Limits...
Homocysteine Triggers Inflammatory Responses in Macrophages through Inhibiting CSE-H2S Signaling via DNA Hypermethylation of CSE Promoter.

Li JJ, Li Q, Du HP, Wang YL, You SJ, Wang F, Xu XS, Cheng J, Cao YJ, Liu CF, Hu LF - Int J Mol Sci (2015)

Bottom Line: Unfortunately, Hcy-lowering strategies were found to have limited effects in reducing cardiovascular events.DNMT inhibition or knockdown reversed the decrease of CSE transcription induced by Hcy in macrophages.In sum, our findings demonstrate that Hcy may trigger inflammation through inhibiting CSE-H2S signaling, associated with increased promoter DNA methylation and transcriptional repression of cse in macrophages.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, the Second Affiliated Hospital of Soochow University, Soochow University, Suzhou 215004, China. dragonrabbit@163.com.

ABSTRACT
Hyperhomocysteinemia (HHcy) is an independent risk factor of atherosclerosis and other cardiovascular diseases. Unfortunately, Hcy-lowering strategies were found to have limited effects in reducing cardiovascular events. The underlying mechanisms remain unclear. Increasing evidence reveals a role of inflammation in the pathogenesis of HHcy. Homocysteine (Hcy) is a precursor of hydrogen sulfide (H2S), which is formed via the transsulfuration pathway catalyzed by cystathionine β-synthase and cystathionine γ-lyase (CSE) and serves as a novel modulator of inflammation. In the present study, we showed that methionine supplementation induced mild HHcy in mice, associated with the elevations of TNF-α and IL-1β in the plasma and reductions of plasma H2S level and CSE expression in the peritoneal macrophages. H2S-releasing compound GYY4137 attenuated the increases of TNF-α and IL-1β in the plasma of HHcy mice and Hcy-treated raw264.7 cells while CSE inhibitor PAG exacerbated it. Moreover, the in vitro study showed that Hcy inhibited CSE expression and H2S production in macrophages, accompanied by the increases of DNA methyltransferase (DNMT) expression and DNA hypermethylation in cse promoter region. DNMT inhibition or knockdown reversed the decrease of CSE transcription induced by Hcy in macrophages. In sum, our findings demonstrate that Hcy may trigger inflammation through inhibiting CSE-H2S signaling, associated with increased promoter DNA methylation and transcriptional repression of cse in macrophages.

No MeSH data available.


Related in: MedlinePlus

Schematic representations of mammalian homocysteine metabolism. Homocysteine metabolism is at the intersection of two main pathways: remethylation and transsulfuration pathway. Intracellular folate cycling is tightly connected to the remethylation pathway, in which methionine is activated by condensation with adenosine triphosphate (ATP) to yield the ubiquitous methyl donor, SAM, which is transformed into SAH by donating its methyl group to the substrates of methylation reactions. Subsequently, SAH gives rise to homocysteine in a reversible reaction that favors SAH over homocysteine production. The transsulfuration process is catalyzed by two vitamin B6-dependent enzymes: CBS and CSE. Hcy can be sequentially converted into cystathionine and then cysteine by CBS and CSE and subsequently results in the generation of H2S and other by-products including homoserine, pyruvate, GSH, taurine, and serine as well. MS, methionine synthase; THF, tetrahydrofolate; MTHFR, methylene tetrahydrofolatereductase; BHMT, betaine-homocysteine S-methyltransferase; DMG, dimethylglycine; SAM, S-adenosyl methionine; SAH, S-adenosylhomocysteine; CBS, cystathionine β-synthase; CSE, cystathionine γ-lyase; GSH, glutathione.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4490461&req=5

ijms-16-12560-f006: Schematic representations of mammalian homocysteine metabolism. Homocysteine metabolism is at the intersection of two main pathways: remethylation and transsulfuration pathway. Intracellular folate cycling is tightly connected to the remethylation pathway, in which methionine is activated by condensation with adenosine triphosphate (ATP) to yield the ubiquitous methyl donor, SAM, which is transformed into SAH by donating its methyl group to the substrates of methylation reactions. Subsequently, SAH gives rise to homocysteine in a reversible reaction that favors SAH over homocysteine production. The transsulfuration process is catalyzed by two vitamin B6-dependent enzymes: CBS and CSE. Hcy can be sequentially converted into cystathionine and then cysteine by CBS and CSE and subsequently results in the generation of H2S and other by-products including homoserine, pyruvate, GSH, taurine, and serine as well. MS, methionine synthase; THF, tetrahydrofolate; MTHFR, methylene tetrahydrofolatereductase; BHMT, betaine-homocysteine S-methyltransferase; DMG, dimethylglycine; SAM, S-adenosyl methionine; SAH, S-adenosylhomocysteine; CBS, cystathionine β-synthase; CSE, cystathionine γ-lyase; GSH, glutathione.

