Cystathionine γ-Lyase Protects against Renal Ischemia/Reperfusion by Modulating Oxidative Stress

Bos, Eelke M.; Wang, Rui; Snijder, Pauline M.; Boersema, Miriam; Damman, Jeffrey; Fu, Ming; Moser, Jill; Hillebrands, Jan-Luuk; Ploeg, Rutger J.; Yang, Guangdong; Leuvenink, Henri G. D.; Goor, Harry van

doi:10.1681/asn.2012030268

Cited by 170 publications

(167 citation statements)

References 40 publications

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“…Previously, it was demonstrated that CSE deficiency is linked to increased levels of oxidative stress (42). As a readout for oxidative stress, we used OxyBlot analysis as previously described (43).…”

Section: Overexpression Of Cse Reduces Levels Of Oxidative Damage Of mentioning

confidence: 99%

Overexpression of Cystathionine γ-Lyase Suppresses Detrimental Effects of Spinocerebellar Ataxia Type 3

Snijder

Baratashvili

Grzeschik

et al. 2015

Mol Med

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Spinocerebellar ataxia type 3 (SCA3) is a polyglutamine (polyQ) disorder caused by a CAG repeat expansion in the ataxin-3 (ATXN3) gene resulting in toxic protein aggregation. Inflammation and oxidative stress are considered secondary factors contributing to the progression of this neurodegenerative disease. There is no cure that halts or reverses the progressive neurodegeneration of SCA3. Here we show that overexpression of cystathionine γ-lyase, a central enzyme in cysteine metabolism, is protective in a Drosophila model for SCA3. SCA3 flies show eye degeneration, increased oxidative stress, insoluble protein aggregates, reduced levels of protein persulfidation and increased activation of the innate immune response. Overexpression of Drosophila cystathionine γ-lyase restores protein persulfidation, decreases oxidative stress, dampens the immune response and improves SCA3-associated tissue degeneration. Levels of insoluble protein aggregates are not altered; therefore, the data implicate a modifying role of cystathionine γ-lyase in ameliorating the downstream consequence of protein aggregation leading to protection against SCA3-induced tissue degeneration. The cystathionine γ-lyase expression is decreased in affected brain tissue of SCA3 patients, suggesting that enhancers of cystathionine γ-lyase expression or activity are attractive candidates for future therapies.

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Section: Overexpression Of Cse Reduces Levels Of Oxidative Damage Of mentioning

confidence: 99%

Overexpression of Cystathionine γ-Lyase Suppresses Detrimental Effects of Spinocerebellar Ataxia Type 3

Snijder

Baratashvili

Grzeschik

et al. 2015

Mol Med

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“…[28][29][30][31] The proangiogenic effect of H 2 S was first described by Cai et al, who showed that an exogenously administrated H 2 S donor (sodium hydrosulfide [NaHS]) promoted proliferation, migration, and tube-like structure formation in endothelial cells in vitro. 32 In vivo, it was demonstrated that H 2 S is a proangiogenic factor in a model of hind limb ischemia.…”

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confidence: 99%

Hydrogen Sulfide Attenuates sFlt1-Induced Hypertension and Renal Damage by Upregulating Vascular Endothelial Growth Factor

Holwerda¹,

Burke²,

Faas³

et al. 2014

Journal of the American Society of Nephrology

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Soluble fms-like tyrosine kinase 1 (sFlt1), a circulating antiangiogenic protein, is elevated in kidney diseases and contributes to the development of preeclampsia. Hydrogen sulfide is a vasorelaxant and proangiogenic gas with therapeutic potential in several diseases. Therefore, we evaluated the potential therapeutic effect and mechanisms of action of hydrogen sulfide in an animal model of sFlt1-induced hypertension, proteinuria, and glomerular endotheliosis created by adenovirus-mediated overexpression of sFlt1 in Sprague-Dawley rats. We injected sFlt1-overexpressing animals intraperitoneally with the hydrogen sulfide-donor sodium hydrosulfide (NaHS) (50 mmol/kg, twice daily) or vehicle (n=7 per group). Treatment with NaHS for 8 days significantly reduced sFlt1-induced hypertension, proteinuria, and glomerular endotheliosis. Measurement of plasma protein concentrations with ELISA revealed a reduction of free plasma sFlt1 and an increase of free plasma vascular endothelial growth factor (VEGF) after treatment with NaHS. Renal VEGF-A mRNA expression increased significantly with NaHS treatment. In vitro, NaHS was proangiogenic in an endothelial tube assay and attenuated the antiangiogenic effects of sFlt1. Stimulation of podocytes with NaHS resulted in both short-term VEGF release (120 minutes) and upregulation of VEGF-A mRNA levels (24 hours). Furthermore, pretreatment of mesenteric vessels with a VEGF receptor 2-neutralizing antibody significantly attenuated NaHS-induced vasodilation. These results suggest that hydrogen sulfide ameliorates sFlt1-induced hypertension, proteinuria, and glomerular endotheliosis in rats by increasing VEGF expression. Further studies are warranted to evaluate the role of hydrogen sulfide as a novel therapeutic agent for vascular disorders such as preeclampsia.

