Abstract
The present study tested the hypothesis that p38α MAPK inhibition leads to cell cycle re-entry of neonatal ventricular cardiomyocytes (NNVMs) and de novo nestin expression in response to thrombin and after apex resection of the neonatal rat heart. Thrombin (1 U/ml) treatment of 1-day old NNVMs did not induce cell cycle re-entry or nestin expression. Acute exposure of NNVMs to thrombin increased p38α MAPK and HSP27 phosphorylation and p38α/β MAPK inhibitor SB203580 abrogated HSP27 phosphorylation. Thrombin and SB203580 co-treatment of NNVMs led to bromodeoxyuridine incorporation and nestin expression. SB203580 (5 mg/kg) administration immediately after apex resection of 1-day old neonatal rat hearts and continued for two additional days shortened the fibrin clot length sealing the exposed left ventricular chamber. SB203580-treatment increased the density of troponin-T(+)-NNVMs that incorporated bromodeoxyuridine and expressed nuclear phosphohistone-3. Nestin(+)-NNVMs were selectively detected at the border of the fibrin clot and SB203580 potentiated the density that re-entered the cell cycle. These data suggest that the greater density of ventricular cardiomyocytes and nestin(+)-ventricular cardiomyocytes that re-entered the cell cycle after SB203580 treatment of the apex-resected neonatal rat heart during the acute phase of fibrin clot formation may be attributed in part to inhibition of thrombin-mediated p38α MAPK signalling.
Highlights
The adult heart of lower vertebrates possess the intrinsic capacity to regenerate myocardial tissue after injury via the proliferation of pre-existing mononucleated ventricular cardiomyocytes[1,2,3]
The reported recruitment of p38α MAPK signalling after thrombin stimulation of neonatal ventricular cardiomyocytes may prevent cell cycle re-entry after apex resection[11,12]
Engel and colleagues demonstrated that p38α MAPK activity was significantly repressed during the embryonic proliferative phase of heart development and expression of a dominant-negative form of the serine/threonine kinase increased cell cycle re-entry and cytokinesis of fetal cardiomyocytes delineated by nuclear phosphohistone-3 staining[17]
Summary
The adult heart of lower vertebrates (e.g. zebrafish, newts) possess the intrinsic capacity to regenerate myocardial tissue after injury via the proliferation of pre-existing mononucleated ventricular cardiomyocytes[1,2,3]. Www.nature.com/scientificreports reported that the adult rodent heart contains a modest population of pre-existing mononucleated ventricular cardiomyocytes and exploiting their potential proliferative phenotype may represent a viable approach to initiate a partial regenerative response after ischemic injury[6,7]. The intermediate filament protein facilitated cell cycle re-entry as shRNA-mediated depletion of constitutive nestin expression in embryonic rat ventricular cardiomyocytes or preventing induction in neonatal rat ventricular cardiomyocytes co-treated with PDBu and the p38α/β MAPK inhibitor SB203580 attenuated bromodeoxyuridine incorporation[15,16] Based on these data, it is tempting to speculate that the local accumulation of thrombin during the acute phase of fibrin clot formation after ventricular apex resection of the neonatal heart may partially suppress cell cycle re-entry of ventricular cardiomyocytes and prevent de novo nestin expression via recruitment of p38α MAPK-dependent signalling events. A second series of experiments will test the hypothesis that administration of the p38α/β MAPK inhibitor SB203580 during the acute phase of fibrin clot formation after ventricular apex resection of the neonatal rat heart increases the density of ventricular cardiomyocytes and subpopulation of nestin(+)-ventricular cardiomyocytes that re-enter the cell cycle translating to a partial cardiac regenerative response
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