Inhibition of the calcineurin-NFAT signalling cascade in the treatment of heart failure.

Abstract

Calcineurin (Cn), a serine/threonine phosphatase, plays a crucial role in the development of myocardial hypertrophy. Cn is a cytosolic phosphatase which dephosphorylates various target molecules, e.g. the transcriptional factor nuclear factor of activated T cells (NFAT), thereby enabling its nuclear translocation. Recently, it was demonstrated that not only NFAT, but also Cn is translocated into the nucleus. The nuclear coexistence of Cn and NFAT is important for the full transcriptional activity of the Cn-NFAT signalling cascade. Once Cn and NFAT have entered the nucleus of cardiomyocytes, the transcription of genes characteristic for myocardial hypertrophy (e.g. BNP, ANP) is initiated. The nuclear localization sequence (NLS), a region spanning amino acids 172-183 of calcineurin Abeta (CnAbeta) is essential for recognition and shuttling of Cn into the nucleus by importinbeta (1). A synthetic import blocking peptide (IBP) that mimics the NLS of Cn was tested recently. The NLS analogon IBP saturates the Cn binding site of importinbeta(1) thereby preventing binding of Cn and importin. This inhibits the translocation of Cn into the nucleus. Inhibiting the Cn/importin interaction with competing synthetic peptides is one of several new approaches to prevent the development of myocardial hypertrophy. Several patents have also been filed on molecules related to inhibition of Cn-NFAT signalling.

• Authors: Franziska Panther, Tatjana Williams, Oliver Ritter
• Journal: Recent patents on cardiovascular drug discovery (Recent Pat Cardiovasc Drug Discov) Vol. 4 Issue 3 Pg. 180-6 (Nov 2009) United Arab Emirates
• PMID: 19925438 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)

Chemical References

• Calcineurin Inhibitors
• KPNB1 protein, human
• NFATC Transcription Factors
• NFATC1 protein, human
• Nuclear Localization Signals
• beta Karyopherins
• Calcineurin
• PPP3CB protein, human

Topics

• Active Transport, Cell Nucleus (physiology)
• Animals
• Calcineurin (physiology)
• Calcineurin Inhibitors
• Heart Failure (drug therapy, metabolism, therapy)
• Humans
• NFATC Transcription Factors (antagonists & inhibitors, physiology)
• Nuclear Localization Signals (genetics, metabolism)
• Protein Binding (physiology)
• Signal Transduction (genetics, physiology)
• Treatment Outcome
• beta Karyopherins (genetics, physiology)