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Therapeutic Chemical Screen Identifies Phosphatase Inhibitors to Reconstitute PKB Phosphorylation and Cardiac Contractility in ILK-Deficient Zebrafish

Pott, A.; Shahid, M.; Köhler, D.; Pylatiuk, C.; Weinmann, K.; Just, S.; Rottbauer, W.

Abstract:
Patients with inherited dilated cardiomyopathy (DCM) often suffer from severe heart failure based on impaired cardiac contractility leading to increased morbidity and mortality. Integrin-linked kinase (ILK) as a part of the cardiac mechanical stretch sensor was found to be an essential genetic regulator of cardiac contractility. Integrin-linked kinase localizes to z-disks and costameres in vertebrate hearts and regulates the activity of the signaling molecule protein kinase B (PKB/Akt) by controlling its phosphorylation. Despite identification of several potential drug targets in the ILK signaling pathway, pharmacological treatment strategies to restore contractile function in ILK-dependent cardiomyopathies have not been established yet. In recent years, the zebrafish has emerged as a valuable experimental system to model human cardiomyopathies as well as a powerful tool for the straightforward high-throughput in vivo small compound screening of therapeutically active substances. Using the ILK deficient zebrafish heart failure mutant main squeeze (msq), which shows reduced PKB phosphorylation and thereby impaired cardiac contractile force, we identified here, in an automated small compound screen, the protein phosphatase inhibitors calyculin A and okadaic acid significantly restoring myocardial contractile function by reconstituting PKB phosphorylation in msq ILK-deficient zebrafish embryos.

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Verlagsausgabe §
DOI: 10.5445/IR/1000088428
Veröffentlicht am 17.12.2018
Originalveröffentlichung
DOI: 10.3390/biom8040153
Scopus
Zitationen: 4
Web of Science
Zitationen: 3
Cover der Publikation
Zugehörige Institution(en) am KIT Institut für Angewandte Informatik (IAI)
Publikationstyp Zeitschriftenaufsatz
Publikationsjahr 2018
Sprache Englisch
Identifikator ISSN: 2218-273X
urn:nbn:de:swb:90-884281
KITopen-ID: 1000088428
HGF-Programm 47.01.02 (POF III, LK 01)
Biol.Netzwerke u.Synth.Regulat. IAI
Erschienen in Biomolecules
Band 8
Heft 4
Seiten Art. Nr.: 153
Schlagwörter dilated cardiomyopathy, integrin-linked kinase-protein kinase B (ILK-PKB) signaling, small chemical compounds, phosphatase inhibitors
Nachgewiesen in Scopus
Web of Science
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