Skip Navigation

Cardiovascular Research 2003 59(2):271-276; doi:10.1016/S0008-6363(03)00462-0
© 2003 by European Society of Cardiology
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Riksen, N. P.
Right arrow Articles by Smits, P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Riksen, N. P.
Right arrow Articles by Smits, P.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

Copyright © 2003, European Society of Cardiology

Potential role for adenosine in the pathogenesis of the vascular complications of hyperhomocysteinemia

Niels P. Riksena,b, Gerard A. Rongena,b, Henk J. Blomc, Frans G.M. Russela, Godfried H.J. Boersb and Paul Smitsa,b,*

aDepartment of Pharmacology–Toxicology, University Medical Centre Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands
bDepartment of Internal Medicine, University Medical Centre Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands
cDepartment of Pediatrics, University Medical Centre Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands

* Corresponding author. Department of Pharmacology–Toxicology University Medical Centre Nijmegen P.O. Box 9101, 6500 HB Nijmegen, The Netherlands. Tel.: +31-24-361-3691; fax: +31-24-361-4214. p.smits{at}pharmtox.umcn.nl

Received 8 January 2003; accepted 16 May 2003


   Abstract
Top
 Abstract
1. Introduction
 2. Role of homocysteine...
 3. Formation and metabolism...
 4. Adenosine in...
 5. Effects of endogenous...
 6. Conclusion
 References
 
Hyperhomocysteinemia is an independent risk factor for cardiovascular disease. Most previous investigations focused on the role of homocysteine as direct pathogenetic factor for these adverse vascular events. However, the exact pathophysiological mechanism is still unknown. In this review we discuss the hypothesis that a decreased extracellular concentration of adenosine could contribute to the adverse cardiovascular effects of hyperhomocysteinemia. Fundamental to this hypothesis is that, in vivo, any increase in the plasma concentration of homocysteine reflects an increased intracellular homocysteine concentration, which inevitably will result in a decrease in the adenosine concentration. In this situation, the hydrolase reaction catalysed by S-adenosylhomocysteine hydrolase will reverse and S-adenosylhomocysteine will accumulate at the expense of adenosine. Stimulation of adenosine receptors by adenosine results in various cardio- and vasoprotective actions, like modulation of vascular resistance, presynaptic inhibition of norepinephrine release, ischaemic preconditioning, inhibition of platelet aggregation, modulation of inflammation and regulation of vascular cell proliferation and death. In this respect, a decrease in the adenosine concentration could contribute significantly to the cardiovascular effects of hyperhomocysteinemia.

KEYWORDS Hyperhomocysteinemia; Adenosine; S-Adenosylhomocysteine hydrolase; Pathophysiology; Atherosclerosis

This article is referred to in the Editorial by A. Deussen (pages 259–261) in this issue.


   1. Introduction
Top
 Abstract
 1. Introduction
2. Role of homocysteine...
 3. Formation and metabolism...
 4. Adenosine in...
 5. Effects of endogenous...
 6. Conclusion
 References
 
Patients with homocysteinuria have severe hyperhomocysteinemia and are particularly prone to occlusive vascular disease at young age [1]. Over the last 2 decades it became evident that even a mildly elevated plasma concentration of homocysteine is an independent risk factor for cardiovascular disease [2].

Up to now, the underlying mechanism causing the cardiovascular complications in hyperhomocysteinemia has been poorly understood. Most investigators in the field focused on the role of homocysteine itself and, more recently, of S-adenosylhomocysteine [3]. In this review we discuss the hypothesis that a decreased extracellular concentration of the endogenous nucleoside adenosine could contribute to the pathogenesis of the adverse vascular effects of hyperhomocysteinemia. Fundamental to this hypothesis is that, in vivo, any increase in the plasma concentration of homocysteine will result in a decrease in the adenosine concentration. Since adenosine is a potent cardio- and vasoprotective substance, a decrease in the plasma concentration may contribute to the adverse cardiovascular sequelae of hyperhomocysteinemia.


   2. Role of homocysteine and S-adenosylhomocysteine
Top
 Abstract
 1. Introduction
 2. Role of homocysteine...
3. Formation and metabolism...
 4. Adenosine in...
 5. Effects of endogenous...
 6. Conclusion
 References
 
Since McCully, in 1969, linked elevated plasma homocysteine concentrations with vascular disease [4], many investigations have been conducted to define the causes of atherothrombotic complications in hyperhomocysteinemia. However, up to now, no generally accepted mechanism has been described. Most investigations focused on the role of homocysteine itself.

