Reduced adenosine receptor stimulation as a pathogenic factor in hyperhomocysteinemia

In this review we discuss the hypothesis, and current evidence, that a decreased concentration of the endogenous purine-nucleoside adenosine contributes to the increased cardiovascular risk of patients with hyperhomocysteinernia. In hyperhomocysteinernia, the reaction equilibrium of the reaction catalysed by S-adenosylhomocysteine hydrolase will shift towards synthesis of S-adenosylhomocysteine, at the expense of free adenosine. Adenosine receptor stimulation induces several cardiovascular protective effects, such as vasodilation, inhibition of thrombocyte aggregation, of inflammation and of vascular smooth muscle cell proliferation. A decreased adenosine concentration could, therefore, well contribute to the cardiovascular complications of hyperhomocysteinernia. Previous animal studies have shown that administration of homocysteine decreases extracellular adenosine, associated with increased synthesis of S-adenosylhomocysteine. Recently, we showed that in patients with classical homocystinuria, cellular adenosine uptake is enhanced, thus limiting adenosine-induced vasoclilation. These observations provide us with additional pharmacological targets, such as adenosine uptake inhibition, to reduce cardiovascular risk in patients with hyperhomocysteinemia.