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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Abstract

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
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Salmeron-Sanchez, Professor Manuel and Nosalski, Mr Ryszard and Maffia, Dr Pasquale and Skiba, Mr Dominik and Guzik, Professor Tomasz and Graham, Dr Delyth and Mcginnigle, Dr Eilidh and Denby, Dr Laura and Nguyen Dinh Cat, Dr Aurelie and Siedlinski, Mr Mateusz and Medina-Ruiz, Dr Laura and Cantini, Dr Marco 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 > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
College of Science and Engineering > School of Engineering > Biomedical Engineering
Journal Name:Circulation Research
Publisher:American Heart Association
ISSN:0009-7330
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