Homocysteinylation of Metallothionein Impairs Intracellular Redox Homeostasis
2006; Lippincott Williams & Wilkins; Volume: 27; Issue: 1 Linguagem: Inglês
10.1161/01.atv.0000254151.00086.26
ISSN1524-4636
AutoresStephen Colgan, Richard C. Austin,
Tópico(s)Fluoride Effects and Removal
ResumoHomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 27, No. 1Homocysteinylation of Metallothionein Impairs Intracellular Redox Homeostasis Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBHomocysteinylation of Metallothionein Impairs Intracellular Redox HomeostasisThe Enemy Within! Stephen M. Colgan and Richard C. Austin Stephen M. ColganStephen M. Colgan From the Henderson Research Centre, Hamilton, Ontario, Canada. and Richard C. AustinRichard C. Austin From the Henderson Research Centre, Hamilton, Ontario, Canada. Originally published1 Jan 2007https://doi.org/10.1161/01.ATV.0000254151.00086.26Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:8–11Heart disease and stroke are major causes of death and morbidity in North America, and they exact high personal, community, and health care costs. Most heart attacks and strokes are caused by thrombosis superimposed on disrupted atherosclerotic lesions, a process known as atherothrombosis.1,2 A number of risk factors are known to accelerate atherothrombosis, including hypercholesterolemia, smoking, diabetes, hypertension, and obesity. Numerous clinical and epidemiological studies have established hyperhomocysteinemia as an independent risk factor for cardiovascular disease and stroke.3–8 Patients with inborn errors of methionine metabolism caused by deficiencies in cystathionine β-synthase or 5,10-methylenetetrahydrofolate reductase present with severe hyperhomocysteinemia and have a 50% chance of developing a major vascular event by the age of 30 years if untreated.6 This vascular risk is substantially decreased by homocysteine-lowering therapy (dietary supplementation with folic acid, B-vitamins, and/or betaine), even if the treatment does not completely normalize total plasma homocysteine levels.8 Unlike severe hyperhomocysteinemia, mild hyperhomocysteinemia attributable to deficiencies in dietary folic acid and/or B-vitamins is common in the general population. Despite the association between hyperhomocysteinemia and increased cardiovascular risk, several recent clinical trials have failed to show a preventative benefit of homocysteine-lowering therapy in cardiovascular patients with mild hyperhomocysteinemia.9,10 Although not completely understood, the results of these studies could imply that homocysteine-lowering therapy is ineffective in patients with established cardiovascular disease or that vitamin therapy has other, potentially adverse effects that neutralize its homocysteine-lowering benefit.11See page 49A direct causal relationship between hyperhomocysteinemia and atherosclerosis has been reported in diet- and/or genetic-induced mouse models of hyperhomocysteinemia.12–15 Previous studies have also reported that human cells relevant to atherothrombotic disease, including vascular endothelial cells and smooth muscle cells, are particularly sensitive to the cytotoxic effects of homocysteine that may result from the limited capacity of these cells to metabolize intracellular homocysteine.16–19 However, the underlying cellular targets of homocysteine that cause cell dysfunction and contribute to atherothrombosis are incompletely understood. In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Barbato and colleagues20 provide important and intriguing evidence that intracellular targets of homocysteine may be the root cause of endothelial cell dysfunction that contributes to atherothrombotic disease.Atherothrombotic disease is considered a form of chronic inflammation,1,21,22 and previous findings have revealed that homocysteine induces the production of proinflammatory cytokines, including interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) in monocytes, smooth muscle cells, and human vascular endothelial cells.23–25 An important feature of atherogenesis is the increased infiltration of monocytes into the subendothelial space. As such, MCP-1 increases the susceptibility of monocytes to adhere to the vascular endothelium, promoting infiltration and subsequent atherogenesis.The reactive thiol group of homocysteine is readily oxidized to form reactive oxygen species (ROS),26 suggesting that cytotoxic effects of homocysteine occur through a mechanism involving autooxidation and oxidative damage. However, this hypothesis has been challenged because it does not explain why cysteine, a thiol-containing amino acid that is present in plasma at much higher concentrations than homocysteine and is readily autooxidized, does not cause endothelial cell injury and is not considered a risk factor for cardiovascular disease.27 Thus, homocysteine-induced oxidative stress likely impacts atherogenesis by mechanisms that are unrelated