Abstract
Systemic sclerosis (SSc) is a lethal disease that is characterized by auto-immunity, vascular injury, and progressive fibrosis of multiple organ systems. Despite the fact that the exact etiology of SSc remains unknown, oxidative stress has been associated with a large range of SSc-related complications. In addition to the well-known detrimental properties of reactive oxygen species (ROS), gasotransmitters (e.g., nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H2S)) are also thought to play an important role in SSc. Accordingly, the diverse physiologic actions of NO and CO and their role in SSc have been previously studied. Recently, multiple studies have also shown the importance of the third gasotransmitter H2S in both vascular physiology and pathophysiology. Interestingly, homocysteine (which is converted into H2S through the transsulfuration pathway) is often found to be elevated in SSc patients; suggesting defects in the transsulfuration pathway. Hydrogen sulfide, which is known to have several effects, including a strong antioxidant and vasodilator effect, could potentially play a prominent role in the initiation and progression of vasculopathy. A better understanding of the actions of gasotransmitters, like H2S, in the development of SSc-related vasculopathy, could help to create early interventions to attenuate the disease course. This paper will review the role of H2S in vascular (patho-)physiology and potential disturbances in SSc. Moreover, current data from experimental animal studies will be reviewed. Lastly, we will evaluate potential interventional strategies.
Highlights
Systemic sclerosis (SSc) is a severe progressive fibrotic connective tissue disease that often affects multiple systems [1,2]
This review focuses on the role of H2S the pathogenesis of SSc-related vasculopathy in relation to its functional properties in the healthy vascular system
A current hypothesis is that both VEGF and H2S-induced endothelial cells (ECs) migration involve the same downstream pathways, and this assumption is supported by Papapetropoulos et al (2009), who reported that “VEGF-induced angiogenesis was suppressed in aortic rings of cystathionine γ-lyase (CSE)-deficient mice” [88]
Summary
Systemic sclerosis (SSc) is a severe progressive fibrotic connective tissue disease that often affects multiple systems [1,2]. The pathogenesis still remains unknown and effective disease-modifying treatment is currently unavailable. Endothelial dysfunction is a main event in the pathogenesis of SSc [7], and the vascular bed is a major target for immune-inflammatory injury. The exact etiology of SSc remains unknown, but some studies have suggested that gasotransmitters play an important role in its pathogenesis. Three main gasotransmitters have been discovered, namely, hydrogen sulfide (H2S), carbon monoxide (CO), and nitric oxide (NO) [12] As these gases perform critical roles, a deviation of their normal level may be associated with the occurrence of several diseases ranging from neurodegenerative diseases to auto-immune diseases. An assessment of the role played by H2S in SSc-related vasculopathy could lead to a better understanding of this disease, which could subsequently help to create early interventions to attenuate the disease course. We evaluate the effects of H2S-based therapeutic interventions
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