Cardiomyocytes functioning has been shown to be regulated by elevated concentration of cytoplasmic free calcium, [Ca+2+]i. In hypertrophy, cardiomyocyte cell size is increased. This involves an enhanced protein synthesis, up-regulation of fetal cardiac genes and induction of immediate early genes (1). Signaling pathways leading to cardiac hypertrophy are all associated with an increase in intracellular Ca+2concentration. (1). Also, changes in cytosolic Ca+2 play a central role in the regulation of key nuclear events, including regulation of gene expression (2). In addition, numerous data highlight the role of Ca+2 release in inflammatory heart disease, heart failure myocardial ischemia, reperfusion and apoptosis (2).
Cohen–Armon and collaborators found recently that the highly conserved and abundant chromatin-bound protein PARP-1 (polyADP-ribose polymerase-1) is rapidly activated in depolarized brain cortical neurons in response to Ca+2 release into the nucleoplasm (3). PARP-1 is known to be activated by nicked DNA promoting cell death under stress conditions, thereby catalyzing a transient (t1/2=1 min) post-translational modification of nuclear proteins by polyADP-ribosylation. This modification is initiated by ADP-ribose binding to glutamic and aspartic moieties of nuclear proteins and proceeds by polymerization of ADP-riboses via glycoside bonds into high polymers. NAD-derived ADP-ribose polymers interfere with the binding of proteins to DNA (4). Therefore, PARP-1 activation and polyADP-ribosylation of histones, transcription factors, RNA-polymerase II, DNA-polymerases, topoisomerases and ligases affects chromatin structure, DNA transcription and repair (4).
In this work we show that in cardiomyocytes, beating is accompanied by a rhythmic release of Ca+2 into the nucleoplasm. PARP-1 is rapidly and dose-dependenly activated by applying Ca+2 to isolated nuclei of cardiomyocytes, or by agents promoting Ca+2-release from intracellular Ca+2 stores. In addition, prolonged inhibition of PARP-1 activity reduces most significantly their beating rate. These results suggest a possible physiological role of polyADP-ribosylation in normal functioning of cardiomyocytes. The rhythmic release of Ca+2 into the nucleus, and dose dependent activation of PARP-1 apparently take part in a mechanism controlling the activity of transcription factors in the nucleus of cardiomyocytes. The results of this research are prepared for submission to J Biol Chem.
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