Sirtuin 7 is decreased in pulmonary fibrosis and regulates the fibrotic phenotype of lung fibroblasts

Abstract

Pulmonary fibrosis is a severe condition with no cure and limited therapeutic options. A better understanding of its pathophysiology is needed. Recent studies have suggested that pulmonary fibrosis may be driven by accelerated aging-related mechanisms. Sirtuins (SIRTs), particularly SIRT1, SIRT3, and SIRT6, are well-known mediators of aging; however, limited data exist on the contribution of sirtuins to lung fibrosis. We assessed the mRNA and protein levels of all seven known sirtuins in primary lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-associated interstitial lung disease (SSc-ILD) in comparison with lung fibroblasts from healthy controls. These unbiased tests revealed a tendency for all sirtuins to be expressed at lower levels in fibroblasts from patients compared with controls, but the greatest decrease was observed with SIRT7. Similarly, SIRT7 was decreased in lung tissues of bleomycin-challenged mice. Inhibition of SIRT7 with siRNA in cultured lung fibroblasts resulted in an increase in collagen and α-smooth muscle actin (α-SMA). Reciprocally, overexpression of SIRT7 resulted in lower basal and TGF-β-induced levels of COL1A1, COL1A2, COL3A1, and α-SMA mRNAs, as well as collagen and α-SMA proteins. Induced changes in SIRT7 had no effect on endogenous TGF-β mRNA levels or latent TGF-β activation, but overexpression of SIRT7 reduced the levels of Smad3 mRNA and protein. In conclusion, the decline in SIRT7 in lung fibroblasts has a profibrotic effect, which is mediated by changes in Smad3 levels.

Sirtuins and Accelerated Aging in Scleroderma

“…At the time of preparation of this review, there are only a handful of reports that have directly addressed the involvement of SIRTs in SSc [99–102, 111, 112, 121]. Most have focused on SIRT1 [99–102], but literature is emerging on the role of SIRT3 [111, 112] and SIRT7 [121].…”

“…Most have focused on SIRT1 [99–102], but literature is emerging on the role of SIRT3 [111, 112] and SIRT7 [121]. The prevailing message from these studies is that SIRTs play an antifibrotic role in SSc and engage in mutual negative feedback with the TGF-β signaling pathway, the most potent known driver of fibrosis.…”

“…The majority of studies have shown decreased SIRT expression in tissues and fibroblasts from patients with SSc compared to controls and in experimental fibrosis in mice [99–101, 111, 112, 121]. Decreases in SIRT1 were observed in fibrotic skin and dermal fibroblasts from patients with SSc [100, 101] and in peripheral blood mononuclear cells of SSc patients with pulmonary fibrosis compared to patients without fibrosis [99].…”

“…Reciprocal increases in acetylated MnSOD, a known target of SIRT3 deacetylase activity and marker of reduced SIRT3 activity, have also been shown in skin and lung of SSc patients compared to healthy controls [111] and type 2 alveolar epithelial cells (AT2) in explanted IPF lung tissues [114]. A recent study assessed the expression of all seven SIRTs in lung tissues and fibroblasts from patients with SSc and IPF [121]. The authors found a tendency for all seven SIRTs to be decreased in patients with fibrosis, with a particularly notable decrease in SIRT7.…”

“…The authors found a tendency for all seven SIRTs to be decreased in patients with fibrosis, with a particularly notable decrease in SIRT7. Although the specific mechanism for this decline is unknown, several studies have demonstrated downregulation of SIRT mRNA and protein [101, 111–113, 121] levels by TGF-β in human dermal and lung fibroblasts [101, 111–113, 121] and murine skin and lung tissues [101, 112]. Decreased SIRT expression in SSc may be a marker both of aging, given the known decline of SIRTs with age, and TGF-β-driven fibrosis.…”