Obesity Research Working Group
Extensive Research Description
An important part of the RNA components of the transcriptional regulatory network is the so-called, microRNAs (miRNAs), 20-22nt single stranded non-coding RNAs that act mainly as posttranscriptional repressors. They have been shown to control the transcriptional networks by acting on multiple targets and regulating the protein dosage of entire signaling pathways and have been implicated in many diseases. Recently, long non-coding RNAs (lncRNA) and circular RNAs (circRNAs) have also been described to regulate gene expression in different ways.
In our laboratory we study the contribution of non-coding RNAs, including microRNAs, to the regulation of endothelial cell and macrophage functions. Both cell types play major role in controlling both angiogenic and inflammatory responses and the interplay between these two cell types has been shown to be critical for several pathophysiological conditions like atherosclerosis, cancer (tumor growth), adipose tissue expansion and wound healing, among others. Intriguingly, miRNAs can be transferred from cell to cell by exosomes, small vesicles that have been shown to mediate the transfer of proteins and RNAs, thus facilitating the exchange of information among cells this might have important implications in autocrine and paracrine communication between both macrophages and endothelial cells. This is an area of research that we are also investigating in our laboratory.
To this end, we are utilizing different approaches combining molecular and cellular biology, biochemistry, together with genetically modified mouse models.
Three main projects are currently ongoing:
1) Contribution of microRNAs to the regulation of endothelial cell functions. Our major focus involves studying the role of VEGF and TNF-regulated microRNAs on endothelial cell responses, as well as the identification of the molecular mechanisms whereby these cytokines regulate the biogenesis and activity of endothelial microRNAs.
2) To characterize novel regulatory mechanisms for macrophage activation and function.
3) Identification and characterization of regulatory RNAs species in exosomes derived form different set of activated macrophages, as well as their contribution to the regulation of endothelial cell functions in different pathophysiological conditions.
- Genetic Dissection of the Impact of miR-33a and miR-33b during the Progression of Atherosclerosis. Price NL, Rotllan N, Canfrán-Duque A, Zhang X, Pati P, Arias N, Moen J, Mayr M, Ford DA, Baldán Á, Suárez Y, Fernández-Hernando C. Cell Rep. 2017 Oct 31;21(5):1317-1330. doi: 10.1016/j.celrep.2017.10.023. PMID: 29091769
- Macrophage deficiency of miR-21 promotes apoptosis, plaque necrosis, and vascular inflammation during atherogenesis. Canfrán-Duque A, Rotllan N, Zhang X, Fernández-Fuertes M, Ramírez-Hidalgo C, Araldi E, Daimiel L, Busto R, Fernández-Hernando C, Suárez Y. EMBO Mol Med. 2017 Sep;9(9):1244-1262. doi: 10.15252/emmm.201607492. PMID: 28674080
- Lanosterol Modulates TLR4-Mediated Innate Immune Responses in Macrophages. Araldi E, Fernández-Fuertes M, Canfrán-Duque A, Tang W, Cline GW, Madrigal-Matute J, Pober JS, Lasunción MA, Wu D, Fernández-Hernando C, Suárez Y. Cell Rep. 2017 Jun 27;19(13):2743-2755. doi: 10.1016/j.celrep.2017.05.093. PMID: 28658622
- Haskins JW, Zhang S, Means RE, Kelleher JK, Cline GW, Canfrán-Duque A, Suárez Y, Stern DF. Neuregulin-activated ERBB4 induces the SREBP-2 cholesterol biosynthetic pathway and increases low-density lipoprotein uptake. Sci Signal. 2015 Nov 3;8(401):ra111. doi: 10.1126/scisignal.aac5124.
- Chamorro-Jorganes A, Lee MY, Araldi E, Landskroner-Eiger S, Fernández-Fuertes M, Sahraei M, Quiles de Rey M, van Solingen C, Ju Y, Fernández-Hernando C, Sessa WC and Suárez Y. VEGF-induced expression of miR-17~92 cluster in endothelial cells is mediated by ERK/ELK1 activation and regulates angiogenesis. Circ Res. 2015 Oct 15. pii: CIRCRESAHA.115.307408. [Epub ahead of print]
- Goedeke L, Rotllan N, Canfrán-Duque A, Aranda JF, Ramírez CM, Araldi E, Lin C-S, Anderson NN, Wagschal A, de Cabo R, Horton JD, Lasunción MA, Näär AM, Suárez Y and Fernández-Hernando C. MicroRNA-148a regulates LDL receptor and ABCA1 expression to control circulating lipoprotein levels. Nat Med. 2015 Nov;21(11):1280-9. doi: 10.1038/nm.3949. Epub 2015 Oct 5.
- van Solingen C, Araldi E, Chamorro-Jorganes A, Fernández-Hernando C, Suárez Y. Improved repair of dermal wounds in mice lacking microRNA-155. J Cell Mol Med. (2014). [Epub ahead of print]
- Chamorro-Jorganes A, Araldi E, Noemi Rotllan, Daniel Cirera-Salinas, Suárez Y. Autoregulation of glypican-1 by intronic microRNA-149 fine-tunes the angiogenic response to fibroblast growth factor in human endothelial cells. J Cell Sci .127: 1169-1178 (2014)
- Chamorro-Jorganes A, Araldi E, Penalva LO, Sandhu D, Fernández-Hernando C, Suárez Y. MicroRNA-16 and microRNA-424 regulate cell-autonomous angiogenic functions in endothelial cells via targeting vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1. Arterioscler Thromb Vasc Biol. 31(11):2595-606. (2011)
- Suárez Y*, Rayner KJ*, Dávalos A, Parathath S, Fitzgerald ML, Tamehiro N, Fisher EA, Moore KJ, Fernández-Hernando C. "miR-33 Contributes to the Regulation of Cholesterol Homeostasis". Science. 328: 1570-1573 (2010)
- Suárez Y, Wang C, Manes TD, Pober JS. TNF-induced miRNAs Regulate TNF-induced expression of E-Selectin and ICAM-1 on Human Endothelial Cells: Feedback Control of Inflammation. Cutting Edge: J Immunol 184(1):21-5 (2010)
- Suárez Y, Fernández-Hernando C, Yu Y, Gerber SA, Harrison KD, Pober JS, Iruela-Arispe ML, Merkenschlager M and. Sessa WC. Dicer-dependent endothelial microRNAs are necessary for post-natal angiogenesis. PNAS 105(37):14082-14087, (2008)
- Suárez Y, Fernández-Hernando C, Pober JS, Sessa WC. Dicer dependent microRNAs regulate gene expression and functions in human endothelial cells. Circ Res 100(8):1164-73, (2007)