According to most investigators, endothelial cell injury caused by hyperhomocysteinemia plays a key role in the pathogenesis of cardiovascular complications (reviews [3,5]). In vivo, hyperhomocysteinemia rapidly impairs endothelial function [6,7]. Many in vitro studies have presented evidence of effects of homocysteine on platelets, endothelial cells, vascular smooth muscle cells and on coagulation (review [3]). However, these studies were not able to provide conclusive mechanisms for the vascular damage associated with hyperhomocysteinemia. Some reports showed that even millimolar concentrations of homocysteine do not induce platelet aggregation in vitro [8]. Further, many publications which did point towards direct vasotoxic or thrombogenic effects of homocysteine in vitro are hardly relevant to the clinical situation. Often, these studies used very high concentrations reduced homocysteine (1–10 mM). This is highly unphysiologic because total homocysteine concentrations are most often between 10 and 30 µmol/l in plasma of patients with mild hyperhomocysteinemia. Moreover, in blood almost all homocysteine is present in its oxidized disulfide form and only a very small amount of 1%, or even less, of the total pool of blood homocysteine, is present in its reduced form [9]. This means that 10 mM of homocysteine in vitro is about 50 000 times the plasma level normally occurring in patients with mild hyperhomocysteinemia [10].

In summary, no coherent, generally accepted view has emerged to explain the pathophysiology of atherosclerotic and thrombotic complications in hyperhomocysteinemia. One potential explanation for these inconsistent results is that not hyperhomocysteinemia itself causes vascular damage, but that high levels of homocysteine are merely a marker for another risk factor. Recently, several studies have provided evidence that not homocysteine, but S-adenosylhomocysteine (SAH), may play an important role in the vascular complications of hyperhomocysteinemia [11–14]. When concentrations of homocysteine are high, the hydrolase reaction catalysed by the SAH hydrolase reverses and SAH is formed from homocysteine and adenosine. SAH in turn is a potent inhibitor of transmethylation reactions in the cell [15,16]. Interestingly, a recent case–control study showed that plasma SAH was a more sensitive marker of cardiovascular disease than plasma homocysteine [17]. Wang et al. showed that incubation of cultured endothelial cells with exogenous homocysteine, only in the presence of adenosine, increases intracellular levels of SAH and inhibits carboxymethylation of p21ras, resulting in a decreased cellular proliferation [11].

So we can conclude that hyperhomocysteinemia is an independent risk factor for cardiovascular disease and that endothelial dysfunction is the most important mediating mechanism. A direct role for homocysteine itself in the pathophysiology of cardiovascular complications, however, has not been convincingly shown. In conformity with the hypothesis that there might be other risk factors, associated with high levels of homocysteine, for the development of cardiovascular complications, we now focus on the possible role of adenosine in this pathogenesis.


   3. Formation and metabolism of homocysteine in man
Top
 Abstract
 1. Introduction
 2. Role of homocysteine...
 3. Formation and metabolism...
4. Adenosine in...
 5. Effects of endogenous...
 6. Conclusion
 References
 
Fig. 1 shows the biochemical reactions of homocysteine formation, which are relevant to the current discussion. During the conversion of methionine to homocysteine, first S-adenosylmethionine is formed with the use of adenosine-5-triphosphate (ATP). In the human body, S-adenosylmethionine is the ultimate methyl donor of many vital reactions, like DNA, RNA, protein and phospholipid methylation. After demethylation, SAH is generated and further hydrolyzed by the enzyme SAH hydrolase to homocysteine and adenosine. So, the net balance shows that methionine and ATP are converted to homocysteine, a methyl group and adenosine. This pathway may significantly contribute to the production of adenosine in man (Fig. 1, left panel). Metabolic balance studies in normal adults have shown that the generation of adenosine from SAH is about 20 mmol per day [18]. Several in vitro studies have quantified the rate of adenosine production from this transmethylation pathway in rat and guinea pig heart [19–23]. It was shown that during normoxia, SAH hydrolysis significantly contributes to the intracellular adenosine production (up to one third of total). During hypoxia, however, adenosine is predominantly derived from enhanced hydrolysis of adenosine-monophosphate (AMP). It should be realized that the contribution of the transmethylation pathway to adenosine production can differ significantly between various organ systems [15].


