MiR-19b targets pulmonary endothelial syndecan-1 following hemorrhagic shock

Feng Wu,Rosemary Ann Kozar,Jian-Ying Wang,Carrie Sims,Wei Chao

doi:10.1038/s41598-020-73021-3

Abstract

Hemorrhagic shock results in systemic injury to the endothelium contributing to post-shock morbidity and mortality. The mechanism involves syndecan-1, the backbone of the endothelial glycocalyx. We have shown in a rodent model that lung syndecan-1 mRNA is reduced following hemorrhage, whereas the molecular mechanism underlying the mRNA reduction is not clear. In this study, we present evidence that miR-19b targets syndecan-1 mRNA to downregulate its expression. Our results demonstrate that miR-19b was increased in hemorrhagic shock patients and in-vitro specifically bound to syndecan-1 mRNA and caused its degradation. Further, hypoxia/reoxygenation (H/R), our in vitro hemorrhage model, increased miR-19b expression in human lung microvascular endothelial cells, leading to a decrease in syndecan-1 mRNA and protein. H/R insult and miR-19b mimic overexpression comparably exaggerated permeability and enhanced endothelial barrier breakdown. The detrimental role of miR-19b in inducing endothelial dysfunction was confirmed in vivo. Lungs from mice undergoing hemorrhagic shock exhibited a significant increase in miR-19b and a concomitant decrease in syndecan-1 mRNA. Pretreatment with miR-19b oligo inhibitor significantly decreased lung injury, inflammation, and permeability and improved hemodynamics. These findings suggest that inhibition of miR-19b may be a putative therapeutic avenue for mitigating post shock pulmonary endothelial dysfunction in hemorrhage shock.

Highlights

Hemorrhagic shock results in systemic injury to the endothelium contributing to post-shock morbidity and mortality
Results miR‐19b is increased in hemorrhagic shock patients. miRNAs exist in stable form in the systemic circulation
Consistent with the findings of Uhlich et al.[15], miR-19b was significantly increased in the plasma of hemorrhagic shock patients (94% male) with a 13-fold increase compared to that of healthy donor controls (100% males) (Fig. 1)

Summary

Introduction

Hemorrhagic shock results in systemic injury to the endothelium contributing to post-shock morbidity and mortality. Our results demonstrate that miR-19b was increased in hemorrhagic shock patients and in-vitro bound to syndecan-1 mRNA and caused its degradation. Hypoxia/reoxygenation (H/R), our in vitro hemorrhage model, increased miR-19b expression in human lung microvascular endothelial cells, leading to a decrease in syndecan-1 mRNA and protein. Pretreatment with miR-19b oligo inhibitor significantly decreased lung injury, inflammation, and permeability and improved hemodynamics These findings suggest that inhibition of miR-19b may be a putative therapeutic avenue for mitigating post shock pulmonary endothelial dysfunction in hemorrhage shock. Survivors of hemorrhagic shock develop an endotheliopathy of trauma which is a systemic response to activated endothelial cells leading to abnormalities in coagulation, inflammation, and endothelial barrier integrity[4]. We examined if miR-19b-induced downregulation of Sdc[1] mRNA following hemorrhagic shock results in breakdown of endothelial cell barrier integrity and subsequent organ dysfunction

Methods

Results

Conclusion