T cell-derived miRNA-214 mediates perivascular fibrosis in hypertension

Nosalski, R. et al. (2020) T cell-derived miRNA-214 mediates perivascular fibrosis in hypertension. Circulation Research, 126, pp. 988-1003. (doi: 10.1161/CIRCRESAHA.119.315428) (PMID:32065054) (PMCID:PMC7147427)

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Rationale: Despite increasing understanding of the prognostic importance of vascular stiffening linked to perivascular fibrosis in hypertension, the molecular and cellular regulation of this process is poorly understood. Objective: To study the functional role of microRNA-214 (miR-214) in the induction of perivascular fibrosis and endothelial dysfunction driving vascular stiffening. Methods and Results: Out of 381 miRs screened in the perivascular tissues (PVAT) in response to angiotensin II (Ang II)-mediated hypertension, miR-214 showed the highest induction (8-fold, p=0.0001). MiR-214 induction was pronounced in perivascular and circulating T cells, but not in PVAT adipocytes. Global deletion of miR-214-/- prevented Ang II-induced periaortic fibrosis Col1a1, Col3a1, Col5a1 and Tgfb1 expression, hydroxyproline accumulation and vascular stiffening, without difference in blood pressure. Mechanistic studies revealed that miR-214-/- mice were protected against endothelial dysfunction, oxidative stress and increased Nox2, all of which were induced by Ang II in WT mice. Ang II-induced recruitment of T cells into PVAT was abolished in miR-214-/- mice. Adoptive transfer of miR-214-/- T cells into RAG1-/- mice resulted in reduced perivascular fibrosis compared to the effect of WT T cells. Ang II induced hypertension caused significant change in the expression of 1380 T cell genes in WT, but only 51 in miR-214-/-. T cell activation, proliferation and chemotaxis pathways were differentially affected. miR-214-/- prevented Ang II-induction of pro-fibrotic T cell cytokines (IL-17, TNF-alpha, IL-9 and IFN-ý)and chemokine receptors (CCR1, CCR2, CCR4, CCR5, CCR6 and CXCR3). This manifested in reduced in vitro and in vivo T cell chemotaxis resulting in attenuation of profibrotic perivascular inflammation. Translationally, we show that miR-214 is increased in plasma of hypertensive patients and is directly correlated to pulse wave velocity as a measure of vascular stiffness. Conclusions: T cell-derived miR-214 controls pathological perivascular fibrosis in hypertension mediated by T cell recruitment and local profibrotic cytokine release.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Nosalski, Dr Ryszard and Maffia, Professor Pasquale and Skiba, Mr Dominik and Graham, Dr Delyth and Denby, Dr Laura and Nguyen Dinh Cat, Dr Aurelie and Siedlinski, Mr Mateusz and Salmeron-Sanchez, Professor Manuel and Guzik, Professor Tomasz and Mcginnigle, Dr Eilidh and Cantini, Dr Marco and Medina-Ruiz, Dr Laura and Graham, Professor Gerard
Authors: Nosalski, R., Siedlinski, M., Denby, L., Mcginnigle, E., Nowak, M., Nguyen Dinh Cat, A., Medina-Ruiz, L., Cantini, M., Skiba, D., Wilk, G., Osmenda, G., Rodor, J., Salmeron-Sanchez, M., Graham, G., Maffia, P., Graham, D., Baker, A. H., and Guzik, T. J.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
College of Medical Veterinary and Life Sciences > School of Infection & Immunity
College of Science and Engineering > School of Engineering > Biomedical Engineering
Research Centre:College of Medical Veterinary and Life Sciences > School of Infection & Immunity > Centre for Immunobiology
Journal Name:Circulation Research
Publisher:American Heart Association
ISSN (Online):1524-4571
Published Online:17 February 2020
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in Circulation Research 126:988–1003
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
170444Assessing the contribution of microRNA to in-stent restenosisTomasz GuzikBritish Heart Foundation (BHF)FS/14/49/30838Institute of Cardiovascular & Medical Sciences
300798A study of the roles of the immune and inflammatory systems in hypertensionTomasz GuzikEuropean Research Council (ERC)726318CAMS - Cardiovascular Science
169623Role of non-coding RNA in vascular pathologyAndrew BakerBritish Heart Foundation (BHF)RG/14/3/30706Institute of Cardiovascular & Medical Sciences
190391BHF Chair of Translational Cardiovascular SciencesAndrew BakerBritish Heart Foundation (BHF)CH/11/2/28733Institute of Cardiovascular & Medical Sciences
303613Engineered microenvironments to harvest stem cell response to viscosity for cartilage repairMarco CantiniMedical Research Council (MRC)MR/S005412/1ENG - Biomedical Engineering
301095UKRMP2 Acellular/Smart Materials 3D Architecture HubManuel Salmeron-SanchezMedical Research Council (MRC)MMRE_P75176 (MR/R015651/1ENG - Biomedical Engineering