The myocardial endocannabinoid system has been linked to stress response and cardioprotection. In chronic heart failure (CHF), protective CB2 receptors are markedly up-regulated while CB1 receptors are slightly down-regulated. We here provide evidence that myocardial CB receptors are subject to microRNA regulation. By a combined computational and experimental approach we show that CB1 receptors are regulated by miR-494, and CB2 receptors are targeted by miR-665. Moreover, we demonstrate that in CHF, miR-665 expression is significantly decreased while miR-494 is slightly increased, which is concordant with the previously reported alterations of CB receptors. These results suggest that in CHF, altered expression of specific miRNAs may contribute to a compensatory response of the diseased myocardium. (C) 2014 Elsevier Inc. All rights reserved.