Induction of microRNA-138 by pro-inflammatory cytokines causes endothelial cell dysfunction |
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Authors: | Anagha Sen Patrick Most Karsten Peppel |
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Affiliation: | 1. Center for Translational Medicine, Jefferson Medical College, Philadelphia, PA, USA;2. Laboratory for Molecular and Translational Cardiology, Department of Internal Medicine III, University of Heidelberg, INF 350, 69120 Heidelberg, Germany;3. DZHK (German Center for Cardiovascular Research), Partner site Heidelberg/Mannheim, Heidelberg University Hospital, INF 410, 69120 Heidelberg, Germany |
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Abstract: | 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 Ca2+ 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. |
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Keywords: | Ang II, Angiotensin II Akt, v-Akt murine thymoma viral oncogene homolog BH4, (6R-)5,6,7,8-tetrahydro-L-biopterin CaM, calmodulin CLI, critical limb ischemia EC, endothelial cell Et-1, endothelin-1 eNOS, endothelial nitric oxide synthase FAD, flavin adenine dinucleotide FMN, flavin mononucleotide GM, gastrocnemius muscle HIF1-α, hypoxia inducible factor 1 alpha HMVEC, human microvascular endothelial cell NADPH, nicotinamide-adenine-dinucleotide phosphate PKC, protein kinase C SKO, S100A1 knockout TNF, tumor necrosis factor-alpha VEGF, vascular endothelial growth factor WT, wild-type |
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