Adult mammalian cardiomyocytes have extremely limited capacity to regenerate, and it is believed that a strong intrinsic mechanism is prohibiting the cardiomyocytes from entering the cell cycle. microRNAs that promote proliferation in cardiomyocyte can be used as probes to identify novel genes suppressing cardiomyocytes proliferation, thus dissecting the mechanism(s) preventing cardiomyocytes from duplication. In particular, miR-199a-3p has been found as a potent activator of proliferation in rodent cardiomyocyte, although its molecular targets remain elusive. Here, we identified Cd151 as a direct target of miR-199a-3p, and its expression is greatly suppressed by miR-199a-3p. Cd151 gain-of-function reduced cardiomyocyte proliferation, conversely Cd151 loss-of-function increased cardiomyocytes proliferation. Overexpression of Cd151 blocks the activating effect of miR-199a-3p on cardiomyocyte proliferation, suggesting Cd151 is a functional target of miR-199a-3p in cardiomyocytes. Mechanistically, we found that Cd151 induces p38 expression, a known negative regulator of cardiomyocyte proliferation, and pharmacological inhibition of p38 rescued the inhibitory effect of Cd151 on proliferation. Together, this work proposes Cd151 as a novel suppressor of cardiomyocyte proliferation, which may provide a new molecular target for developing therapies to promote cardiac regeneration. (C) 2019 Elsevier Inc. All rights reserved.