A critical life-supporting role for cystathionine γ-lyase in the absence of dietary cysteine supply

Mani, Sarathi; Yang, Guangdong; Wang, Rui

doi:10.1016/j.freeradbiomed.2011.01.038

Cited by 77 publications

(75 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although the hyperhomocysteinemia (HHcy) in CSE-deficient mice observed in the current study is consistent with previous reports (16), this is the first report of increase of thiosulfate levels induced by CSE deficiency. Increased thiosulfate levels in CSE-deficient mice may be due to the markedly upregulated SQR expression levels in the mutants, which may accelerate conversion of persulfide to thiosulfate.…”

Section: Discussionsupporting

confidence: 93%

See 1 more Smart Citation

Cystathionine γ-Lyase Deficiency Protects Mice from Galactosamine/Lipopolysaccharide-Induced Acute Liver Failure

Shirozu

Tokuda

Marutani

et al. 2014

Antioxidants & Redox Signaling

Self Cite

View full text Add to dashboard Cite

Aims: Acute liver failure (ALF) is a fatal syndrome attributed to massive hepatocyte death. Hydrogen sulfide (H 2 S) has been reported to exert cytoprotective or cytotoxic effects. Here, we examined the role of cystathionine clyase (CSE, an enzyme produces H 2 S) in ALF induced by D-Galactosamine (GalN) and lipopolysaccharide (LPS). Results: Wild-type (WT) mice exhibited high mortality rate, prominent liver injury, and increased plasma alanine aminotransferase levels after GalN/LPS challenge. Congenital deficiency or chemical inhibition of CSE by DLpropargylglycine attenuated GalN/LPS-induced liver injury. CSE deficiency markedly improved survival rate and attenuated GalN/LPS-induced upregulation of inflammatory cytokines and activation of caspase 3 and poly (ADP-ribose) polymerase (PARP) in the liver. CSE deficiency protected primary hepatocytes from GalN/tumor necrosis factor-a (TNF-a)-induced cell death without affecting LPS-induced TNF-a production from primary peritoneal macrophages. Beneficial effects of CSE deficiency were associated with markedly elevated homocysteine and thiosulfate levels, upregulation of NF-E2 p45-related factor 2 (Nrf2) and antioxidant proteins, activation of Akt-dependent anti-apoptotic signaling, and inhibition of GalN/LPS-induced JNK phosphorylation in the liver. Finally, administration of sodium thiosulfate (STS) attenuated GalN/LPS-induced liver injury via activation of Aktand Nrf2-dependent signaling and inhibition of GalN/LPS-induced JNK phosphorylation in WT mice. Innovation: These results suggest that inhibition of CSE or administration of STS prevents acute inflammatory liver failure by augmenting thiosulfate levels and upregulating antioxidant and anti-apoptotic defense in the liver. Conclusion: Congenital deficiency or chemical inhibition of CSE increases thiosulfate levels in the liver and prevents ALF at least in part by augmentation of antioxidant and anti-apoptotic mechanisms. Antioxid. Redox Signal. 20,[204][205][206][207][208][209][210][211][212][213][214][215][216]

show abstract

Section: Discussionsupporting

confidence: 93%

“…We confirmed that free plasma sulfide levels are lower in CSE-deficient mice than in WT mice at baseline, as previously reported (16,33). However, plasma sulfide levels did not differ between two genotypes after GalN/LPS challenge.…”

Section: Discussionsupporting

confidence: 91%

Cystathionine γ-Lyase Deficiency Protects Mice from Galactosamine/Lipopolysaccharide-Induced Acute Liver Failure

Shirozu

Tokuda

Marutani

et al. 2014

Antioxidants & Redox Signaling

Self Cite

View full text Add to dashboard Cite

show abstract

“…15 Plasma homocysteine levels of CSE-KO mice fed with the control or atherogenic diet were 18 times higher than those of age-matched WT mice, which is in line with our previous study. 20 Zhou et al 35 reported that dietinduced hyperhomocysteinemia does not independently cause atherosclerosis in C57BL/6J mice. In our study, no significant change was observed in plasma hyperhomocysteinemia levels after NaHS treatment of CSE-KO mice.…”

