Pentastatin, a matrikine of the collagen IVα5, is a novel endogenous mediator of pulmonary endothelial dysfunction

Author:

Mutgan Ayse Ceren12ORCID,Jandl Katharina23ORCID,Radic Nemanja1,Valzano Francesco2,Kolb Dagmar4ORCID,Hoffmann Julia2,Foris Vasile5,Wilhelm Jochen6ORCID,Boehm Panja M.7,Hoetzenecker Konrad7,Olschewski Andrea28ORCID,Olschewski Horst25ORCID,Heinemann Akos3ORCID,Wygrecka Malgorzata69ORCID,Marsh Leigh M.12ORCID,Kwapiszewska Grazyna126ORCID

Affiliation:

1. Division of Physiology and Pathophysiology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria

2. Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria

3. Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria

4. Core Facility Ultrastructure Analysis, Center for Medical Research, Medical University of Graz, Graz, Austria

5. Division of Pulmonology, Medical University of Graz, Graz, Austria

6. Institute for Lung Health, Member of the German Lung Center (DZL), Giessen, Germany

7. Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria

8. Department of Anaesthesiology and Intensive Care Medicine, Medical University of Graz, Graz, Austria

9. Center for Infection and Genomics of the Lung, Universities of Giessen and Marburg Lung Center, Giessen, Germany

Abstract

This study is the first to show that pentastatin, the matrikine of the basement membrane (BM) collagen IVα5 polypeptide, triggers rapid pulmonary arterial endothelial cell barrier disruption, activation, and apoptosis in vitro and ex vivo. Mechanistically, pentastatin partially acts through binding to the β1-integrin subunit and the Rho/ROCK pathway. These findings are the first to link pentastatin to pulmonary endothelial dysfunction and, thus, suggest a major role for BM-matrikines in pulmonary vascular diseases such as pulmonary hypertension.

Funder

Medical University of Graz

Austrian Society for Pneumology

Österreichische Forschungsförderungsgesellschaft

Austrian Science Fund

Deutsche Forschungsgemeinschaft

Publisher

American Physiological Society

Subject

Cell Biology,Physiology

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