to autooxidation. Ex vivo studies have revealed that hyperhomocysteinemia causes abnormal vasodilation by inducing intracellular production of ROS such as superoxide anion radicals.28 Recent in vivo work by Lentz and colleagues has determined that elevated plasma homocysteine concentrations impair the normal vasodilatory response of the endothelium leading to increased arterial thrombosis.29–31 Mice with genetic- or diet-induced hyperhomocysteinemia had decreased vasodilation in response to acetylcholine, which corresponded with decreased time to vessel occlusion. This effect correlated with increased superoxide and hydrogen peroxide production, and vasodilation was restored toward normal with the addition of a superoxide scavenger. Although superoxide is believed to limit the normal vasodilation response by reacting with endothelial nitric oxide to generate peroxynitrite,32,33 the mechanism by which homocysteine induces superoxide production remains unclear.Protein-bound homocysteine accounts for 70% to 80% of plasma total homocysteine in healthy individuals.34 Many plasma proteins form stable disulfide bonds with homocysteine including albumin,35,36 factor V,37 fibronectin,38 and transthyretin.39 Although the details for complex formation between homocysteine and factor V, fibronectin, and transthyretin are incomplete, a fairly comprehensive picture on the formation of albumin-S-S-homocysteine has emerged.35,36 These studies imply that homocysteine can interact with a host of different cellular and plasma proteins to form mixed-disulfide conjugates that alter protein function, a concept termed the "molecular targeting hypothesis" by Donald Jacobsen in 2000.27An established cellular mechanism that potentially stems from the "molecular targeting hypothesis" is the observation that homocysteine-induced vascular injury involves protein misfolding in the endoplasmic reticulum (ER), leading to ER stress and activation of the unfolded protein response (UPR).17,40–45 Activation of the UPR initially enhances cell survival by ensuring that the adverse effects of ER stress are dealt with in a timely and efficient manner. However, prolonged or severe ER stress induced by homocysteine causes endothelial cell dysfunction and apoptosis through the upregulation of proapoptotic factors such as growth arrest- and DNA damage-inducible gene 153 (GADD153)46 and T cell death associated gene 51 (TDAG51).16Although evidence of homocysteinylation of extracellular proteins is well established, little is known of the intracellular protein targets of homocysteine and it may even be argued that the intracellular reducing environment of the cytosol (as opposed to the ER) does not favor protein-S-S-homocysteine bond formation. However, Barbato and colleagues20 hypothesized that metallothionein (MT), an intracellular zinc-binding chaperone and superoxide radical scavenger, may be an intracellular target of homocysteine because of its extremely rich cysteine content. Their findings now provide novel evidence that MT is indeed a target of homocysteinylation in cultured human vascular endothelial cells and that formation of this homocysteine-S-S-MT mixed–disulfide conjugate could potentially compromise the atheroprotective properties of MT (Figure). First, homocysteinylation impaired the zinc binding properties of MT and increased intracellular free zinc concentrations. As a direct consequence of this elevation in free zinc, the expression of early growth response-1 (Egr-1), a zinc finger transcription factor that regulates proinflammatory and procoagulant genes associated with atherothrombosis,47,48 was dramatically elevated. Second, the superoxide radical scavenging ability of metallothionein was inhibited after homocysteinylation, thereby leading to superoxide production and increased oxidative stress. The targeting of MT by intracellular homocysteine represents a unique molecular mechanism of homocysteine-induced endothelial cell dysfunction and provides a plausible explanation as to how homocysteine disrupts intracellular redox homeostasis. Download figureDownload PowerPointHomocysteinylation of metallothionein (MT) in human vascular endothelial cells impairs intracellular redox potential and increases the expression of early growth response-1 (Egr-1). MT is a ubiquitous intracellular zinc (Zn2+) binding chaperone having superoxide (O2) radical scavenging properties (left side of diagram). Increased levels of intracellular homocysteine (Hcy) in endothelial cells can occur via several mechanisms, including the uptake of extracellular methionine (Met) and/or Hcy, or the impairment in intracellular Hcy metabolism. Barbato and colleagues20 demonstrate that increased intracellular levels of Hcy targets MT by forming a mixed-disulfide conjugate in the cytosol, thereby releasing Zn2+ and impairing the O2 radical scavenging properties of MT. The elevation in intracellular free Zn2+ attributable to the