Cardiomyocytes possess a unique ability to transition from mononucleate to the

Cardiomyocytes possess a unique ability to transition from mononucleate to the mature binucleate Rosiglitazone (BRL-49653) phenotype in late fetal development and around birth. the proliferative capacity of cardiomyocytes. [6]. In humans there is considerable debate about the amount of binucleate cells present in the adult heart with values ranging from 25 to 60% [6]. Rodents and sheep by contrast have approximately 90% of the cardiomyocyte population binucleated [6]. The physiological importance of binucleation is still poorly understood. A plausible explanation is that multinucleation optimizes cellular response enhancing cell survival when coping with stress [7]. Another argument is that binucleation occurs to meet the high metabolic demand of cardiomyocytes. As such binucleation has an advantageous role in enabling the cell to generate twice the amount of RNA to synthesize proteins [3]. This review discusses factors involved in cardiomyocyte transition including alterations to its timing the underlying molecular mechanisms and the role of epigenetic regulation and therapeutic targets. Premature transition The intrauterine environment is highly influential on the health of an individual. Its influence can lead Rosiglitazone (BRL-49653) to structural and functional adaptations of several organs including the heart. Rosiglitazone (BRL-49653) Persistence of these adaptations can increase vulnerability later in life to diseases including metabolic syndrome and cardiovascular disease [6 8 9 Altered cardiomyocyte number could be responsible for this increased Rosiglitazone (BRL-49653) susceptibility. In support animal studies provide evidence that fetal stress caused by hypoxia [10] glucocorticoids [11] or maternal malnutrition [12 13 affects the number of cardiomyocytes and the ability of the heart to cope with stress later in life. Hypoxia Hypoxia is a major fetal stressor induced under a variety of conditions including nicotine exposure high altitude pregnancy preeclampsia and placental insufficiency. The long-term implications of this adverse environment have been well established [8 14 Recent studies have shown that hypoxia directly reduces proliferation in fetal rat cardiomyocytes [15]. In other studies maternal hypoxia was found to result in increased size and percent of binucleate cardiomyocytes [10] along with remodeling of the fetal and neonatal rat heart [16]. Fetal sheep Rosiglitazone (BRL-49653) anemia studies by Jonker studies reveal this can be achieved by hypoxia-induced dedifferentiation [20]. These studies indicate a possible dual role of hypoxia in regulating cardiomyocyte proliferation. Altogether demonstrating that hypoxia is involved in cardiac remodeling and can directly affect cardiomyocyte endowment of the heart. Glucocorticoids Glucocorticoids are a class of hormones essential to normal lung development and the regulation of the cardiovascular system. Although glucocorticoids are essential to the development and survival of the fetus excessive exposure has negative implications including delayed maturation of astrocytes [21] reduced birth weights [22] and altered glucocorticoid receptor expression [23]. Evidence exists for a role of glucocorticoids in regulating cardiomyocyte development. Early studies by Rudolph reported a reduction in cardiomyocyte proliferation after fetal sheep cortisol infusion associated with hypertrophic growth [24]. However more recently studies in fetal sheep revealed increased proliferation without an increase in cardiomyocyte size after cortisol infusion [11]. In this latter study no differences in length width and overall percentage binucleation of cardiomyocytes were observed between cortisol-treated and nontreated groups. In addition the Mouse monoclonal to CD16.COC16 reacts with human CD16, a 50-65 kDa Fcg receptor IIIa (FcgRIII), expressed on NK cells, monocytes/macrophages and granulocytes. It is a human NK cell associated antigen. CD16 is a low affinity receptor for IgG which functions in phagocytosis and ADCC, as well as in signal transduction and NK cell activation. The CD16 blocks the binding of soluble immune complexes to granulocytes. cortisol treatment did not drive the maturation Rosiglitazone (BRL-49653) of cardiomyocytes but rather stimulated their entry into the cell cycle suggesting cortisol is associated with hyperplastic growth. These opposing results are probably the result of the different methods of quantification used by the researchers; and are further discussed by Giraud [11]. In the fetal rat low-dose dexamethasone a synthetic glucocorticoid was found to decrease fetal bodyweight when administered prenatally by Torres [25]. In this study the dexamethasone-treated group was found to have increased.