Equilibrative Nucleoside tTransporter 1 and 4: which one is a Better Target for Cardioprotection against Ischemia-reperfusion Injury?

Abstract

The cardioprotective effects of adenosine and adenosine receptor agonists in the treatment of ischemic heart disease have been studied extensively. However, their therapeutic outcomes are limited by systemic side effects (e.g. hypotension, bradycardia and sedation). Equilibrative nucleoside transporter (ENT) inhibitors may be a better alternative. By reducing the uptake of extracellular adenosine, ENT1 inhibitors amplify and prolong the cardioprotective and vasodilator effects of endogenous adenosine. ENT1 inhibitors should have fewer systemic side effects because they selectively increase the extracellular adenosine levels in tissues undergoing accelerated adenosine formation (e.g. in ischemic myocardium). Nonetheless, ENT1 inhibitors may adversely affect tissues that lack de novo nucleotide biosynthesis (e.g. erythrocytes, leukocytes and intestine). ENT1 inhibitors may also affect the cellular uptake and hence the efficacies of anti-cancer and anti-viral nucleoside analogs used in chemotherapy. ENT4, a novel type of ENT, is abundant in the heart but its function is unclear. Our studies show that ENT4 contributes to adenosine transport in cardiomyocytes, especially under acidic and ischemic conditions. Interestingly, ENT4 in cardiomyocytes is upregulated in hypertension. This may help to explain why hypertensive patients are in high risk of ischemic heart disease. Inhibition of ENT4 exerts cardioprotective effect against ischemia-reperfusion injury. Unlike ENT1, ENT4 transports adenosine specifically but not other nucleosides. Therefore, ENT4 inhibitors do not affect tissues which rely on ENT1 for de novo nucleotide synthesis. ENT4 inhibitors also have no interaction with anti-cancer and anti-viral nucleoside drugs. Taken together, we believe that inhibition of ENT4 may be an attractive approach for treating ischemic heart disease.