Compositions and methods for increasing proliferation and / or de-differentiation of postmitotic mammalian cardiomyocytes are disclosed to slow, reduce, or prevent the onset of cardiac damage. In addition, the methods and compositions of the invention can used to produce de-differentiated cardiomyocytes, which can then be used in tissue grafting, implantation or transplantation. The invention is based, in part, on the discovery that postmitotic mammalian cardiomyocytes can proliferate as a result of targeted disruption of p38 MAP kinase. p38 inhibition with optional growth factor stimulation can induce cytokinesis in adult cardiomyocytes.