Homocysteine-Induced Endothelin-1 Release Is Dependent on Hyperglycaemia and Reactive Oxygen Species Production in Bovine Aortic Endothelial Cells

Sethi, Amarjit Singh; Lees, Delphine M.; Douthwaite, Julie A.; Dawnay, Anne; Corder, Roger

doi:10.1159/000090947

Cited by 31 publications

(22 citation statements)

References 76 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Replacement of this cysteine residue with serine prevents the modification and, therefore, makes the protein insensitive to the redox regulation. The existence of this mechanism of control may shed light on previous observations of upregulated ET-1 expression upon exposure of endothelial cells to oxidants (46,51). The regulation of the mRNA-destabilizing capacity of GAPDH by oxidative and nitrosative stress presents an extremely interesting scenario regarding the endothelium, where the contribution of NO and oxidants to the vascular pathophysiology is important (24,48).…”

Section: Discussionmentioning

confidence: 80%

Glyceraldehyde-3-Phosphate Dehydrogenase Regulates Endothelin-1 Expression by a Novel, Redox-Sensitive Mechanism Involving mRNA Stability

Rodrı́guez-Pascual

Redondo‐Horcajo

Magán-Marchal

et al. 2008

Molecular and Cellular Biology

111

View full text Add to dashboard Cite

The regulation of the synthesis of the endothelial-derived vasoconstrictor endothelin-1 (ET-1) is a complex process encompassing transcriptional as well as mRNA stability mechanisms. We have described recently the existence of a mechanism for the control of ET-1 expression based on the mRNA-destabilizing capacity of specific cytosolic proteins through interaction with AU-rich elements (AREs) present in the 3 untranslated region of the gene. We now identify glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a protein which binds to the AREs and is responsible for the destabilization of the mRNA. Oxidant stress alters the binding of GAPDH to the mRNA and its capacity to modulate ET-1 expression, a phenomenon occurring through specific S glutathionylation of the catalytically active residue Cys 152. Finally, we provide data consistent with a role for GAPDH in mRNA unwinding, yielding this molecule more prone to degradation. In contrast, S-thiolated GAPDH appears unable to modify mRNA unwinding, thus facilitating enhanced stability. Taken together, these results describe a novel, redox-based mechanism regulating mRNA stability and add a new facet to the panoply of GAPDH cellular homeostatic actions.The endothelium contributes greatly to vascular homeostasis by functioning as a sensor of physical and chemical stimuli and responding to them with specific signals. Vascular tone and blood pressure are regulated by endothelial cells through a tight balance of the levels of vasodilator and vasoconstrictor substances, the most important being nitric oxide (NO) and endothelin-1 (ET-1), respectively. In addition to its constrictor action, ET-1 has been shown to be involved in normal tissue repair and also in the pathogenesis of fibrotic diseases (38). All of these ET-1 biological actions can lead to pathophysiological processes under certain circumstances. In this respect, elevated circulating and tissue ET-1 levels have been measured in patients suffering from certain vascular diseases, such as atherosclerosis, pulmonary hypertension, or skin and lung fibrosis (2, 32). Therefore, ET-1 production and secretion by vascular endothelial cells must be tightly regulated. Endothelial cells synthesize ET-1 as a propeptide of 212 residues, preproendothelin-1, which is then subjected to specific proteolysis to yield the bioactive ET-1 peptide of 21 amino acids. The regulation of the expression is a complex process that occurs mainly at the mRNA level and involves both transcriptional and posttranscriptional mechanisms (26,27,31,45). Although the analysis of the transcription of the gene has attracted most of the attention, posttranscriptional mechanisms have recently been revealed as essential steps in the regulation of the biosynthesis (37, 43).Generally speaking, many of the processes dealing with specific regulatory mechanisms at the posttranscriptional level take place within genetic elements present in the 3Ј untranslated region (3Ј UTR) of the genes (10,17,20). Adenine-and uridine-rich elements (AREs), which are often found in...

show abstract

Section: Discussionmentioning

confidence: 80%

Glyceraldehyde-3-Phosphate Dehydrogenase Regulates Endothelin-1 Expression by a Novel, Redox-Sensitive Mechanism Involving mRNA Stability

Rodrı́guez-Pascual

Redondo‐Horcajo

Magán-Marchal

et al. 2008

Molecular and Cellular Biology

111

View full text Add to dashboard Cite

show abstract

“…However, in endothelial cells, there is only indirect evidence that ET-1 can increase mitochondrial ROS. For example, the combined metabolic burden of homocysteine and high glucose stimulates ET-1 synthesis in bovine aortic endothelial cells via a mechanism dependent on the production of mitochondrial ROS (29). Furthermore, in human aortic endothelial cells, uncoupling protein 2 overexpression decreases ET-1 mRNA expression and prevents the disruption of the mitochondrial membrane potential induced by lysophophatidylcholine (30).…”

Section: Discussionmentioning

confidence: 99%

Endothelin-1 Induces a Glycolytic Switch in Pulmonary Arterial Endothelial Cells via the Mitochondrial Translocation of Endothelial Nitric Oxide Synthase

