Next Article in Journal
Squalene Found in Alpine Grassland Soils under a Harsh Environment in the Tibetan Plateau, China
Next Article in Special Issue
Semantic Multi-Classifier Systems Identify Predictive Processes in Heart Failure Models across Species
Previous Article in Journal / Special Issue
Atrial Fibrillation Predicts Long-Term Outcome after Transcatheter Edge-to-Edge Mitral Valve Repair by MitraClip Implantation
Article Menu
Issue 4 (December) cover image

Export Article

Open AccessArticle
Biomolecules 2018, 8(4), 153; https://doi.org/10.3390/biom8040153

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

1
Department of Internal Medicine II, Ulm University, Albert-Einstein-Allee 23, D-89081 Ulm, Germany
2
Department of Internal Medicine III, University of Heidelberg, D-69120 Heidelberg, Germany
3
Institute of Applied Computer Science, Karlsruhe Institute of Technology, D-76344 Eggenstein-Leopoldshafen, Germany
These authors contributed equally to this work.
These authors contributed equally to this work.
*
Authors to whom correspondence should be addressed.
Received: 20 September 2018 / Revised: 24 October 2018 / Accepted: 30 October 2018 / Published: 19 November 2018
(This article belongs to the Special Issue Biomolecules for Translational Approaches in Cardiology)
Full-Text   |   PDF [1909 KB, uploaded 19 November 2018]   |  

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. View Full-Text
Keywords: dilated cardiomyopathy; integrin-linked kinase-protein kinase B (ILK-PKB) signaling; small chemical compounds; phosphatase inhibitors dilated cardiomyopathy; integrin-linked kinase-protein kinase B (ILK-PKB) signaling; small chemical compounds; phosphatase inhibitors
Figures

Figure 1

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
SciFeed

Share & Cite This Article

MDPI and ACS Style

Pott, A.; Shahid, M.; Köhler, D.; Pylatiuk, C.; Weinmann, K.; Just, S.; Rottbauer, W. Therapeutic Chemical Screen Identifies Phosphatase Inhibitors to Reconstitute PKB Phosphorylation and Cardiac Contractility in ILK-Deficient Zebrafish. Biomolecules 2018, 8, 153.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]
Biomolecules EISSN 2218-273X Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top