Mentions: CBS and CSE play important roles in Hcy metabolism and H2S synthesis, as summarized in Figure 6. On the one hand, Hcy can be sequentially converted into cystathionine and then cysteine by CBS and CSE, respectively. Both CBS and CSE can use cysteine as substrates for H2S synthesis. On the other hand, Hcy can be directly converted by CSE into homoserine and H2S. Therefore, it is conceivable that deficiency in either cbs or cse, or vitamin B6 may result in HHcy and decrease H2S production in the blood. CBS deficiency may lead to HHcy [15]. However, the role of CSE in HHcy and its associated pathogenesis is poorly understood. In this study, we showed that the plasma Hcy level was inversely related to H2S level in methionine-treated mice, which is absent from any genetic or Vitamin B6 deficiency. The observations were confirmed in our in vitro study, and consistent with a recent report that Hcy reduced H2S production in mouse glomerular mesangial cells [16]. Furthermore, we provided the evidence that the down-regulation of CSE may be responsible for the decrease of H2S production in Hcy-treated cells and mice with HHcy. In addition, our study demonstrated that Hcy enhanced DNA methylation in cse promoter and repressed its transcription in macrophages. In fact, CSE is predominantly expressed in the heart, vascular tissues and peripheral monocyte/macrophages, and serves as a major source of H2S production in the cardiovascular and immune systems. The relevance of CSE in HHcy-associated cardiovascular diseases should not be underestimated. Our study not only reveals a novel epigenetic regulation of CSE transcription, but also implies that disruption of H2S biosynthesis and homeostasis may be an effector of HHcy-associated pathogenesis. Thus, modulation of H2S may become a potential therapeutic strategy for HHcy-related disorders. Actually, H2S was recently reported to inhibit myocardial injury [6], decrease colitis severity [17] and attenuate neurodegeneration and neurovascular dysfunction [8] in rodent models associated with HHcy. Moreover, a most recent study by Christopher Hine et al. [18] revealed that endogenous H2S production is essential for dietary restriction benefits. Hence, it would be of great relevance to monitor the plasma H2S level in patients with HHcy.


Homocysteine Triggers Inflammatory Responses in Macrophages through Inhibiting CSE-H2S Signaling via DNA Hypermethylation of CSE Promoter.

Li JJ, Li Q, Du HP, Wang YL, You SJ, Wang F, Xu XS, Cheng J, Cao YJ, Liu CF, Hu LF - Int J Mol Sci (2015)

Schematic representations of mammalian homocysteine metabolism. Homocysteine metabolism is at the intersection of two main pathways: remethylation and transsulfuration pathway. Intracellular folate cycling is tightly connected to the remethylation pathway, in which methionine is activated by condensation with adenosine triphosphate (ATP) to yield the ubiquitous methyl donor, SAM, which is transformed into SAH by donating its methyl group to the substrates of methylation reactions. Subsequently, SAH gives rise to homocysteine in a reversible reaction that favors SAH over homocysteine production. The transsulfuration process is catalyzed by two vitamin B6-dependent enzymes: CBS and CSE. Hcy can be sequentially converted into cystathionine and then cysteine by CBS and CSE and subsequently results in the generation of H2S and other by-products including homoserine, pyruvate, GSH, taurine, and serine as well. MS, methionine synthase; THF, tetrahydrofolate; MTHFR, methylene tetrahydrofolatereductase; BHMT, betaine-homocysteine S-methyltransferase; DMG, dimethylglycine; SAM, S-adenosyl methionine; SAH, S-adenosylhomocysteine; CBS, cystathionine β-synthase; CSE, cystathionine γ-lyase; GSH, glutathione.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4490461&req=5

