期刊
CIRCULATION RESEARCH
卷 126, 期 8, 页码 988-1003出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.119.315428
关键词
blood pressure; collagen; fibrosis; hypertension; inflammation
资金
- European Research Council [ERC-CoG-726318, ERC-338991]
- National Science Centre, Poland [2011/03/B/NZ4/02454, 2013/11/N/NZ4/00310]
- British Heart Foundation [GuzikFS/14/49/30838, Baker-RG/14/3/30706, CH/11/2/28733]
- Kidney Research UK [LD-PD6/2012]
- MRC [MR/S005412/1]
- UK Regenerative Medicine Platform [MR/R015651/1]
- MRC [MR/S005412/1, MR/R015651/1] Funding Source: UKRI
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-alpha, IL-9, and IFN-gamma) 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.
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