Ischemia/reperfusion-induced apoptosis: connecting nitric oxide and cell cycle regulators

See article by Maejima et al. [1] (pages 308–320) in this issue. Cardiomyocytes are able to divide throughout the fetal period of life and continue to increase in cell number up to the first 2-3 days after birth. Thereafter, they undergo terminal differentiation. Although in certain pathological conditions, such as myocardial infarction, cardiomyocyte proliferation has been observed also in the adult heart [2], postnatal cardiomyocytes are normally irreversibly withdrawn from the cell cycle, resulting in the loss of their regenerative capacity. In response to some stimuli, such as increased overload and ischemia, cardiac myocytes can grow by hypertrophy, which is accompanied by the upregulation of protein synthesis [3]. Hypertrophic and mitogenic stimuli share similar intracellular responses, such as multiple second messenger systems and induction of various immediate-early genes. Actually, serum stimulation of neonatal, terminally-differentiated cardiomyocytes, similarly to what happens in proliferating cells, upregulates some of the cell cycle regulators such as G1 cyclins and associated cyclin-dependent kinases (cdks), which are required for the induction of cardiac hypertrophy [4]. The cdk enzymes are members of a conserved family of serine/threonine kinases whose activity is dependent on the presence of activating subunits known as cyclins. The abundance of specific cyclins increases during phases of the cell cycle in which they are required, thus regulating cell cycle progression. Such a control system operates at the level of checkpoints that occur at the G1/S phase boundary, in the S phase, and during the G2/M phases. For example, cdk2 binds cyclin A or E at the transition G1/S of the cycle and the complex may phosphorylate specific proteins, thus allowing the cell cycle processes to continue. Whereas cyclin binding is required for cdk kinase activity, other proteins can inhibit the enzymatic activity of cyclin/cdk complexes and prevent cell cycle progression. The p21 … *Corresponding author. Tel.: +39-51-2091203; fax: +39-51-2091224. claudio.stefanelli{at}unibo.it