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Pantethine Prevents Murine Systemic Sclerosis Through the Inhibition of Microparticle Shedding
Niloufar Kavian1, Wioleta Marut1, Amélie Servettaz2
1Université Paris Descartes, Sorbonne Paris-Cité, Institut Cochin, INSERM U1016, and Hôpital Cochin, AP-HP, Paris, France.
Objective:
Endothelial cell (EC) damage in systemic sclerosis (SSc) is reflected by the shedding of microparticles (MPs). The aim of this study was to show that inhibiting MP release using pantethine or by inactivating ATP-binding cassette transporter A1 (ABCA1) ameliorates murine SSc.
Methods:
First, the effects of pantethine on MP shedding and on basal oxidative and nitrosative stresses in ECs and fibroblasts were determined in vitro. The effects of pantethine were then tested in vivo. SSc was induced in BALB/c mice by daily intradermal injection of HOCl. Mice were simultaneously treated daily with pantethine by oral gavage.
Results:
In vitro, pantethine inhibited MP shedding from tumor necrosis factor-stimulated ECs and abrogated MP-induced oxidative and nitrosative stresses in ECs and fibroblasts. Ex vivo, pantethine also restored redox homeostasis in fibroblasts from mice with SSc. In vivo, mice with SSc displayed skin and lung fibrosis associated with increased levels of circulating MPs and markers of oxidative and endothelial stress, which were normalized by administration of pantethine or inactivation of ABCA1.
Conclusion:
Pantethine is a well-tolerated molecule that represents a potential treatment of human SSc.
Insights
Pantethine reduces microparticle release and oxidative stress in a mouse model of systemic sclerosis (SSc). This suggests pantethine may be a potential treatment for SSc by protecting against endothelial cell damage.
Area of Science:
- Vascular Biology
- Fibrotic Diseases
- Pharmacology
Background:
- Endothelial cell (EC) damage in systemic sclerosis (SSc) is indicated by microparticle (MP) shedding.
- ATP-binding cassette transporter A1 (ABCA1) plays a role in MP release.
Purpose of the Study:
- To investigate if pantethine or ABCA1 inactivation can ameliorate SSc in a murine model.
- To assess the impact of pantethine on MP shedding and oxidative stress.
Main Methods:
- In vitro studies determined pantethine's effects on MP shedding and stress in ECs and fibroblasts.
- In vivo studies involved inducing SSc in mice with HOCl and treating them with pantethine.
- ABCA1 inactivation was also tested as a therapeutic strategy.
Main Results:
- Pantethine inhibited MP shedding and reduced oxidative/nitrosative stress in vitro.
- Ex vivo, pantethine restored redox homeostasis in SSc fibroblasts.
- In vivo, pantethine and ABCA1 inactivation normalized skin/lung fibrosis, circulating MPs, and stress markers in SSc mice.
Conclusions:
- Pantethine effectively reduces MP release and associated stress in experimental SSc.
- Pantethine is well-tolerated and shows potential as a therapeutic agent for human SSc.
