p38 MAPK and the compromised regenerative response of the infarcted adult heart

Mononucleated cardiomyocytes promoted the hyperplasic growth of the embryonic mammalian heart and the proliferative phenotype was retained by neonatal cardiomyocytes for a short duration after birth. Despite the cell cycle re-entry of pre-existing cardiomyocytes, regeneration of the damaged neonatal heart required the coordinated effort of reparative embryonic macrophages. During postnatal development, pre-existing cardiomyocytes underwent karyokinesis in the absence of cytokinesis and the ability to proliferate was lost. However, a paucity of mononucleated cardiomyocytes persisted in the adult heart and an ischemic insult facilitated re-entry into the cell cycle. The latter paradigm provided a semblance of hope that a cardiac regenerative response was possible. However, the selective expansion of pro-inflammatory monocyte-derived macrophages following ischemic injury to the adult heart may have further impeded an already compromised regenerative response. The serine/threonine kinase p38 MAPK was identified as a seminal target of pro-inflammatory cytokines and a smaller infarct was reported after inhibition. The smaller infarct was attributed in part to cardiac regeneration as p38 MAPK suppressed the cell cycle re-entry of neonatal/adult cardiomyocytes in response to peptide growth factors. p38 MAPK-mediated inhibition of cell cycle re-entry may be related in part to the attenuation of nestin expression by pre-existing cardiomyocytes as the intermediate filament protein was directly implicated in the cell proliferation of normal and tumorigenic cells. Thus, targeting the inflammatory response via p38 MAPK inhibition may represent a rational approach to unmask the proliferative potential of pre-existing mononucleated cardiomyocytes and initiate a partial regenerative response of the infarcted adult mammalian heart.