Enhanced Cellular Adenosine Uptake Limits Adenosine Receptor Stimulation in Patients With Hyperhomocysteinemia

Abstract

Objective-Endogenous adenosine has several cardioprotective effects. We postulate that in patients with hyperhomocysteinemia increased intracellular formation of S-adenosylhomocysteine decreases free intracellular adenosine. Subsequently, facilitated diffusion of extracellular adenosine into cells through dipyridamole-sensitive transporters is enhanced, limiting adenosine receptor stimulation. We tested this hypothesis in patients with classical homocystinuria (nϭ9, plasma homocysteine 93.1Ϯ24.7 mol/L) and matched controls (nϭ8, homocysteine 9.1Ϯ1.0). Methods and Results-Infusion of adenosine (0.5, 1.5, 5.0, and 15.0 g/min/dL forearm) into the brachial artery increased forearm blood flow, as measured with venous occlusion plethysmography, to 2.9Ϯ0.4, 4.3Ϯ0.5, 5.6Ϯ1.1, and 9.6Ϯ2.1 in the patients and to 2.8Ϯ0.6, 4.4Ϯ1.0, 9.0Ϯ1.7, and 17.0Ϯ3.1 mL/min/dL in controls (PϽ0.05). However, adenosine-induced vasodilation in the presence of dipyridamole (100 g/min/dL) was similar in both groups (Pϭ0.9). Additionally, in isolated erythrocytes, adenosine uptake was accelerated by incubation with homocysteine (half-time 6.4Ϯ0.3 versus 8.1Ϯ0.5 minutes, PϽ0.001) associated with increased intracellular formation of S-adenosylhomocysteine (PϽ0.0001). Conclusions-In hyperhomocysteinemia, adenosine-induced vasodilation is impaired but is restored by dipyridamole.Accelerated cellular adenosine uptake probably accounts for these observations. These impaired actions of adenosine could well contribute to the cardiovascular complications of hyperhomocysteinemia. Key Words: adenosine Ⅲ hyperhomocysteinemia Ⅲ dipyridamole Ⅲ forearm Ⅲ nucleoside transport H yperhomocysteinemia is an independent risk factor for atherosclerosis and thromboembolism. It is poorly understood which mechanism is responsible for these cardiovascular complications.Recently, we and others have drawn attention to a new hypothesis, focusing on the influence of homocysteine on the metabolism of the endogenous nucleoside adenosine. 1,2 According to this hypothesis, a homocysteine-induced fall in extracellular adenosine contributes to the cardiovascular sequelae of hyperhomocysteinemia. Fundamental to this is the reversibility of the reaction in which S-adenosylhomocysteine (AdoHcy) is hydrolyzed to form homocysteine and adenosine. 3 Although the equilibrium constant of this reaction favors AdoHcy synthesis, under physiological conditions AdoHcy is hydrolyzed to homocysteine and adenosine, because both reaction products are rapidly metabolized. In hyperhomocysteinemia, the reaction shifts toward AdoHcy synthesis at the expense of free intracellular adenosine. Subsequently, facilitated diffusion of extracellular adenosine into the cells through the dipyridamole-sensitive equilibrative nucleoside transporter is enhanced, limiting stimulation of membrane-bound adenosine receptors (Figure 1).By stimulation of these receptors, extracellular adenosine induces several effects, which could protect against the development of atherosclerosis and thrombosis and against ischemia-re...

Adenosine A2B receptor-mediated VEGF induction promotes diabetic glomerulopathy

“…44,45 This decreased activity of ENT1 elicits adenosine signaling by ARs as previously described, using inhibitors of ENT1 activity or in ENT1 À / À mice. 10,19,20 Interestingly, a correlation between ENT1 decreased activity with epithelium mesenchymal transition (EMT) of renal proximal tubule epithelial cells in vitro, was recently demonstrated. 46 EMT is a requisite for progression of tubule-interstitial fibrosis in the diabetic kidney disease.…”

“…14 It has been described that the equilibrative nucleoside transporters (ENTs), characterized by its sodium-independent facilitative transport activity, could have a major contribution on adenosine availability for signaling through adenosine receptor (AR). [15][16][17][18][19][20][21] ENTs activity mediates adenosine uptake to be either metabolized intracellularly, or to accumulate outside when the uptake activity is reduced. We have previously determined that the ENT1's activity decreased in diabetic rats' glomeruli 22 therefore, the handling of the nucleoside could be altered in this pathologic condition.…”

Nucleoside Transport Inhibition by Dipyridamole Prevents Angiogenesis Impairment by Homocysteine and Adenosine

“…Our previous reports have demonstrated that the combination of homocysteine and adenosine exacerbated TNF cytotoxicity and apoptosis in endothelial cells (7,8). This connection between homocysteine and adenosine has been associated with their active involvements in methionine metabolism and cellular methylation, as well as the enhanced cellular uptake of adenosine induced by homocysteine (13). To the best of our knowledge, there is a lack of studies evaluating the potential use of nucleoside transport inhibitors to block cellular adenosine uptake in vascular complications associated with homocysteine.…”

“…It is known that a high level of homocysteine induces the synthesis of S-adenosylhomocysteine using the intracellular adenosine pool. This creates a transmembranous adenosine gradient and subsequently, facilitates the cellular uptake of extracellular adenosine (5,13). Dipyridamole is a clinical anti-platelet drug approved for the prevention of thromboembolism, and secondary prevention of ischaemic stroke and transient ischaemic attack.…”

Adenosine mediates transforming growth factor‐beta 1 release in kidney glomeruli of diabetic rats

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