Role of Krev Interaction Trapped-1 in Prostacyclin-Induced Protection against Lung Vascular Permeability Induced by Excessive Mechanical Forces and Thrombin Receptor Activating Peptide 6.
Mechanisms of vascular endothelial cell (EC) barrier regulation during acute lung injury (ALI) or other pathologies associated with increased vascular leakiness are an active area of research. Adaptor protein krev interaction trapped-1 (KRIT1) participates in angiogenesis, lumen formation, and stabilization of EC adherens junctions (AJs) in mature vasculature. We tested a role of KRIT1 in the regulation of Rho-GTPase signaling induced by mechanical stimulation and barrier dysfunction relevant to ventilator-induced lung injury and investigated KRIT1 involvement in EC barrier protection by prostacyclin (PC). PC stimulated Ras-related protein 1 (Rap1)-dependent association of KRIT1 with vascular endothelial cadherin at AJs, with KRIT1-dependent cortical cytoskeletal remodeling leading to EC barrier enhancement. KRIT1 knockdown exacerbated Rho-GTPase activation and EC barrier disruption induced by pathologic 18% cyclic stretch and thrombin receptor activating peptide (TRAP) 6 and attenuated the protective effects of PC. In the two-hit model of ALI caused by high tidal volume (HTV) mechanical ventilation and TRAP6 injection, KRIT1 functional deficiency in KRIT1(+/-) mice increased basal lung vascular leak and augmented vascular leak and lung injury caused by exposure to HTV and TRAP6. Down-regulation of KRIT1 also diminished the protective effects of PC against TRAP6/HTV-induced lung injury. These results demonstrate a KRIT1-dependent mechanism of vascular EC barrier control in basal conditions and in the two-hit model of ALI caused by excessive mechanical forces and TRAP6 via negative regulation of Rho activity and enhancement of cell junctions. We also conclude that the stimulation of the Rap1-KRIT1 signaling module is a major mechanism of vascular endothelial barrier protection by PC in the injured lung.
Lung Injury Center and Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, Illinois.
Angelo
A
Meliton
Lung Injury Center and Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, Illinois.
Fanyong
F
Meng
Lung Injury Center and Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, Illinois.
Yufeng
Y
Tian
Lung Injury Center and Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, Illinois.
Alok A
AA
Shah
Lung Injury Center and Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, Illinois.
Anna A
AA
Birukova
Lung Injury Center and Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, Chicago, Illinois.
Konstantin G
KG
Birukov
D008841:Actin Cytoskeleton / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001696:Biomechanical Phenomena; D015820:Cadherins / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007365:Intercellular Junctions / Q000187:drug effects / Q000378:metabolism; D000075927:KRIT1 Protein; D008168:Lung / Q000098:blood supply; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000502:physiology*; D009842:Oligopeptides / Q000502:physiology*; D044062:Prostaglandins I / Q000494:pharmacology*; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D012128:Respiratory Distress Syndrome / Q000188:drug therapy / Q000378:metabolism; D000099152:Cadherin 5
D015703:Antigens, CD; D015820:Cadherins; D000075927:KRIT1 Protein; D008869:Microtubule-Associated Proteins; D009842:Oligopeptides; D044062:Prostaglandins I; D011518:Proto-Oncogene Proteins; D000099152:Cadherin 5; C107928:KRIT1 protein, human; C504808:Ser-Phe-Phe-Leu-Arg-Asn
KRIT1; Rap1; RhoA; cyclic stretch; ventilator-induced lung injury