Figure 1
View larger version (34K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 Schematic representation of the biochemical reactions, which are relevant to the current discussion. Under normal conditions, adenosine is formed from the hydrolysis of SAH in man (left part of the diagram). The extracellular concentration contributes to the homeostasis of the vascular system by stimulation of specific adenosine receptors leading to a variety of effects. Under conditions of increased concentrations of homocysteine, the reaction catalysed by SAH hydrolase will function in the opposite direction (right part of the diagram).

 

   4. Adenosine in hyperhomocysteinemia
Top
 Abstract
 1. Introduction
 2. Role of homocysteine...
 3. Formation and metabolism...
 4. Adenosine in...
5. Effects of endogenous...
 6. Conclusion
 References
 
Of all enzymes in the aforementioned metabolic pathway, only SAH hydrolase is able to function in both directions [3,15]. In fact, the equilibrium of the reaction catalyzed by SAH hydrolase favours SAH formation. Nonetheless, the reaction is driven in the opposite direction because the products homocysteine and adenosine are both rapidly removed in the normal in vivo situation, causing the enzyme to function in its cleavage direction. However, in case of increased levels of homocysteine, SAH will accumulate at the expense of adenosine (Fig. 1, right panel). Under these circumstances, intracellular adenosine formation is hampered, increasing the transmembrane adenosine concentration gradient that exists under normoxic conditions [24], and, consequently, the extracellular adenosine concentration is decreased.

It is essential to realise that under baseline normoxic conditions, adenosine is produced continuously in several cell types, originating from two different pathways. The first is the hydrolysis of SAH by SAH hydrolase. A second important pathway in adenosine formation is the intra- and extracellular hydrolysis of AMP by 5'-nucleotidase. Under hypoxic conditions, the hydrolysis of AMP greatly increases and predominates the other pathway. Under normoxic conditions, adenosine is quickly taken up by neighbouring cells via nucleoside transporters and is degraded to inosine by adenosine deaminase or rephosphorylated by adenosine kinase [25]. As such, the plasma concentration of adenosine is determined by the sum of these processes, and a fall in the formation of adenosine originating from the hydrolysis of SAH should inevitably result in a lower plasma adenosine level, provided that other routes of adenosine metabolism remain constant.

Indeed, several studies showed that the administration of homocysteine or homocysteine thiolactone decreases adenosine release [26,27]. In the study by Sciotti and van Wylen, microdialysis probes were used to measure the adenosine concentration in cerebral interstitial fluid (ISF) in a rat model under different conditions [26]. This study showed that infusion of homocysteine thiolactone in the probe, in concentrations of 10–5–10–3 M, decreases basal ISF adenosine concentration and cerebral blood flow. Moreover, it showed that homocysteine thiolactone attenuates the increase in dialysate adenosine during ischaemia. A comparable experiment was conducted in perfused isolated guinea-pig hearts, in which under hypoxic conditions, homocysteine thiolactone was shown to decrease the adenosine concentration in the perfusate by more than 50%, while the tissue content of SAH increased significantly [27]. However, not all studies on this subject showed similar unequivocal results. Deussen et al. found attenuation of adenosine release with homocysteine during hypoxia, but were not able to show an effect of homocysteine on coronary flow during hypoxia [28]. Also, in the dog heart, homocysteine thiolactone was shown not to influence reactive hyperaemia, which is believed to be mediated by adenosine [29]. This discrepancy could be explained by the multitude of mechanisms, other than adenosine, which contribute to reactive hyperaemia [30]. Although these studies convincingly illustrated the mechanism we described of the homocysteine-induced decrease in adenosine concentration, it has to be emphasized that in these experiments, supraphysiological homocysteine concentrations were used and that they do not mimic the situation of hyperhomocysteinemia in man. Moreover, these studies showed that, although the contribution of SAH hydrolysis to basal adenosine formation is limited, under hypoxic conditions (when adenosine production is mostly from AMP hydrolysis) and with high homocysteine levels, this pathway can contribute significantly to intracellular adenosine trapping. Very recently, Chen et al. found that acute as well as chronic hyperhomocysteinemia in rat decreases plasma and renal interstitial adenosine concentration through the inhibition of SAH hydrolase [31]. This study more closely resembled the human situation of hyperhomocysteinemia, in that a plasma homocysteine concentration of approximately 15 µM was induced.