Sun

Kumar

Sharma

et al. 2014

Am J Respir Cell Mol Biol

View full text Add to dashboard Cite

Recent studies have indicated that, during the development of pulmonary hypertension (PH), there is a switch from oxidative phosphorylation to glycolysis in the pulmonary endothelium. However, the mechanisms underlying this phenomenon have not been elucidated. Endothelin (ET)-1, an endothelial-derived vasoconstrictor peptide, is increased in PH, and has been shown to play an important role in the oxidative stress associated with PH. Thus, in this study, we investigated whether there was a potential link between increases in ET-1 and mitochondrial remodeling. Our data indicate that ET-1 induces the redistribution of endothelial nitric oxide synthase (eNOS) from the plasma membrane to the mitochondria in pulmonary arterial endothelial cells, and that this was dependent on eNOS uncoupling. We also found that ET-1 disturbed carnitine metabolism, resulting in the attenuation of mitochondrial bioenergetics. However, ATP levels were unchanged due to a compensatory increase in glycolysis. Further mechanistic investigations demonstrated that ET-1 mediated the redistribution of eNOS via the phosphorylation of eNOS at Thr495 by protein kinase C d. In addition, the glycolytic switch appeared to be dependent on mitochondrial-derived reactive oxygen species that led to the activation of hypoxia-inducible factor signaling. Finally, the cell culture data were confirmed in vivo using the monocrotaline rat model of PH. Thus, we conclude that ET-1 induces a glycolytic switch in pulmonary arterial endothelial cells via the redistribution of uncoupled eNOS to the mitochondria, and that preventing this event may be an approach for the treatment of PH.Keywords: mitochondrial bioenergetics; endothelial nitric oxide synthase uncoupling; protein kinase C d; peroxynitrite; superoxide Clinical RelevanceIt is becoming increasingly clear that the Warburg effect plays an important role in the development of pulmonary hypertension (PH). However, mechanisms underlying the glycolytic switch are unresolved. Our data demonstrate that endothelin-1, which is increased in PH, is capable of inducing aerobic glycolysis in pulmonary endothelial cells.Mitochondria are essential for energy metabolism through their ability to generate cellular ATP through oxidative phosphorylation. Increasing evidence suggests that mitochondrial remodeling is a critical event in a number of cardiovascular diseases, including pulmonary hypertension (PH) (1, 2). PH is a fatal disease characterized by pathologic vascular remodeling, which eventually leads to right ventricular failure and death. Several decades ago, Warburg (3) identified

show abstract

“…For example, Tyagi et al [68] have shown a positive relationship between cellular mitochondrial oxidative stress and systemic hypertension in hHcys. Sethi et al [76] also reported that a combined metabolic burden of Hcys and high glucose stimulates ET-1 synthesis in endothelial cells via a mitochondrial ROS-dependent mechanism and thereby results in cell dysfunction. Given the similarity of pathological changes at the cellular or molecular levels in glomerular injury and arterial damages, mitochondria-derived ROS may also be importantly involved in the initiation and progression of Hcys-induced glomerular sclerosis.…”

Section: Local Oxidative Stressmentioning

confidence: 99%

Mechanisms of Homocysteine-Induced Glomerular Injury and Sclerosis

Li²

2007

Am J Nephrol

View full text Add to dashboard Cite

Hyperhomocysteinemia (hHcys) has been recognized as a critical risk or pathogenic factor in the progression of end-stage renal disease (ESRD) and in the development of cardiovascular complications related to ESRD. Recently, evidence is accumulating that hHcys may directly act on glomerular cells to induce glomerular dysfunction and consequent glomerular sclerosis, leading to ESRD. In this review, we summarize recent findings that reveal the contribution of homocysteine as a pathogenic factor to the development of glomerular sclerosis or ESRD. In addition, we discuss several important mechanisms mediating the pathogenic action of homocysteine in the glomeruli or in the kidney, such as lo- cal oxidative stress, endoplasmic reticulum stress, homocysteinylation, and hypomethylation. Understanding these mechanisms may help design new approaches to develop therapeutic strategies for treatment of hHcys-associated end-organ damage and for prevention of deterioration of kidney function and ultimate ESRD in patients with hypertension and diabetes mellitus or even in aged people with hHcys.

show abstract

Homocysteine-Induced Endothelin-1 Release Is Dependent on Hyperglycaemia and Reactive Oxygen Species Production in Bovine Aortic Endothelial Cells

Cited by 31 publications

References 76 publications

Glyceraldehyde-3-Phosphate Dehydrogenase Regulates Endothelin-1 Expression by a Novel, Redox-Sensitive Mechanism Involving mRNA Stability

Glyceraldehyde-3-Phosphate Dehydrogenase Regulates Endothelin-1 Expression by a Novel, Redox-Sensitive Mechanism Involving mRNA Stability

Endothelin-1 Induces a Glycolytic Switch in Pulmonary Arterial Endothelial Cells via the Mitochondrial Translocation of Endothelial Nitric Oxide Synthase

Mechanisms of Homocysteine-Induced Glomerular Injury and Sclerosis

Contact Info

Product

Resources

About