T-Cell–Derived miRNA-214 Mediates Perivascular Fibrosis in Hypertension

Autor: Julie Rodor, Gerard J. Graham, Ryszard Nosalski, Andrew H. Baker, Laura Denby, Manuel Salmerón-Sánchez, Aurelie Nguyen Dinh Cat, Pasquale Maffia, Grzegorz Osmenda, Dominik Skiba, Grzegorz Wilk, Marco Cantini, Delyth Graham, Tomasz J. Guzik, Eilidh McGinnigle, Laura Medina-Ruiz, Michal Nowak, Mateusz Siedlinski
Přispěvatelé: Nosalski, R., Siedlinski, M., Denby, L., Mcginnigle, E., Nowak, M., Cat, A. N. D., 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., Guzik, T. J.
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Zdroj: Circulation Research
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 & Guzik, T J 2020, ' T-Cell–Derived miRNA-214 Mediates Perivascular Fibrosis in Hypertension ', Circulation Research, vol. 126, no. 8, pp. 988–1003 . https://doi.org/10.1161/CIRCRESAHA.119.315428
ISSN: 1524-4571
0009-7330
DOI: 10.1161/CIRCRESAHA.119.315428
Popis: Supplemental Digital Content is available in the text.
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. Objectives: 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 in response to Ang II (angiotensin 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 perivascular adipose tissue 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 perivascular adipose tissue was abolished in miR-214−/− mice. Adoptive transfer of miR-214−/− T cells into RAG1−/− mice resulted in reduced perivascular fibrosis compared with 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 profibrotic T cell cytokines (IL-17, TNF-α, IL-9, and IFN-γ) 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 patients with hypertension 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.
Databáze: OpenAIRE
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