Cardiovascular dysfunction is a major contributor to sepsis-induced death in critically ill patients. Despite decades of intensive study, the basic mechanisms remain elusive. In particular, therapeutic interventions aimed at a single mediator or pathways of inflammation have failed to improve cardiac function and survival outcome in sepsis. Thus, continuing search for effective therapeutic reagents which target multiple factors is greatly needed. Recent identified microRNAs may provide new targets for effective sepsis therapy. Our latest work has discovered, for example, that: 1) miR-223 (-5p & -3p) are significantly reduced in mouse hearts after severe sepsis; 2) global loss of duplex miR-223 aggravated sepsis-induced cardiac dysfunction and mortality; and 3) miR-223-5p inhibited the expression of TNFR1 and Sema3A (a ligand of TLRs), while miR-223-3p repressed the expression of IL-6, STAT3, MIP-1?MIP-2 in macrophages and myocytes. Given that each of these molecules can potentially contribute to sepsis-induced cardiac dysfunction and mortality, it will be significant to test the effects of global elevation of duplex miR-223 on sepsis-caused injury. Our pilot data also indicate that: 1) lesser amounts of duplex miR-223 are encased within exosomes isolated from the blood of septic mice (referred to as septic exosomes), compared to healthy exosomes and 2) septic exosomes impaired cardiomyocyte contractility and stimulated macrophages to release pro-inflammatory cytokines (i.e. TNF-?IL-6). Thus, it will be important to test whether duplex miR-223 is a critical limiting factor whose reduction contributes to septic exosome-induced detrimental effects on cardiac function and mortality. Finally, an important translational question is raised: are there any positive therapeutic effects of engineering exosomes to contain extra miR-223 on sepsis? In this proposal, we hypothesize that global elevation of duplex miR-223 limits sepsis-induced cardiac dysfunction and mortality through targeting diverse mediators at multiple levels, and loss of duplex miR-223 contributes to septic exosome-triggered cardiac dysfunction. These ideas will be tested by pursuing three specific aims: 1) Using a transgenic mouse model, we will test whether global elevation of duplex miR-223 attenuates sepsis-induced myocardial depression and mortality; 2) Utilizing duplex miR-223-null exosomes and septic exosomes isolated from the blood of miR-223-knockout mice and CLP-operated mice to test whether septic exosome-mediated cardiac dysfunction and mortality is ascribed to the reduction of duplex miR-223; and 3) We will use bone marrow-derived mesenchymal stem cells (MSCs) as a source of miR-223-exosomes to determine the therapeutic effects of duplex-miR-223-engineered exosomes on sepsis-induced cardiac dysfunction and mortality. Together, the proposed studies are expected to unveil a previously unrecognized role of duplex miR-223 in sepsis-induced heart failure. Additionally, they are expected to provide novel insights that lead to the development of original exosome-based therapeutic strategies for reducing septic death.
Sepsis remains the leading cause of death in critically ill patients. The proposed research is relevant to public health because the elucidation of duplex miR-223/exosomes in sepsis-induced cardiac dysfunction and mortality is ultimately expected to open new avenues and develop novel therapeutic tools for transferring those beneficial factors into the septic heart, thereby resulting in an improved contractile function. Thus, the proposed project is relevant to the part of NIH's mission that pertains to advancing fundamental knowledge and translational study that will help to reduce the burdens of human disability.
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