Vascular effects of thrombin: involvement of NOR-1 in thrombin-induced mitogenic stimulus in vascular cells.
Neuron-derived orphan receptor-1 (NOR-1) is a nuclear receptor recently involved in the onset and development of atherosclerosis. NOR-1 is induced in a cell-specific manner by extracellular stimuli. NOR-1 is over-expressed in human atherosclerotic plaques and in porcine arteries subjected to angioplasty, is induced by growth factors in vascular cells and it has been involved in cell migration and proliferation. This article examines the mechanisms that regulate NOR-1 in vascular cells and the effects of NOR-1 knockdown on cell growth induced by mitogens, in particular thrombin. Mitogenic stimuli up-regulates NOR-1 in endothelial cells (ECs) through multiple pathways, including increase of cytosolic calcium, activation of protein kinase C, mitogen-activated protein kinase (MAPK) (ERK1/2 and p38 MAPK) and downstream activation of cAMP response element binding protein (CREB). Inhibition of protease-activated receptor-1 (PAR-1) abolished thrombin-induced NOR-1 up-regulation and DNA synthesis. NOR-1 knockdown reduces DNA synthesis and EC re-growth in an in vitro model of wound repair. NOR-1 could be regarded as a new target to prevent endothelial effects triggered by thrombin and other mitogens.
Martorell
Lluis
L
Centro de Investigacion Cardiovascular, CSIC-ICCC, Hospital de la Santa Creu i Sant Pau, c/Antoni Ma Claret 167, 08025 Barcelona, Spain.
Rodriguez
Cristina
C
Calvayrac
Olivier
O
Gentile
Maurizio
M
Badimon
Lina
L
Martinez-Gonzalez
Jose
J
D050197:Atherosclerosis; D002460:Cell Line; D049109:Cell Proliferation; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D020935:MAP Kinase Signaling System; D008934:Mitogens / Q000378:metabolism; D008954:Models, Biological; D011987:Receptors, Steroid / Q000378:metabolism*; D018179:Receptors, Thrombin / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000378:metabolism*; D013917:Thrombin / Q000737:chemistry* / Q000378:metabolism* / Q000502:physiology*; D014158:Transcription, Genetic
C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; D008934:Mitogens; C490412:NR4A3 protein, human; D011987:Receptors, Steroid; D018179:Receptors, Thrombin; D011988:Receptors, Thyroid Hormone; D004247:DNA; D013917:Thrombin