   5. Effects of endogenous adenosine
Top
 Abstract
 1. Introduction
 2. Role of homocysteine...
 3. Formation and metabolism...
 4. Adenosine in...
 5. Effects of endogenous...
6. Conclusion
 References
 
Extracellular adenosine may exert several physiological effects by stimulation of specific adenosine receptors. These adenosine receptors can be subdivided into A1, A2A, A2B and A3 receptors [32]. By stimulation of these receptors, adenosine exerts a multitude of cardio- and vasoprotective effects by interfering with numerous mechanisms that contribute to the pathogenesis of atherosclerosis and thrombosis.

Firstly, adenosine exhibits direct and indirect effects on vascular tone. Directly, predominantly via activation of A2 receptors, adenosine induces vasodilation [25]. Indirectly, adenosine blocks the synthesis of potent vasoconstrictor factors such as angiotensin II and norepinephrine by inhibiting renin release [33]. At the level of the vascular smooth muscle cell, adenosine has been reported to inhibit the release of the neurotransmitter norepinephrine and to reduce the postsynaptic vasoconstrictor response to {alpha}-adrenoceptor-stimulation in man [34,35].

Secondly, several direct cardioprotective effects of adenosine are known. It exerts negative inotropic, chronotropic and dromotropic cardiac effects [36]. Adenosine has also been reported to play a key role in ischaemic preconditioning of the heart. This phenomenon concerns the observation that short periods of ischaemia render the myocardium resistant to a subsequent more serious ischaemic event [37]. A number of studies have shown that this endogenous cardioprotective mechanism can be reduced by adenosine receptor antagonism [38], and potentiated by dipyridamole, an adenosine uptake inhibitor [39].

Thirdly, adenosine potently inhibits the aggregation of platelets [40,41]. Moreover, adenosine exerts anticoagulant activity by downregulation of tissue factor expression on endothelial cells and by suppressing the expression of P-selectin on platelets [42,43]. These effects may well contribute to the well-known antithrombogenicity of an intact endothelial lining.

Fourthly, adenosine, at concentrations similar to those observed in vivo, is an important anti-inflammatory agent [44,45]. Adenosine receptor stimulation inhibits the activation of neutrophils and protects vascular endothelium from damage by neutrophils [46]. Moreover, adenosine inhibits TNF-{alpha} production in macrophages and monocytes [47], suppresses arachidonic acid release and leukotriene biosynthesis in human neutrophils [48], and is shown to act as an endogenous activator of cellular antioxidant enzyme systems [49].

Fifthly, adenosine has been shown to play an important role in the regulation of vascular cell proliferation and death, which plays a key role in the vascular remodelling process that leads to vaso-occlusive diseases [50]. Smooth muscle cell derived adenosine inhibits the proliferation and collagen synthesis of these muscle cells in an autocrine manner via adenosine A2B receptor stimulation [51–53]. Moreover, a selective A2 receptor agonist was shown to reduce neointimal thickening in an animal model [54]. In contrast to the growth-inhibitory effect on vascular smooth muscle cells, adenosine A2B receptor stimulation induces mitogenic effects on endothelial cell [55]. Besides inhibiting the growth of vascular smooth muscle cells, adenosine has been shown to induce apoptosis of human vascular smooth muscle cells via A2B receptor stimulation [56]. In this way, adenosine could restrict intimal hyperplasia in the early phase of atherosclerosis, but on the other hand, could also play a role in the formation of the necrotic core in advanced atherosclerosis. Regarding the effects of adenosine on vascular cell proliferation and death, the net effect would be to facilitate the recovery of blood vessels from injury by the inhibition of inappropriate migration and proliferation of vascular smooth muscle cells into the intima layer and promoting re-endothelialization via its mitogenic effects on endothelial cells [55].

All these effects make adenosine a powerful endogenous protector against arteriosclerotic and vaso-occlusive disorders and are thought to contribute to the well-documented cardioprotective properties of adenosine receptor stimulation [57,58]. In this respect, a decreased plasma and interstitial adenosine concentration in hyperhomocysteinemia could significantly contribute to the cardiovascular complications of this disorder. The recent study by Chen et al. strongly supports this view by indeed showing a decreased plasma and renal interstitial adenosine concentration in hyperhomocysteinemia in vivo [31].

