Induction of microRNA-138 by pro-inflammatory cytokines causes endothelial cell dysfunction.
Exposure to pro-inflammatory cytokines, such as Angiotensin II, endothelin-1 or TNF leads to endothelial dysfunction, characterized by the reduced production of nitric oxide via endothelial nitric oxide synthase (eNOS). We recently identified the Ca(2+) binding protein S100A1 as an essential factor required for eNOS activity. Here we report that pro-inflammatory cytokines down-regulate expression of S100A1 in primary human microvascular endothelial cells (HMVECs) via induction of microRNA-138 (miR-138), in a manner that depends on the stabilization of HIF1-α. We show that loss of S100A1 in ECs reduces stimulus-induced NO production, which can be prevented by inhibition of miR-138. Our study suggests that targeting miR-138 might be beneficial for the treatment of cardiovascular disease.
Center for Translational Medicine, Jefferson Medical College, Philadelphia, PA, USA.
Anagha
A
Sen
Center for Translational Medicine, Jefferson Medical College, Philadelphia, PA, USA; Laboratory for Molecular and Translational Cardiology, Department of Internal Medicine III, University of Heidelberg, INF 350, 69120 Heidelberg, Germany; DZHK (German Center for Cardiovascular Research), Partner site Heidelberg/Mannheim, Heidelberg University Hospital, INF 410, 69120 Heidelberg, Germany.
Patrick
P
Most
Center for Translational Medicine, Jefferson Medical College, Philadelphia, PA, USA. Electronic address: Karsten.Peppel@Jefferson.edu.
Karsten
K
Peppel
D000804:Angiotensin II / Q000502:physiology; D002318:Cardiovascular Diseases / Q000276:immunology / Q000378:metabolism; D002460:Cell Line; D042783:Endothelial Cells / Q000378:metabolism*; D019332:Endothelin-1 / Q000502:physiology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D018836:Inflammation Mediators / Q000502:physiology; D020935:MAP Kinase Signaling System; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D009418:S100 Proteins / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology*
D019332:Endothelin-1; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D018836:Inflammation Mediators; C546110:MIRN138 microRNA, human; D035683:MicroRNAs; D009418:S100 Proteins; C110294:S100A1 protein; D014409:Tumor Necrosis Factor-alpha; D000804:Angiotensin II; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D020928:Mitogen-Activated Protein Kinases
Angiotensin II; Cytokine; Endothelial dysfunction; Endothelial nitric oxide synthase; Endothelin-1; Tumor necrosis factor-alpha