i.e., α-smooth muscle actin expressing cells whose persistent activation results in excessive synthesis and accumulation of extracellular matrix components, such as collagen and fibronectin, with consequent disrupted physiological architecture of the affected tissues [9,10]
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