A significant role for adenosine in vascular complications is not unique. Recently this was also established for hypertension in the spontaneously hypertensive rat (SHR). Extracellular adenosine levels in cultured vascular smooth muscle cells were significantly lower in SHRs than in Wistar Kyoto rats (WKY) and this difference mediated the enhanced proliferation of vascular smooth muscle cells in SHRs [59]. These results imply that a decrease in adenosine concentration may play a role in the cardiovascular complications of hypertension, in line with the present discussion concerning the pathophysiology of hyperhomocysteinemia. To explore the situation in hyperhomocysteinemia further, the latter study could easily be replicated in CBS deficient mice, an animal model for hyperhomocysteinemia [60]. Moreover, in future experiments, using microdialysis techniques, we will measure interstitial adenosine concentrations in patients with hyperhomocysteinemia and controls to evaluate the role of adenosine in the human situation.


   6. Conclusion
Top
 Abstract
 1. Introduction
 2. Role of homocysteine...
 3. Formation and metabolism...
 4. Adenosine in...
 5. Effects of endogenous...
 6. Conclusion
References
 
Increased levels of homocysteine will reverse the biochemical reaction catalysed by SAH hydrolase, leading to a decreased adenosine formation, or even to net extraction of adenosine from the extracellular compartment. Because of the beneficial effects of adenosine in the cardiovascular system, reduced adenosine formation during hyperhomocysteinemia may be a significant factor in the pathogenesis of the cardiovascular sequelae of this condition.

Time for primary review 34 days.


   Acknowledgements
 
N.P.R. is a recipient of an AGIKO fellowship of the Netherlands Organisation for Scientific Research (ZonMw). G.A.R. is a recipient of a fellowship of the Royal Netherlands Academy of Arts and Sciences. H.J.B. is established investigator of the Netherlands Heart Foundation.


   References
Top
 Abstract
 1. Introduction
 2. Role of homocysteine...
 3. Formation and metabolism...
 4. Adenosine in...
 5. Effects of endogenous...
 6. Conclusion
 References
 

