next network
Novel mechanisms for activation of endothelial cell barrier dysfunction via Thrombin induction
This network was generated using Cytoscape V2.2, yFiles/circular layout with a lexically-driven XML plug-in to the Agilent Literature Search, curated and color coded in Adobe Illustrator CS2.
The vascular barrier is critical to the maintenance of lung function, and thrombin-induced endothelial cell (EC) barrier compromise plays a major role in the pathogenesis of acute lung injury, alveolar flooding, hypoxemia, and respiratory failure. Thrombin-induced endothelial barrier dysfunction is associated with actin (in orange) stress fiber formation and actomyosin contraction.
In endothelial cells, thrombin (f2, yellow node in the center) binds to and cleaves protease-activated receptor PAR-1 (in orange), which leads to activation of heterotrimeric GTP binding proteins G12, G13, Gi, and Gq. The released alpha-subunit of G12/13 induces the guanine nucleotide exchange factor (GEF) p115RhoGEF, and thereby activates Rho. GEFH1 (arhgef2, in green) is a microtubule (MT)-associated Rho-specific GEF, which when released from the MT activates Rho. The small GTPase Rho plays a key role in the initiation of actomyosin contraction and reorganization of the endothelial cytoskeleton. (Birukova Am J Physiol Lung Cell Mol Physiol;2006 290:L540). Thus the Rho-dependent pathway is directly involved in thrombin-induced alteration of EC barrier properties and endothelial barrier dysfunction. (Holinstat et al., JBC 2003)
Recent results demonstrate that atrial natriuretic peptide (ANP:'nappa', in orange) markedly attenuates barrier dysfunction induced by thrombin and promotes EC barrier recovery following pathological stimulation. A hypothetical scheme for ANP-mediated protective effects involves regulation of small GTPases Rac and Rho by Rap- and protein kinase A (PKA)- dependent mechanisms. Rap1 activity is regulated by cAMP-dependent GEF Epac1 (rapgef3). Activation of Epac/Rap1- and PKA-dependent signaling then leads to Tiam1/Vav2-dependent activation of Rac (see the central nodes of the network interconnected to thrombin colored in green). Activated Rac (1) stimulates PAK1 and cytoskeletal Rac effectors; (2) inhibits Rho activity, possibly via PAK1-dependent inhibition of p115RhoGEF activity; (3) attenuates Rho-mediated barrier disruption and (4) may contribute to the maintenance of EC monolayer integrity in injured lungs. Therefore, this novel mechanism of ANP-mediated protective effects against EC barrier dysfunction may be utilized for development of new therapies for prevention of pulmonary vascular leak associated with acute lung inflammation and injury. (Birukova, J. Cell. Physiol 215:715 2007)
In endothelial cells, thrombin (f2, yellow node in the center) binds to and cleaves protease-activated receptor PAR-1 (in orange), which leads to activation of heterotrimeric GTP binding proteins G12, G13, Gi, and Gq. The released alpha-subunit of G12/13 induces the guanine nucleotide exchange factor (GEF) p115RhoGEF, and thereby activates Rho. GEFH1 (arhgef2, in green) is a microtubule (MT)-associated Rho-specific GEF, which when released from the MT activates Rho. The small GTPase Rho plays a key role in the initiation of actomyosin contraction and reorganization of the endothelial cytoskeleton. (Birukova Am J Physiol Lung Cell Mol Physiol;2006 290:L540). Thus the Rho-dependent pathway is directly involved in thrombin-induced alteration of EC barrier properties and endothelial barrier dysfunction. (Holinstat et al., JBC 2003)
Recent results demonstrate that atrial natriuretic peptide (ANP:'nappa', in orange) markedly attenuates barrier dysfunction induced by thrombin and promotes EC barrier recovery following pathological stimulation. A hypothetical scheme for ANP-mediated protective effects involves regulation of small GTPases Rac and Rho by Rap- and protein kinase A (PKA)- dependent mechanisms. Rap1 activity is regulated by cAMP-dependent GEF Epac1 (rapgef3). Activation of Epac/Rap1- and PKA-dependent signaling then leads to Tiam1/Vav2-dependent activation of Rac (see the central nodes of the network interconnected to thrombin colored in green). Activated Rac (1) stimulates PAK1 and cytoskeletal Rac effectors; (2) inhibits Rho activity, possibly via PAK1-dependent inhibition of p115RhoGEF activity; (3) attenuates Rho-mediated barrier disruption and (4) may contribute to the maintenance of EC monolayer integrity in injured lungs. Therefore, this novel mechanism of ANP-mediated protective effects against EC barrier dysfunction may be utilized for development of new therapies for prevention of pulmonary vascular leak associated with acute lung inflammation and injury. (Birukova, J. Cell. Physiol 215:715 2007)
Other Networks
Below are links to NCBI by PMID supporting this network.
© The PMAP Web Site is managed by The Center on Proteolytic Pathways at the Burnham Institute for Medical Research through a grant from the NIH Roadmap.
Copyright 2008. All rights reserved.
The Burnham Institute for Medical Research 10901 N. Torrey Pines Rd., La Jolla, CA 92037.
With problems, comments, or suggestions please contact: pmap_info@burnham.org