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“…H 2 S protects the luminal surface of blood vessel from oxidative stress caused by ischemia/reperfusion injury, as well as from development of atherosclerotic lesions, [28,122].…”

Section: The Roles Of H 2 S and No In Oxidative Stressmentioning

confidence: 99%

“…Moreover, CSE overexpression reduces the amount of reactive oxygen species (ROS) produced during stress in renal tissues [122]. NaHS has been shown to mitigate the methionine-induced production of free radicals in brain ECs (bEnd3) and to enhance the inhibitory action of reduced glutathione (GSH), catalase (CAT), superoxide dismutase (SOD) and L-NAME on ROS production [123].…”

Section: The Roles Of H 2 S and No In Oxidative Stressmentioning

confidence: 99%

“…Here we briefly reviewed the roles of H 2 S and NO in regulation of different EC functions, and their precise role in diseases related to EC dysfunction. H 2 S rescues CSE-KO mice from the injury and mortality associated with renal ischemia.Moreover, CSE overexpression reduces the amount of reactive oxygen species (ROS) produced during stress in renal tissues [122]. NaHS has been shown to mitigate the methionine-induced production of free radicals in brain ECs (bEnd3) and to enhance the inhibitory action of reduced glutathione (GSH), catalase (CAT), superoxide dismutase (SOD) and L-NAME on ROS …”

mentioning

confidence: 99%

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Hydrogen Sulfide and Endothelial Dysfunction: Relationship with Nitric Oxide

Altaany¹,

Moccia²,

Munaron³

et al. 2014

CMC

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The endothelium is a cellular monolayer that lines the inner surface of blood vessels and plays a central role in the maintenance of cardiovascular homeostasis by controlling platelet aggregation, vascular tone, blood fluidity and fibrinolysis, adhesion and transmigration of inflammatory cells, and angiogenesis. Endothelial dysfunctions are associated with various cardiovascular diseases, including atherosclerosis, hypertension, myocardial infarction, and cardiovascular complications of diabetes. Numerous studies have established the antiinflammatory, anti-apoptotic, and anti-oxidant effects of hydrogen sulfide (H 2 S), the latest member to join the gasotransmitter family along with nitric oxide and carbon monoxide, on vascular endothelium. In addition, H 2 S may prime endothelial cells (ECs) toward angiogenesis and contribute to wound healing, aside to its well-known ability to relax vascular smooth muscle cells (VSMCs), thereby reducing blood pressure. Finally, H 2 S may inhibit VSMC proliferation and platelet aggregation. Consistently, a deficit in H 2 S homeostasis is involved in the pathogenesis of atherosclerosis and of hyperglycaemic endothelial injury. Therefore, the application of H 2 S-releasing drugs or using gene therapy to increase endogenous H 2 S level may help restore endothelial function and antagonize the progression of cardiovascular diseases. The present article reviews recent studies on the role of H 2 S in endothelial homeostasis, under both physiological and pathological conditions, and its putative therapeutic applications. Endothelial structure and functionThe endothelium lines the luminal surface of the entire vascular tree and the cardiac chambers, where it is termed endocardium. As a consequence, the endothelium presents a rather broad extension (300 to 1000 m 2 ) and weight (1.5 kg), achieving sizes comparable to other vital organs of the human body [1,2]. The endothelium can, therefore, be regarded as a real "organ spread across the organism" [3] and, as such, not only it is important for the regulation of local tissue functions, but also for maintaining the whole organism homeostasis [4]. Vascular endothelial cells (ECs) possess a polarized architecture: their luminal membrane is directly exposed to hematic constituents and circulating cells, while the basolateral surface is separated from surrounding tissues by a glycoprotein basement membrane -the sub-endothelial basement -which is formed by fibronectin, laminin, and collagen and is secreted by ECs themselves [2].Heterogeneity is, however, the hallmark of endothelium. ECs differ in morphology, function, and gene expression profile, so that even neighbouring cells from the same organ and blood vessel type exhibit distinct features [4]. For instance, vascular ECs may vary in size, shape, thickness and position of the nucleus. Albeit oriented along direction of blood flow, to attenuate the impact of shear stress forces on the vascular wall, microvascular ECs are rather thin (0.1 µm) and spindle-like, whilst their macrovascul...

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Cystathionine γ-Lyase Protects against Renal Ischemia/Reperfusion by Modulating Oxidative Stress

Cited by 170 publications

References 40 publications

Overexpression of Cystathionine γ-Lyase Suppresses Detrimental Effects of Spinocerebellar Ataxia Type 3

Overexpression of Cystathionine γ-Lyase Suppresses Detrimental Effects of Spinocerebellar Ataxia Type 3

Hydrogen Sulfide Attenuates sFlt1-Induced Hypertension and Renal Damage by Upregulating Vascular Endothelial Growth Factor

Hydrogen Sulfide and Endothelial Dysfunction: Relationship with Nitric Oxide

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