Yan Wu1, Pengfei Li1, Andrew J Goodwin2, James A Cook3, Perry V Halushka4,5, Basilia Zingarelli6, Hongkuan Fan1. 1. Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina, USA. 2. Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, Medical University of South Carolina, Charleston, South Carolina, USA. 3. Department of Neurosciences, Medical University of South Carolina, Charleston, South Carolina, USA. 4. Department of Medicine, Medical University of South Carolina, Charleston, South Carolina, USA. 5. Department of Pharmacology, Medical University of South Carolina, Charleston, South Carolina, USA. 6. Division of Critical Care Medicine, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Abstract
BACKGROUND: Sepsis is a life-threatening systemic disease with severe microvascular dysfunction. Pericytes preserve vascular homeostasis. To our knowledge, the potential roles of microRNAs in sepsis-induced pericyte dysfunction have not been explored. METHODS: We determined lung pericyte expression of miR-145a in cecal ligation and puncture (CLP)-induced sepsis. Mouse lung pericytes were isolated and transfected with a miR-145a mimic, followed by stimulation with lipopolysaccharide (LPS). We measured inflammatory cytokine levels. To assess the functions of miR-145a in vivo, we generated a pericyte-specific miR-145a-knockout mouse and determined sepsis-induced organ injury, lung and renal vascular leakage, and mouse survival rates. We used RNA sequencing and Western blotting to analyze the signaling pathways regulated by miR-145a. RESULTS: CLP led to decreased miR-145a expression in lung pericytes. The miR-145a mimic inhibited LPS-induced increases in cytokines. In CLP-induced sepsis, pericytes lacking miR-145a exhibited increased lung and kidney vascular leakage and reduced survival rates. We found that miR-145a could suppress LPS-induced NF-κB activation. In addition, we confirmed that the transcription factor Friend leukemia virus integration 1 (Fli-1) is a target of miR-145a and that Fli-1 activates NF-κB signaling. CONCLUSION: Our results demonstrated that pericyte miR-145a mediates sepsis-associated microvascular dysfunction, potentially by means of Fli-1-mediated modulation of NF-κB signaling.
BACKGROUND:Sepsis is a life-threatening systemic disease with severe microvascular dysfunction. Pericytes preserve vascular homeostasis. To our knowledge, the potential roles of microRNAs in sepsis-induced pericyte dysfunction have not been explored. METHODS: We determined lung pericyte expression of miR-145a in cecal ligation and puncture (CLP)-induced sepsis. Mouse lung pericytes were isolated and transfected with a miR-145a mimic, followed by stimulation with lipopolysaccharide (LPS). We measured inflammatory cytokine levels. To assess the functions of miR-145a in vivo, we generated a pericyte-specific miR-145a-knockout mouse and determined sepsis-induced organ injury, lung and renal vascular leakage, and mouse survival rates. We used RNA sequencing and Western blotting to analyze the signaling pathways regulated by miR-145a. RESULTS:CLP led to decreased miR-145a expression in lung pericytes. The miR-145a mimic inhibited LPS-induced increases in cytokines. In CLP-induced sepsis, pericytes lacking miR-145a exhibited increased lung and kidney vascular leakage and reduced survival rates. We found that miR-145a could suppress LPS-induced NF-κB activation. In addition, we confirmed that the transcription factor Friend leukemia virus integration 1 (Fli-1) is a target of miR-145a and that Fli-1 activates NF-κB signaling. CONCLUSION: Our results demonstrated that pericyte miR-145a mediates sepsis-associated microvascular dysfunction, potentially by means of Fli-1-mediated modulation of NF-κB signaling.
Authors: Pengfei Li; Yue Zhou; Andrew J Goodwin; James A Cook; Perry V Halushka; Xian K Zhang; Carole L Wilson; Lynn M Schnapp; Basilia Zingarelli; Hongkuan Fan Journal: J Infect Dis Date: 2018-11-05 Impact factor: 5.226
Authors: Hongkuan Fan; Andrew J Goodwin; Eugene Chang; Basilia Zingarelli; Keith Borg; Shuwen Guan; Perry V Halushka; James A Cook Journal: Am J Respir Crit Care Med Date: 2014-06-15 Impact factor: 21.405
Authors: Yue Zhou; Pengfei Li; Andrew J Goodwin; James A Cook; Perry V Halushka; Eugene Chang; Hongkuan Fan Journal: Mol Ther Date: 2018-02-27 Impact factor: 11.454