Section: Discussionmentioning

confidence: 99%

“…Both diets were matched for energy content, and mice were allowed free access to food and water for 12 weeks. During the 12 weeks of experimental dietary feeding, all mice were supplemented with dl-cysteine in the drinking water (1 mg/mL) according to Mani et al 20 H 2 S supplement experiments were performed by intraperitoneal injection of NaHS (39 µmol/kg body weight) with phosphate-buffered saline (PBS) injection in other mice as the control. In the antihypertensive drug-treated group, mice were treated with hydralazine in drinking water at 250 mg/L for 12 weeks.…”

Section: Animals and Dietmentioning

confidence: 99%

Decreased Endogenous Production of Hydrogen Sulfide Accelerates Atherosclerosis

et al. 2013

Self Cite

View full text Add to dashboard Cite

A therosclerosis is characterized with plaque formation in large and medium-sized blood vessels. The stiffened and narrowed blood vessels limit blood circulation and increase plaque thrombogenicity, which threatens the functionality of vital organs such as the heart and brain. [1][2][3] The development of atherosclerosis is a chronic pathological process. Vascular remodeling and inflammation, endothelial dysfunction, smooth muscle cell (SMC) proliferation and migration, and accumulation of cholesterol-rich lipoproteins in blood vessel walls are early events of atherogenesis, resulting in the recruitment of circulating monocytes, their adhesion to endothelium via adhesion molecules, and their differentiation into macrophages. 4 The subendothelial accumulation of cholesterol-laden macrophages is morphologically recognized as foam cells. In humans, these fatty streaks can progress to more advanced lesions characterized by a lipid-rich necrotic core and a fibrous cap consisting of SMCs and collagen.Lesion rupture can result from the decreased viability of SMCs that is necessary for collagen production and for the structural integrity of the fibrous cap following the release of matrix metalloproteinases from apoptotic macrophages. 4-8 Editorial see p 2472 Clinical Perspective on p 2534Hydrogen sulfide (H 2 S), a member of the gasotransmitter family, plays a number of important physiological roles within the body, including protection against cardiovascular disease.9-11 Cystathionine γ-lyase (CSE) endogenously produces H 2 S in the cardiovascular system, 12,13 and the deficiency of CSE in mice leads to decreased endogenous H 2 S level, age-dependent increase in blood pressure, impaired endothelium-dependent vasorelaxation, and accumulation of homocysteine in the blood.14 Administration of NaHS (a H 2 S donor) protects rat aortic SMCs from the cytotoxicity caused Background-Cystathionine γ-lyase (CSE) produces hydrogen sulfide (H 2 S) in the cardiovascular system. The deficiency of CSE in mice leads to a decreased endogenous H 2 S level, an age-dependent increase in blood pressure, and impaired endothelium-dependent vasorelaxation. To date, there is no direct evidence for a causative role of altered metabolism of endogenous H 2 S in atherosclerosis development. Methods and Results-Six-week-old CSE gene knockout and wild-type mice were fed with either a control chow or atherogenic paigen-type diet for 12 weeks. Plasma lipid profile and homocysteine levels, blood pressure, oxidative stress, atherosclerotic lesion size in the aortic roots, cell proliferation, and adhesion molecule expression were then analyzed. CSE-knockout mice fed with atherogenic diet developed early fatty streak lesions in the aortic root, elevated plasma levels of cholesterol and low-density lipoprotein cholesterol, hyperhomocysteinemia, increased lesional oxidative stress and adhesion molecule expression, and enhanced aortic intimal proliferation. Treatment of CSE-knockout mice with NaHS, but not N-acetylcysteine or ezetimibe, inhibited the acceler...

show abstract

“…Biochemically, cystathioninuria is usually associated with developmental delay [Harris et al, 1959], diabetes [Mani et al, 2011;Mongeau et al, 1966;Perry et al, 1967], mental retardation, fatty liver, and cystic fibrosis [Endres and Wuttge, 1978]. Cystathioninuria is enzymatically correlated with homocystinuria [Kraus et al, 2009], based on the acute deficiencies of vitamins B 6 and B 12 , as well as folic acid.…”

