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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 ... mehr

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Verlagsausgabe §
DOI: 10.5445/IR/1000088428
Veröffentlicht am 17.12.2018
Zugehörige Institution(en) am KIT Institut für Angewandte Informatik (IAI)
Publikationstyp Zeitschriftenaufsatz
Jahr 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)
Erschienen in Biomolecules
Band 8
Heft 4
Seiten Art. Nr.: 153
Schlagworte dilated cardiomyopathy, integrin-linked kinase-protein kinase B (ILK-PKB) signaling, small chemical compounds, phosphatase inhibitors
Nachgewiesen in Web of Science
Scopus
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