ijms-16-12560-f006: Schematic representations of mammalian homocysteine metabolism. Homocysteine metabolism is at the intersection of two main pathways: remethylation and transsulfuration pathway. Intracellular folate cycling is tightly connected to the remethylation pathway, in which methionine is activated by condensation with adenosine triphosphate (ATP) to yield the ubiquitous methyl donor, SAM, which is transformed into SAH by donating its methyl group to the substrates of methylation reactions. Subsequently, SAH gives rise to homocysteine in a reversible reaction that favors SAH over homocysteine production. The transsulfuration process is catalyzed by two vitamin B6-dependent enzymes: CBS and CSE. Hcy can be sequentially converted into cystathionine and then cysteine by CBS and CSE and subsequently results in the generation of H2S and other by-products including homoserine, pyruvate, GSH, taurine, and serine as well. MS, methionine synthase; THF, tetrahydrofolate; MTHFR, methylene tetrahydrofolatereductase; BHMT, betaine-homocysteine S-methyltransferase; DMG, dimethylglycine; SAM, S-adenosyl methionine; SAH, S-adenosylhomocysteine; CBS, cystathionine β-synthase; CSE, cystathionine γ-lyase; GSH, glutathione.
Mentions: CBS and CSE play important roles in Hcy metabolism and H2S synthesis, as summarized in Figure 6. On the one hand, Hcy can be sequentially converted into cystathionine and then cysteine by CBS and CSE, respectively. Both CBS and CSE can use cysteine as substrates for H2S synthesis. On the other hand, Hcy can be directly converted by CSE into homoserine and H2S. Therefore, it is conceivable that deficiency in either cbs or cse, or vitamin B6 may result in HHcy and decrease H2S production in the blood. CBS deficiency may lead to HHcy [15]. However, the role of CSE in HHcy and its associated pathogenesis is poorly understood. In this study, we showed that the plasma Hcy level was inversely related to H2S level in methionine-treated mice, which is absent from any genetic or Vitamin B6 deficiency. The observations were confirmed in our in vitro study, and consistent with a recent report that Hcy reduced H2S production in mouse glomerular mesangial cells [16]. Furthermore, we provided the evidence that the down-regulation of CSE may be responsible for the decrease of H2S production in Hcy-treated cells and mice with HHcy. In addition, our study demonstrated that Hcy enhanced DNA methylation in cse promoter and repressed its transcription in macrophages. In fact, CSE is predominantly expressed in the heart, vascular tissues and peripheral monocyte/macrophages, and serves as a major source of H2S production in the cardiovascular and immune systems. The relevance of CSE in HHcy-associated cardiovascular diseases should not be underestimated. Our study not only reveals a novel epigenetic regulation of CSE transcription, but also implies that disruption of H2S biosynthesis and homeostasis may be an effector of HHcy-associated pathogenesis. Thus, modulation of H2S may become a potential therapeutic strategy for HHcy-related disorders. Actually, H2S was recently reported to inhibit myocardial injury [6], decrease colitis severity [17] and attenuate neurodegeneration and neurovascular dysfunction [8] in rodent models associated with HHcy. Moreover, a most recent study by Christopher Hine et al. [18] revealed that endogenous H2S production is essential for dietary restriction benefits. Hence, it would be of great relevance to monitor the plasma H2S level in patients with HHcy.

Bottom Line: Unfortunately, Hcy-lowering strategies were found to have limited effects in reducing cardiovascular events.DNMT inhibition or knockdown reversed the decrease of CSE transcription induced by Hcy in macrophages.In sum, our findings demonstrate that Hcy may trigger inflammation through inhibiting CSE-H2S signaling, associated with increased promoter DNA methylation and transcriptional repression of cse in macrophages.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, the Second Affiliated Hospital of Soochow University, Soochow University, Suzhou 215004, China. dragonrabbit@163.com.

ABSTRACT
Hyperhomocysteinemia (HHcy) is an independent risk factor of atherosclerosis and other cardiovascular diseases. Unfortunately, Hcy-lowering strategies were found to have limited effects in reducing cardiovascular events. The underlying mechanisms remain unclear. Increasing evidence reveals a role of inflammation in the pathogenesis of HHcy. Homocysteine (Hcy) is a precursor of hydrogen sulfide (H2S), which is formed via the transsulfuration pathway catalyzed by cystathionine β-synthase and cystathionine γ-lyase (CSE) and serves as a novel modulator of inflammation. In the present study, we showed that methionine supplementation induced mild HHcy in mice, associated with the elevations of TNF-α and IL-1β in the plasma and reductions of plasma H2S level and CSE expression in the peritoneal macrophages. H2S-releasing compound GYY4137 attenuated the increases of TNF-α and IL-1β in the plasma of HHcy mice and Hcy-treated raw264.7 cells while CSE inhibitor PAG exacerbated it. Moreover, the in vitro study showed that Hcy inhibited CSE expression and H2S production in macrophages, accompanied by the increases of DNA methyltransferase (DNMT) expression and DNA hypermethylation in cse promoter region. DNMT inhibition or knockdown reversed the decrease of CSE transcription induced by Hcy in macrophages. In sum, our findings demonstrate that Hcy may trigger inflammation through inhibiting CSE-H2S signaling, associated with increased promoter DNA methylation and transcriptional repression of cse in macrophages.

No MeSH data available.


Related in: MedlinePlus