  1. Mudd S.H., Skovby F., Levy H.L., et al. The natural history of homocystinuria due to cystathionine β-synthase deficiency. Am J Hum Genet (1985) 37:1–31.[Web of Science][Medline]
  2. The Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta-analysis. J. Am. Med. Assoc (2002) 288:2015–2022.[Abstract/Free Full Text]
  3. Mudd S.H., Levy H.L., Kraus J.P. Disorders of transsulfuration. In: The metabolic and molecular basis of inherited disease—Scriver C.R., Beaudet A.L., Sly W.S., Vale D., eds. (2001) New York: McGraw-Hill. 2007–2056.
  4. McCully K.S. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol (1969) 56:111–128.[Web of Science][Medline]
  5. Medina M., Urdiales J.L., Amores-Sanchez M.I. Roles of homocysteine in cell metabolism: old and new functions. Eur J Biochem (2001) 268:3871–3882.[Web of Science][Medline]
  6. Nappo F., De Rosa N., Marfella R., et al. Impairment of endothelial functions by acute hyperhomocysteinemia and reversal by antioxidant vitamins. J. Am. Med. Assoc. (1999) 281:2113–2118.[Abstract/Free Full Text]
  7. Chambers J.C., McGregor A., Jean-Marie J., Obeid O.A., Kooner J.S. Demonstration of rapid onset vascular endothelial dysfunction after hyperhomocysteinemia: an effect reversible with vitamin C therapy. Circulation (1999) 99:1156–1160.[Abstract/Free Full Text]
  8. Stamler J.S., Osborne J.A., Jaraki O., et al. Adverse vascular effects of homocysteine are modulated by endothelium-derived relaxing factor and related oxides of nitrogen. J Clin Invest (1993) 91:308–318.[Web of Science][Medline]
  9. Mansoor M.A., Guttormsen A.B., Fiskerstrand T., et al. Redox status and protein binding of plasma aminothiols during the transient hyperhomocysteinemia that follows homocysteine administration. Clin Chem (1993) 39:980–985.[Abstract/Free Full Text]
  10. Blom H.J., van der Molen E.F. Pathobiochemical implications of hyperhomocysteinemia. Fibrinolysis (1994) 8:86–87.[Web of Science]
  11. Wang H., Yoshizumi M., Lai K., et al. Inhibition of growth and p21ras methylation in vascular endothelial cells by homocysteine but not cysteine. J Biol Chem (1997) 272:25380–25385.[Abstract/Free Full Text]
  12. Dayal S., Bottiglieri T., Arning E., et al. Endothelial dysfunction and elevation of S-adenosylhomocysteine in cystathionine β-synthase-deficient mice. Circ Res (2001) 88:1203–1209.[Abstract/Free Full Text]
  13. Yi P., Melnyk S., Pogribna M., et al. Increase in plasma homocysteine associated with parallel increases in plasma S-adenosylhomocysteine and lymphocyte DNA hypomethylation. J Biol Chem (2000) 275:29318–29323.[Abstract/Free Full Text]
  14. Hultberg B., Andersson A., Isaksson A. Hypomethylation as a cause of homocysteine-induced cell damage in human cell lines. Toxicology (2000) 147:69–75.[CrossRef][Web of Science][Medline]
  15. Ueland P.M. Pharmacological and biochemical aspects of S-adenosylhomocysteine and S-adenosylhomocysteine hydrolase. Pharmacol Rev (1982) 34:223–253.[Web of Science][Medline]
  16. Kredich N.M., Martin D.V. Jr. Role of S-adenosylhomocysteine in adenosine-mediated toxicity in cultured mouse T lymphoma cells. Cell (1977) 12:931–938.[CrossRef][Web of Science][Medline]
  17. Kerins D.M., Koury M.J., Capdevila A., Rana S., Wagner C. Plasma S-adenosylhomocysteine is a more sensitive indicator of cardiovascular disease than plasma homocysteine. Am J Clin Nutr (2001) 74:723–729.[Abstract/Free Full Text]
  18. Hershfield M.S., Mitchell B.S. Immunodeficiency diseases caused by adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency. In: The metabolic and molecular basis of inherited disease—Scriver C.R., Beaudet A.L., Sly W.S., Vale D., eds. (2001) New York: McGraw-Hill. 2585–2625.
  19. Lloyd H.G., Schrader J. Adenosine metabolism in the guinea pig heart: the role of cytosolic S-adenosyl-L-homocysteine hydrolase, 5'-nucleotidase and adenosine kinase. Eur Heart J (1993) 14(Suppl_I):27–33.[Abstract]
  20. Lloyd H.G., Deussen A., Wuppermann H., Schrader J. The transmethylation pathway as a source for adenosine in the isolated guinea-pig heart. Biochem J (1988) 252:489–494.[Web of Science][Medline]
  21. Achterberg P.W., de Tombe P.P., Harmsen E., de Jong J.W. Myocardial S-adenosylhomocysteine hydrolase is important for adenosine production during normoxia. Biochim Biophys Acta (1985) 840:393–400.[Medline]
  22. Kroll K., Deussen A., Sweet I.R. Comprehensive model of transport and metabolism of adenosine and S-adenosylhomocysteine in the guinea pig heart. Circ Res (1992) 71:590–604.[Abstract/Free Full Text]
