New approach to prevent myocardial hypertrophy: the import blocking peptide.
Calcineurin, a serine/threonine phosphatase, plays a crucial role in the development of myocardial hypertrophy. Calcineurin is a cytosolic phosphatase that dephosphorylates the nuclear factor of activated T cells (NFAT), a transcription factor. Until now, it has been postulated that dephosphorylated NFAT is shuttled into the nucleus. Recent evidence demonstrates that not only NFAT, but also calcineurin, is localized in the nucleus. Once calcineurin and NFAT enter the nucleus of cardiomyocytes, transcription of genes that are characteristic for myocardial hypertrophy (e.g., brain natriuretic peptide and atrial natriuretic peptide) occurs. Although the exact nuclear function of calcineurin remains unclear, its co-existence with NFAT is important for the full transcriptional activity of the calcineurin/NFAT signaling cascade. The principal effect of nuclear calcineurin is likely the prolonged nuclear retention period of NFAT. Potential effects of nuclear calcineurin include an antagonistic function to glycogen synthase kinase 3beta, which phosphorylates NFAT for its export out of the nucleus, or direct antagonization of the export of NFAT, catalyzed by the chromosome region maintenance 1, which would leave NFAT nuclear. The nuclear localization sequence (NLS) region at the amino acid sequence from position 172 to 183 of calcineurin Abeta is essential for shuttling calcineurin into the nucleus by importinbeta(1). A synthetic import blocking peptide (IBP) that mimics the nuclear localization sequence of calcineurin was generated. The NLS analog on IBP saturates the calcineurin binding site of importinbeta(1). This prevents the binding of calcineurin to importin and inhibits the nuclear shuttling of calcineurin. Inhibition of the calcineurin/importinbeta(1) interaction by competing synthetic peptides represents a new approach to the inhibition of the development of myocardial hypertrophy.
University of Wuerzburg, Department of Medicine I, Department of Molecular Cardiology, Josef-Schneider-Str. 2, 97080 Wuerzburg, Germany. hallhuber_m@klinik.uni-wuerzburg.de
Matthias
M
Hallhuber
Oliver
O
Ritter