Section: Introductionmentioning

confidence: 99%

Biochemical and Pharmacokinetic Properties of PEGylated Cystathionine γ-Lyase from <b><i>Aspergillus carneus</i></b> KF723837

Elsayed¹,

Yassin²,

Khalaf³

et al. 2015

Microb Physiol

View full text Add to dashboard Cite

Cystathionine γ-lyase (CGL) was purified to its electrophoretic homogeneity from Aspergillus carneus by various chromatographic approaches. The purified enzyme has four identical subunits of 52 kDa based on SDS and native PAGE analyses. To improve its structural stability, purified CGL was modified by covalent binding to polyethylene glycol moieties. The specific activity of free-CGL and PEG-CGL was 59.71 and 48.71 U/mg, respectively, with a PEGylation yield of 81.5 and 70.7% modification of surface ε-amino groups. Free- and modified CGL have the same pattern of pH stability (8.0-9.0). At 50°C, the thermal stability [half-life time (T_1/2)] of PEG-CGL was increased by 40% in comparison to free-CGL. The activity of CGL was completely inhibited by hydroxylamine and Hg⁺², with no effect by EDTA. Free-CGL (0.04 mM^-1s^-1) and PEG-CGL (0.03 mM^-1s^-1) have a similar catalytic efficiency to L-cystathionine as a substrate. The inhibition constant values of propargylglycine were 0.31 and 0.52 µM for the free- and PEG-CGL, respectively. By in vitro proteolysis, PEG-CGL retains >50% of its initial activity compared to <10% of the free-CGL for acid protease for 30 min. From in vivo pharmacokinetics in New Zealand white rabbits, the T_1/2 was 19.1 and 28.9 h for the Holo free-CGL and PEG-CGL, respectively, ensuring the role of PEGylation on shielding the CGL surface from proteolytic attack, reducing its antigenicity, and stabilizing its internal Schiff base. By external infusion of pyridoxal 5′-phosphate (10 µM), the T_1/2 of free- and PEG-CGL was prolonged to 24 and 33 h, respectively, so dissociation of pyridoxal 5′-phosphate was one of the main causes of loss of enzyme activity. The biochemical and hematological responses of rabbits to free- and PEG-CGL were assessed, with relative similarity to the negative control, confirming the nil toxicity of enzymes. The titer of IgG was duplicated in response to free- versus PEG-CGL after 45 days. To the best of our knowledge, this is the first report concerned with purification and PEGylation of CGL from fungi, with higher affinity for L-cystathionine. With further molecular studies, CGL will be a promising enzyme against various cardiovascular diseases and antioxidant deficiency, as well as for generation of a neurotransmitter (H₂S).

show abstract

A critical life-supporting role for cystathionine γ-lyase in the absence of dietary cysteine supply

Cited by 77 publications

References 42 publications

Cystathionine γ-Lyase Deficiency Protects Mice from Galactosamine/Lipopolysaccharide-Induced Acute Liver Failure

Cystathionine γ-Lyase Deficiency Protects Mice from Galactosamine/Lipopolysaccharide-Induced Acute Liver Failure

Decreased Endogenous Production of Hydrogen Sulfide Accelerates Atherosclerosis

Biochemical and Pharmacokinetic Properties of PEGylated Cystathionine γ-Lyase from <b><i>Aspergillus carneus</i></b> KF723837

Contact Info

Product

Resources

About

A critical life-supporting role for cystathionine γ-lyase in the absence of dietary cysteine supply

Cited by 77 publications

References 42 publications

Cystathionine γ-Lyase Deficiency Protects Mice from Galactosamine/Lipopolysaccharide-Induced Acute Liver Failure

Cystathionine γ-Lyase Deficiency Protects Mice from Galactosamine/Lipopolysaccharide-Induced Acute Liver Failure

Decreased Endogenous Production of Hydrogen Sulfide Accelerates Atherosclerosis

Biochemical and Pharmacokinetic Properties of PEGylated Cystathionine &#947;-Lyase from <b><i>Aspergillus carneus</i></b> KF723837

Contact Info

Product

Resources

About

Biochemical and Pharmacokinetic Properties of PEGylated Cystathionine γ-Lyase from <b><i>Aspergillus carneus</i></b> KF723837