Dysregulation of Krüppel-like Factor 2 and Myocyte Enhancer Factor 2D Drive Cardiac Microvascular Inflammation and Dysfunction in Diabetes

Author:

Samak Mostafa12,Kues Andreas1,Kaltenborn Diana1,Klösener Lina123ORCID,Mietsch Matthias12ORCID,Germena Giulia12ORCID,Hinkel Rabea123ORCID

Affiliation:

1. Laboratory Animal Science Unit, Leibniz-Institut für Primatenforschung, Deutsches Primatenzentrum GmbH, Kellnerweg 4, 37077 Göttingen, Germany

2. DZHK (German Centre for Cardiovascular Research), Partner Site Göttingen, 37075 Göttingen, Germany

3. Institute for Animal Hygiene, Animal Welfare and Farm Animal Behaviour, University of Veterinary Medicine, 30173 Hannover, Germany

Abstract

Cardiovascular complications are the main cause of morbidity and mortality from diabetes. Herein, vascular inflammation is a major pathological manifestation. We previously characterized the cardiac microvascular inflammatory phenotype in diabetic patients and highlighted micro-RNA 92a (miR-92a) as a driver of endothelial dysfunction. In this article, we further dissect the molecular underlying of these findings by addressing anti-inflammatory Krüppel-like factors 2 and 4 (KLF2 and KLF4). We show that KLF2 dysregulation in diabetes correlates with greater monocyte adhesion as well as migratory defects in cardiac microvascular endothelial cells. We also describe, for the first time, a role for myocyte enhancer factor 2D (MEF2D) in cardiac microvascular dysfunction in diabetes. We show that both KLFs 2 and 4, as well as MEF2D, are dysregulated in human and porcine models of diabetes. Furthermore, we prove a direct interaction between miR-92a and all three targets. Altogether, our data strongly qualify miR-92a as a potential therapeutic target for diabetes-associated cardiovascular disease.

Funder

Deutsche Sonderforschungsbereich

European Research Council

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

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