Decreased Serum Levels of SIRT1 and SIRT3 Correlate with Severity of Skin and Lung Fibrosis and Peripheral Microvasculopathy in Systemic Sclerosis

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.

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

“…Among the seven SIRT isotypes (SIRT1–SIRT7), SIRT1, SIRT6, and SIRT7 are mainly nuclear, while others are mostly cytoplasmic (SIRT2) or mitochondrial (SIRT3, SIRT4, and SIRT5) [ 125 ]. Since SIRT1 and SIRT3 have recently emerged as noteworthy players in regulating angiogenesis [ 126 , 127 , 128 ], our group recently conducted a study in order to evaluate the association of these circulating deacetylases with the severity of SSc-related peripheral microvascular damage [ 129 ]. In this study, we provided the evidence that serum levels of both SIRT1 and SIRT3 are decreased in SSc patients compared to healthy controls and that their decrease correlated with the severity of NVC abnormalities, with SIRT3 also being related to the occurrence of ischemic DUs.…”

“…In this study, we provided the evidence that serum levels of both SIRT1 and SIRT3 are decreased in SSc patients compared to healthy controls and that their decrease correlated with the severity of NVC abnormalities, with SIRT3 also being related to the occurrence of ischemic DUs. Of note, via logistic regression analysis, we further demonstrated that, between the two SIRTs, SIRT3 may better mirror peripheral vascular disease activity and severity [ 129 ].…”

The role of sirtuins in dermal fibroblast function

“…Wei et al showed that the pro-fibrotic effect of TGFβ was diminished by activation of SIRT1, while Zerr et al showed downregulate of SIRT1 diminished TGFβ/Smad signaling ( 117 , 118 ). More recently, Manetti et al measured circulating SIRT1 and SIRT3 levels in a cohort of SSc patients and healthy controls, and found significantly decreased serum levels of both SIRT1 and SIRT3, as well as an association with the extent of skin involvement ( 127 ). Further, Akamata et al revealed that SIRT3 activity was significantly reduced in SSc biopsies and that its activation can augment TGFβ signaling and the fibrotic response ( 123 ).…”

“…Finally, SIRT7 may inhibit fibroblast migration. both SIRT1 and SIRT3, as well as an association with the extent of skin involvement (127). Further, Akamata et al revealed that SIRT3 activity was significantly reduced in SSc biopsies and that its activation can augment TGFβ signaling and the fibrotic response (123).…”

Sirtuins and Hypoxia in EMT Control

“…A link between unresolved inflammation and features of EMT during fibrogenesis in hypertrophic scar tissue has been suggested, with an increased expression of the mesenchymal marker FSP1 observed along with the EMT proteins SNAIL2 and TWIST [93]. Interestingly, decreased SIRT1 and SIRT3 serum levels have been measured in scleroderma patients compared to controls [94]. Moreover, SIRT1 has been shown to reduce skin fibrosis through TGFβ/Smad3 inhibition [95].…”