  23. Deussen A., Lloyd H.G., Schrader J. Contribution of S-adenosylhomocysteine to cardiac adenosine formation. J Mol Cell Cardiol (1989) 21:773–782.[CrossRef][Web of Science][Medline]
  24. Deussen A., Stappert M., Schafer S., Kelm M. Quantification of extracellular and intracellular adenosine production: understanding the transmembranous concentration gradient. Circulation (1999) 99:2041–2047.[Abstract/Free Full Text]
  25. Tabrizchi R., Bedi S. Pharmacology of adenosine receptors in the vasculature. Pharmacol Ther (2001) 91:133–147.[CrossRef][Web of Science][Medline]
  26. Sciotti V.M., Van Wylen D.G. Attenuation of ischemia-induced extracellular adenosine accumulation by homocysteine. J Cereb Blood Flow Metab (1993) 13:208–213.[Web of Science][Medline]
  27. Schrader J., Schutz W., Bardenheuer H. Role of S-adenosylhomocysteine hydrolase in adenosine metabolism in mammalian heart. Biochem J (1981) 196:65–70.[Web of Science][Medline]
  28. Deussen A., Borst M., Schrader J. Formation of S-adenosylhomocysteine in the heart. I: An index of free intracellular adenosine. Circ Res (1988) 63:240–249.[Abstract/Free Full Text]
  29. Sadick N., German D.C., McHale P.A., Greenfield J.C. Jr., Kredich N.M. Functional and reactive hyperemia are unaltered by homocysteine in conscious dogs. Basic Res Cardiol (1985) 80:280–290.[CrossRef][Web of Science][Medline]
  30. Kingsbury M.P., Robinson H., Flores N.A., Sheridan D.J. Investigation of mechanisms that mediate reactive hyperaemia in guinea-pig hearts: role of K(ATP) channels, adenosine, nitric oxide and prostaglandins. Br J Pharmacol (2001) 132:1209–1216.[CrossRef][Web of Science][Medline]
  31. Chen Y.F., Li P.L., Zou A.P. Effect of hyperhomocysteinemia on plasma or tissue adenosine levels and renal function. Circulation (2002) 106:1275–1281.[Abstract/Free Full Text]
  32. Fredholm B.B., Ijzerman A.P., Jacobson K.A., Klotz K.N., Linden J. International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev (2001) 53:527–552.[Abstract/Free Full Text]
  33. Jackson E.K. Adenosine: a physiological brake on renin release. Annu Rev Pharmacol Toxicol (1991) 31:1–35.[CrossRef][Web of Science][Medline]
  34. Smits P., Lenders J.W., Willemsen J.J., Thien T. Adenosine attenuates the response to sympathetic stimuli in humans. Hypertension (1991) 18:216–223.[Abstract/Free Full Text]
  35. Rongen G.A., Lenders J.W., Lambrou J., et al. Presynaptic inhibition of norepinephrine release from sympathetic nerve endings by endogenous adenosine. Hypertension (1996) 27:933–938.[Abstract/Free Full Text]
  36. Belardinelli L., Linden J., Berne R.M. The cardiac effects of adenosine. Prog Cardiovasc Dis (1989) 32:73–97.[CrossRef][Web of Science][Medline]
  37. Murry C.E., Jennings R.B., Reimer K.A. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation (1986) 74:1124–1136.[Abstract/Free Full Text]
  38. Mullane K. Myocardial preconditioning. Part of the adenosine revival. Circulation (1992) 85:845–847.[Free Full Text]
  39. Miura T., Ogawa T., Iwamoto T., Shimamoto K., Iimura O. Dipyridamole potentiates the myocardial infarct size-limiting effect of ischemic preconditioning. Circulation (1992) 86:979–985.[Abstract/Free Full Text]
  40. Edlund A., Siden A., Sollevi A. Evidence for an anti-aggregatory effect of adenosine at physiological concentrations and for its role in the action of dipyridamole. Thromb Res (1987) 45:183–190.[CrossRef][Web of Science][Medline]
  41. Cristalli G., Vittori S., Thompson R.D., et al. Inhibition of platelet aggregation by adenosine receptor agonists. Naunyn Schmiedebergs Arch Pharmacol (1994) 349:644–650.[CrossRef][Web of Science][Medline]
  42. Deguchi H., Takeya H., Urano H., et al. Adenosine regulates tissue factor expression on endothelial cells. Thromb Res (1998) 91:57–64.[CrossRef][Web of Science][Medline]
  43. Minamino T., Kitakaze M., Asanuma H., et al. Endogenous adenosine inhibits P-selectin-dependent formation of coronary thromboemboli during hypoperfusion in dogs. J Clin Invest (1998) 101:1643–1653.[Web of Science][Medline]
  44. Cronstein B.N. Adenosine, an endogenous anti-inflammatory agent. J Appl Physiol (1994) 76:5–13.[Abstract/Free Full Text]
  45. Ohta A., Sitkovsky M. Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage. Nature (2001) 414:916–920.[CrossRef][Medline]
