Role of D-type cyclins in heart development and disease

A defining feature of embryonic cardiomyocytes is their relatively high rates of proliferation. A gradual reduction in proliferative capacity throughout development culminates in permanent cell cycle exit by the vast majority of cardiomyocytes around the perinatal period. Accordingly, the adult heart has severely limited capacity for regeneration in response to injury or disease. The D-type cyclins (cyclin D1, D2, and D3) along with their catalytically active partners, the cyclin dependent kinases, are positive cell cycle regulators that play important roles in regulating proliferation of cardiomyocytes during normal heart development. While expression of D-type cyclins is generally low in the adult heart, expression levels are augmented in association with cardiac hypertrophy, but are uncoupled from myocyte cell division. Accordingly, re- activation of D-type cyclin expression in the adult heart has been implicated in pathophysiological processes via mechanisms distinct from those that drive proliferation during cardiac development. Growth factors and other exogenous agents regulate D- type cyclin production and activity in embryonic and adult cardiomyocytes. Understanding differences in the precise intracellular mediators downstream from these signalling molecules in embryonic versus adult cardiomyocytes could prove valuable for designing strategies to reactivate the cell cycle in cardiomyocytes in the setting of cardiovascular disease in the adult heart. Key words: D-type cyclins, heart development, hypertrophy, cell cycle, cardiovascular disease. Les cardiomyocytes embryonnaires se caracterisent par un taux de proliferation relativement eleve. Chez la majorite des cardiomyocytes, la reduction graduelle de leur capacite proliferative au cours du developpement culmine en une sortie permanente du cycle cellulaire autour de la periode perinatale. Consequemment, le coeur adulte possede une capacite extremement limitee de regeneration en reponse a un dommage ou une maladie. Les cyclines de type D (cycline D1, D2 et D3) et leurs partenaires actifs sur le plan catalytique, les kinases dependantes des cyclines, sont des regulateurs positifs du cycle cellulaire qui jouent un role important en regulant la proliferation des cardiomyocytes durant le developpement normal du coeur. Alors que l'expression des cyclines de type D est generalement faible dans le coeur adulte, leur niveau d'expression est augmente lors de l'hypertrophie cardiaque mais il n'est pas couple a la division des myocytes. Ainsi, la reactivation de l'expression des cyclines de type D dans le coeur adulte a ete impliquee dans des processus pathophysiologiques par l'intermediaire de mecanismes distincts de ceux qui controlent la proliferation lors du developpement cardiaque. Les facteurs de croissance et autres agents exogenes regulent la production et l'activite des cyclines de type D chez les cardiomyocytes embryonnaires et adultes. Il pourrait s' averer important de comprendre comment les cardiomyocytes embryonnaires et adultes different sur le plan des mediateurs intracellulaires precis qui agissent en aval de ces molecules de signalisation, afin d'elaborer des strategies pour reactiver le cycle cellulaire des cardiomyocytes lors de la maladie cardiovasculaire du coeur adulte. Mots-cles : cyclines de type D, developpement de coeur, hypertrophie, cycle cellulaire, maladie cardiovasculaire. [Traduit par la Redaction]
Introduction During embryogenesis, the heart transforms from a simple tubular structure to a specialized 4-chambered pump. The morphological changes associated with heart formation are the result of the tightly controlled [...]