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

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 Kruppel-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.

Automated summary

Cardiovascular complications are the leading cause of morbidity and mortality in diabetes, primarily due to vascular inflammation. This study investigates the molecular basis of these complications, focusing on the anti-inflammatory factors KLF2, KLF4, and MEF2D. The dysregulation of these factors in diabetes is associated with increased monocyte adhesion and migratory defects in cardiac microvascular endothelial cells. The study also reveals a direct interaction between miR-92a and these factors, highlighting miR-92a as a potential therapeutic target for diabetes-associated cardiovascular disease.