Accumulating studies highlight a critical role for endothelial cell (EC) inflammation and dysfunction in the pathogenesis of septic shock and sepsis-induced lung injury, leading causes of death among critically ill patients. Excessive generation of pro-inflammatory mediators can lead to collateral vascular dysfunction, an effect that confers pro-adhesive, pro-permeability, and pro-thrombotic properties to ECs. Therefore, modulating these events in the vascular endothelium may provide a novel therapeutic approach to limit the sequelae of sepsis and sepsis-induced lung injury. MicroRNAs (miRNAs) are small, non-coding RNAs that suppress the expression of target genes at the post-transcriptional level and are involved in a range of biological responses. However, the role of microRNAs in sepsis-associated endothelial dysfunction remains poorly defined. Using a microarray profiling approach in ECs, we identified that miR-181b expression is rapidly reduced in the vascular endothelium from endotoxemic mice - observations that are recapitulated in human subjects with sepsis in vivo. Our studies have uncovered that miR-181b inhibits targets that control 2 key signaling pathways, NF-kB and AKT/eNOS, that govern EC adhesion, vascular permeability, and proinflammatory mediators implicated in sepsis and sepsis-induced lung injury. Preliminary functional studies in ECs reveal that miR-181b potently inhibits effects on leukocyte adhesion, EC permeability, and thrombin-induced EC inflammation. MiR-181b suppresses the activation of the NF-kB pathway uniquely in ECs by binding to the 3'UTR of importin-a3, a protein involved in NF-kB nuclear translocation in ECs and not leukocytes. In contrast, miR-181b induces eNOS-phosphorylation by directly targeting the phosphatase PHLPP2, known to inhibit AKT-phosphorylation. Finally, treatment of mice by systemic intravenous administration of miR-181b mimics as replacement therapy reduces endotoxemia-induced EC inflammatory markers, leukocyte accumulation, lung injury, and markedly improves survival. Thus, we hypothesize that miR-181b may serve as a critical homeostatic regulator of ECs and vascular dysfunction in sepsis and sepsis-induced lung injury. To further understand the protective role of miR-181b in sepsis, we propose:
in Aim1, to delineate the proximal events during sepsis regulating miR-181b expression.
In Aim2, using inflammatory stimuli including human plasma samples from patients with sepsis and sepsis-induced lung injury, we will dissect the mechanisms by which miR-181b regulates NF-kB and AKT signaling in response to EC dysfunction.
In Aim3, we will explore the effect and timing of altered miR-181b expression, or its targets (using genetic, siRNA, or pharmacological approaches to importin-a3 or PHLPP2), on experimental models of sepsis and EC function in vivo. Successful completion of the proposed studies will identify significant insights regarding miR-181b function in EC inflammation, vascular leak, and microvascular thrombosis, and may provide discrete, novel targets for sepsis-induced lung injury.
One of the hallmarks of sepsis, a multi-organ systemic inflammatory response syndrome triggered by severe infection, is impaired endothelial cell dysfunction due to excessive production of inflammatory mediators, an effect leading to vascular compromise including microvascular leakage, thrombosis, and ultimately organ injury and death. We have identified a novel microRNA, miR-181b, that is dynamically regulated by pro- or anti-inflammatory stimuli in endothelial cells and our studies indicate that miR-181b or identified small molecule therapeutics may restore endothelial integrity and reduce tissue injury during sepsis. The proposed studies will provide a detailed understanding underlying the role of miR-181b with the goal of developing therapies for the treatment of sepsis and sepsis-induced lung injury.
| Haemmig, Stefan; Simion, Viorel; Feinberg, Mark W (2018) Long Non-Coding RNAs in Vascular Inflammation. Front Cardiovasc Med 5:22 |
| Ozdemir, Denizhan; Feinberg, Mark W (2018) MicroRNAs in diabetic wound healing: Pathophysiology and therapeutic opportunities. Trends Cardiovasc Med : |
| Simion, Viorel; Haemmig, Stefan; Feinberg, Mark W (2018) LncRNAs in vascular biology and disease. Vascul Pharmacol : |
| Haemmig, Stefan; Feinberg, Mark W (2017) Targeting LncRNAs in Cardiovascular Disease: Options and Expeditions. Circ Res 120:620-623 |
| Haemmig, Stefan; Simion, Viorel; Yang, Dafeng et al. (2017) Long noncoding RNAs in cardiovascular disease, diagnosis, and therapy. Curr Opin Cardiol 32:776-783 |
| Haemmig, Stefan; Feinberg, Mark W (2017) MicroRNAs as Harbingers of High-Risk Carotid Artery Atherosclerotic Disease? Circ Res 120:596-598 |
| Zhang, Yu; Sun, Xinghui; Icli, Basak et al. (2017) Emerging Roles for MicroRNAs in Diabetic Microvascular Disease: Novel Targets for Therapy. Endocr Rev 38:145-168 |
| Feinberg, Mark W; Moore, Kathryn J (2016) MicroRNA Regulation of Atherosclerosis. Circ Res 118:703-20 |
| Icli, Basak; Nabzdyk, Christoph S; Lujan-Hernandez, Jorge et al. (2016) Regulation of impaired angiogenesis in diabetic dermal wound healing by microRNA-26a. J Mol Cell Cardiol 91:151-9 |
| Icli, Basak; Feinberg, Mark W (2016) Plasticity of Arterial and Venous Endothelial Cell Identity: Some Nerve! Circ Res 119:574-6 |
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