  46. Cronstein B.N., Levin R.I., Belanoff J., Weissmann G., Hirschhorn R. Adenosine: an endogenous inhibitor of neutrophil-mediated injury to endothelial cells. J Clin Invest (1986) 78:760–770.[Web of Science][Medline]
  47. Sajjadi F.G., Takabayashi K., Foster A.C., Domingo R.C., Firestein G.S. Inhibition of TNF-{alpha} expression by adenosine: role of A3 adenosine receptors. J Immunol (1996) 156:3435–3442.[Abstract]
  48. Flamand N., Boudreault S., Picard S., et al. Adenosine, a potent natural suppressor of arachidonic acid release and leukotriene biosynthesis in human neutrophils. Am J Respir Crit Care Med (2000) 161:S88–S94.[Free Full Text]
  49. Maggirwar S.B., Dhanraj D.N., Somani S.M., Ramkumar V. Adenosine acts as an endogenous activator of the cellular antioxidant defense system. Biochem Biophys Res Commun (1994) 201:508–515.[CrossRef][Web of Science][Medline]
  50. Burnstock G. Purinergic signaling and vascular cell proliferation and death. Arterioscler Thromb Vasc Biol (2002) 22:364–373.[Abstract/Free Full Text]
  51. Dubey R.K., Gillespie D.G., Mi Z., Suzuki F., Jackson E.K. Smooth muscle cell-derived adenosine inhibits cell growth. Hypertension (1996) 27:766–773.[Abstract/Free Full Text]
  52. Dubey R.K., Gillespie D.G., Shue H., Jackson E.K. A(2B) receptors mediate antimitogenesis in vascular smooth muscle cells. Hypertension (2000) 35:267–272.[Abstract/Free Full Text]
  53. Dubey R.K., Gillespie D.G., Jackson E.K. Adenosine inhibits collagen and total protein synthesis in vascular smooth muscle cells. Hypertension (1999) 33:190–194.[Abstract/Free Full Text]
  54. Takiguchi Y., Nagano M., Ikeda Y., Nakashima M. Early administration of YT-146, an adenosine A2 receptor agonist, inhibits neointimal thickening after rat femoral artery endothelium injury. Eur J Pharmacol (1995) 281:205–207.[CrossRef][Web of Science][Medline]
  55. Dubey R.K., Gillespie D.G., Jackson E.K. A(2B) adenosine receptors stimulate growth of porcine and rat arterial endothelial cells. Hypertension (2002) 39:530–535.[Abstract/Free Full Text]
  56. Peyot M.L., Gadeau A.P., Dandre F., et al. Extracellular adenosine induces apoptosis of human arterial smooth muscle cells via A(2b)-purinoceptor. Circ Res (2000) 86:76–85.[Abstract/Free Full Text]
  57. Van Belle H. Nucleoside transport inhibition: a therapeutic approach to cardioprotection via adenosine? Cardiovasc Res (1993) 27:68–76.[Web of Science][Medline]
  58. Thornton J.D., Liu G.S., Olsson R.A., Downey J.M. Intravenous pretreatment with A1-selective adenosine analogues protects the heart against infarction. Circulation (1992) 85:659–665.[Abstract/Free Full Text]
  59. Dubey R., Mi Z., Gillespie D.G., Jackson E.K. Dysregulation of extracellular adenosine levels by vascular smooth muscle cells from spontaneously hypertensive rats. Arterioscler Thromb Vasc Biol (2001) 21:249–254.[Abstract/Free Full Text]
  60. Watanabe M., Osada J., Aratani Y., et al. Mice deficient in cystathionine β-synthase: animal models for mild and severe homocyst(e)inemia. Proc Natl Acad Sci USA (1995) 92:1585–1589.[Abstract/Free Full Text]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Ann Rheum DisHome page
N P Riksen, P Barrera, P H H van den Broek, P L C M van Riel, P Smits, and G A Rongen
Methotrexate modulates the kinetics of adenosine in humans in vivo
Ann Rheum Dis, April 1, 2006; 65(4): 465 - 470.
[Abstract] [Full Text] [PDF]

Home page
 Arterioscler. Thromb. Vasc. Bio.Home page
N. P. Riksen, G. A. Rongen, G. H.J. Boers, H. J. Blom, P. H.H. van den Broek, and P. Smits
Enhanced Cellular Adenosine Uptake Limits Adenosine Receptor Stimulation in Patients With Hyperhomocysteinemia
Arterioscler Thromb Vasc Biol, January 1, 2005; 25(1): 109 - 114.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
S. J. Moat, S. N. Doshi, D. Lang, I. F. W. McDowell, M. J. Lewis, and J. Goodfellow
Treatment of coronary heart disease with folic acid: is there a future?
Am J Physiol Heart Circ Physiol, July 1, 2004; 287(1): H1 - H7.
[Full Text] [PDF]

Home page
 Cardiovasc ResHome page
A. Deussen
Adenosine--the missing link to understanding homocysteine pathogenicity or more smoke on the horizon?
Cardiovasc Res, August 1, 2003; 59(2): 259 - 261.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Riksen, N. P.
Right arrow Articles by Smits, P.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Riksen, N. P.
Right arrow Articles by Smits, P.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?