Endothelial HSPA12B Exerts Protection Against Sepsis-Induced Severe Cardiomyopathy via Suppression of Adhesion Molecule Expression by miR-126.

Xia Zhang,Li Liu,Tuanzhu Ha,David Williams,Chuanfu Li,Xiaohui Wang,John Kalbfleisch,Min Fan,Fei Tu,Kun Yang

doi:10.3389/fimmu.2020.00566

Abstract

Heat shock protein A12B (HSPA12B) is predominately expressed in endothelial cells (ECs) and has been reported to protect against cardiac dysfunction from endotoxemia or myocardial infarction. This study investigated the mechanisms by which endothelial HSPA12B protects polymicrobial sepsis–induced cardiomyopathy. Wild-type (WT) and endothelial HSPA12B knockout (HSPA12B–/–) mice were subjected to polymicrobial sepsis induced by cecal ligation and puncture (CLP). Cecal ligation and puncture sepsis accelerated mortality and caused severe cardiac dysfunction in HSPA12B–/– mice compared with WT septic mice. The levels of adhesion molecules and the infiltrated immune cells in the myocardium of HSPA12B–/– septic mice were markedly greater than in WT septic mice. The levels of microRNA-126 (miR-126), which targets adhesion molecules, in serum exosomes from HSPA12B–/– septic mice were significantly lower than in WT septic mice. Transfection of ECs with adenovirus expressing HSPA12B significantly increased miR-126 levels. Increased miR-126 levels in ECs prevented LPS-stimulated expression of adhesion molecules. In vivo delivery of miR-126 carried by exosomes into the myocardium of HSPA12B–/– mice significantly attenuated CLP sepsis increased levels of adhesion molecules, and improved CLP sepsis–induced cardiac dysfunction. The data suggest that HSPA12B protects against sepsis-induced severe cardiomyopathy via regulating miR-126 expression which targets adhesion molecules, thus decreasing the accumulation of immune cells in the myocardium.

Highlights

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host innate and inflammatory responses to the infection [1]
The present study has shown that endothelial cells (ECs)-specific HSAP12B exerts a protective role in polymicrobial sepsis–induced cardiomyopathy
Deficiency of endothelial-specific Heat shock protein A12B (HSPA12B) (HSPA12B−/−) results in severe cardiac dysfunction and poor survival outcome following polymicrobial sepsis, suggesting that endothelial HSP12B serves a protective role in cardiac function in sepsis

Summary

Introduction

Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host innate and inflammatory responses to the infection [1]. Cardiovascular dysfunction is a major complication associated with sepsis-induced morbidity and mortality [7;9]. Cardiomyopathy is present in >40% of sepsis patients [3, 4] and is associated with mortality rates of up to 70% [3, 4]. Endothelial cell (EC) dysfunction contributes to multiple organ damage and high morbidity and mortality in sepsis/septic shock [5]. Pathogen-associated molecular patterns, such as LPS or endogenous ligands, generated during sepsis/septic shock stimulate EC activation. Activated ECs have upregulated expression of chemokines and adhesion molecules, which attract and promote immune cell infiltration and inflammatory response, resulting in organ injury [9]. Preservation of endothelial function is an important approach for attenuating sepsis-induced outcomes

Methods

Results

Conclusion