Degree Name

PhD (Doctor of Philosophy)

Program

Biomedical Sciences

Date of Award

8-2016

Committee Chair or Co-Chairs

Chuanfu Li

Committee Members

David L. William, Race L. Kao, John Kalbfleisch, Krishna Singh, Robert Wondergerm

Abstract

Sepsis is the most frequent cause of mortality in most intensive care units. Cardiovascular dysfunction is a major complication associated with sepsis, with high mortality rates up to 70%. Currently, there is no effective treatment approach for sepsis.

The integrity of the endothelium is fundamental for the homeostasis of the cardiovascular system. Sepsis induces endothelial cell injury which is the key factor for multiple organ failure. The increased expression of adhesion molecules and chemokines in endothelial cell promotes leukocytes infiltration into the tissue. The loss of tight junction proteins and increased permeability of the endothelial cells will provoke tissue hypoxia and subsequent organ failure. Therefore, preservation of endothelial function is a critical approach for improving sepsis-induced outcome.

Here, we showed that endothelial specific protein HSPA12B plays a critical role in the preservation of cardiovascular function in polymicrobial sepsis. HSPA12B is the newest member of HSP70 family which predominantly expresses in endothelial cells. We observed that HSPA12B deficiency (HSPA12B-/-) exaggerated polymicrobial sepsis-induced endothelial dysfunction, leading to worse cardiac dysfunction. HSPA12B-/- significantly increases the expression of adhesion molecules, decreases tight junction protein levels and enhances vascular permeability. HSPA12B-/- alsomarkedly promotes the infiltration of inflammatory cells into the myocardium and inflammatory cytokine production.

We investigated the cardioprotective mechanisms of HSPA12B in sepsis induced cardiovascular dysfunction. Exosomes play a critical role in intercellular communication. Exosome is a natural vehicle of microRNAs. We found that exosomes isolated from HSPA12B-/- septic mice induced more expression of adhesion molecules in endothelial cells and inflammation in macrophages. Interestingly, the levels of miR-126 in serum exosomes isolated from HSPA12B-/- septic mice were significantly lowers than in WT septic mice. Importantly, delivery of miR-126 carried exosomes significantly improved cardiac function, suppressed the expression of adhesion molecules, reduced immune cell infiltration in the myocardium, and improved vascular permeability in HSPA12B-/- septic mice. The data suggests that HSPA12B is essential for endothelial function in sepsis and that miR-126 containing exosomes plays a critical role in cardiovascular-protective mechanisms of endothelial HSPA12B in polymicrobial sepsis.

Document Type

Dissertation - unrestricted

Copyright

Copyright by the authors.

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