Cyclin-dependent kinase inhibitor expression in human heart failure - A comparison with fetal development

Aims Terminal differentiation of cardiac myocyte is associated with their p ermanent withdrawal from the cell cycle. In adult end-stage heart failure, significant numbers of myocytes express proliferating cell nuclear antigen yet fail to progress to cell division. Cyclin dependent kinase inhibitors a re powerful inhibitors of the cell cycle and may play a direct role both in myocyte development and in preventing cell division in the adult. Methods and Results The expression of the CIP/KIP cyclin dependent kinase i nhibitors p21, p27, p57 and the retinoblastoma protein was examined in acut e (seen in brain dead transplant donors) and end-stage heart failure by Wes tern blot analysis and compared to that seen in human and rat cardiac devel opment. The expression of p21 showed a gradual increase during development in both rat and man, becoming maximal in adulthood. p27 levels showed an in itial rise with subsequent continual expression throughout life. p57 expres sion was detectable at only early stages in rat but persisted throughout li fe in man. In both acute and end-stage heart failure the levels of p21, p27 and p57 reverted to a pattern similar to that observed in human fetal hear t: p21 and p27 declined while p57 expression was significantly increased. I n contrast, retinoblast protein levels declined during human heart developm ent but were unaltered in heart failure. Conclusions The expression of p21, but not p27 or p57, is consistent with a role in the gradual withdrawal of cardiac myocytes from cell cycle during development. In adult heart failure cyclin dependent kinase inhibitor expre ssion reverts to the fetal pattern but is insufficient to initiate cell cyc le activation.