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

Recent Patents on Cardiovascular Drug Discovery
Franziska PantherOliver Ritter

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 ...Continue Reading

Citations

Jul 26, 2011·Fiziologiia cheloveka·S A Kryzhnovskiĭ, M B Vititnova
Dec 20, 2011·Endocrine-related Cancer·Gavin P VinsonJohn R Puddefoot
Oct 12, 2011·Drugs·Morris KarmazynXiaohong Tracey Gan
Sep 3, 2016·Journal of Molecular and Cellular Cardiology·Dmitry Terentyev, Shanna Hamilton
Sep 21, 2011·Laboratory Investigation; a Journal of Technical Methods and Pathology·Ying LiJun-Hui Luo
May 16, 2017·Canadian Journal of Physiology and Pharmacology·Morris Karmazyn, Xiaohong Tracey Gan

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