homocysteinylation of MT increases the expression of Egr-1, an early/intermediate transcription factor that mediates the expression of a wide range of cellular factors having proatherogenic and thrombotic properties, including monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), intercellular adhesion molecule 1 (ICAM-1) and tissue factor (TF). The homocysteinylation-induced combination of increased Egr-1 expression and reactive oxygen species (ROS) would be expected to cause endothelial cell dysfunction and contribute to the development and progression of atherothrombosis (components depicted in red). Additional intracellular targets of homocysteinylation (depicted as question mark) and their effect on protein folding/function in the cytosol and endoplasmic reticulum of endothelial cells are currently under investigation. SAM indicates S-adenosylmethionine; SAH, S-adenosylhomocysteine; MS, methionine synthase. A, acceptor molecule; A-CH3, methylated acceptor molecule.The findings that homocysteinylation of MT impairs cellular redox homeostasis and induces the expression of Egr-1 raises important biochemical and physiological questions. Are there additional intracellular targets of homocysteinylation that alter endothelial cell function and contribute to atherothrombotic disease? Given the observation that homocysteine impairs MT structure/function even in the presence of physiologically relevant concentrations of reduced glutathione, the possibility of other intracellular protein targets certainly exists. It is well known that homocysteine causes ER stress in cultured endothelial cells17,40–44 and is associated with atherosclerotic lesion development in hyperhomocysteinemic mice.49 However, the cellular mechanism by which homocysteine causes ER stress is not known. Could the homocysteinylation of ER target proteins leading to protein misfolding explain the ER stress-inducing effects of homocysteine? Previous studies by Jakubowski and colleagues have also demonstrated that metabolic conversion of homocysteine to a chemically reactive metabolite, Hcy-thiolactone, causes protein N-homocysteinylation through the formation of amide bonds with ε-amino groups of protein lysine residues.50 Could N-homocysteinylation of intracellular protein targets also contribute to the cytotoxic effects observed in cell types relevant to atherothrombotic disease? Although Barbato and colleagues provide compelling evidence that the induction of Egr-1 is associated with a rise in intracellular free zinc, are there any other cellular mechanisms that could explain the effect of homocysteine on Egr-1 expression? Of interest, recent studies have demonstrated that ER stress can also induce Egr-1 expression.51 Given the ER stress–inducing effects of homocysteine, it is conceivable that the effect of homocysteine on Egr-1 may involve multiple mechanisms, depending on cell type and capacity to metabolize intracellular homocysteine. Finally, recent studies have established an important link between homocysteine-induced oxidative stress and endothelial cell dysfunction in diet- and genetic-induced mouse models of hyperhomocysteinemia.29–31 Therefore, will the reported findings by Barbato and colleagues20 in cultured vascular endothelial cells be confirmed in these mouse models? If this indeed holds true, it will provide the foundation for future investigations aimed at exploring the intracellular protein targets of homocysteine that contribute to atherothrombotic disease.In summary, the current findings by Barbato and colleagues are exciting because they shift the focus of homocysteine toxicity to the intracellular arena and provide novel evidence as to how homocysteine affects multiple cellular stress pathways. These studies also imply that total plasma homocysteine levels may be insignificant with regards to the pathophysiology of hyperhomocysteinemia if the cytotoxic effects of homocysteine are compartmentalized in cells and tissues. Approaches aimed at reducing the enemy within (ie, intracellular levels of homocysteine) may be the best way of alleviating endothelial cell dysfunction and attenuating the development and progression of atherothrombosis.Sources of FundingResearch in the laboratory of Dr Austin is supported by the Heart and Stroke Foundation of Ontario (T-5385) and the Canadian Institutes of Health Research (MOP-67116, MOP-74477). R.C.A. is a Career Investigator of the Heart and Stroke Foundation of Ontario. S.M.C. is a recipient of a Graduate Studentship from the Canadian Liver Foundation.DisclosuresNone.FootnotesCorrespondence to Dr Richard C. Austin, Henderson Research Centre, 60 Wing, Room 207, 711 Concession Street, Hamilton, Ontario, L8V 1C3. E-mail [email protected] References 1 Ross R. Atherosclerosis–an inflammatory disease. N Engl J Med. 1999; 340: 115–126.CrossrefMedlineGoogle Scholar2 Fuster V, Badimon L, Badimon JJ, Chesebro JH. 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