OP.3D.02] MICRORNA-214 IS INVOLVED IN THE REGULATION OF PERIVASCULAR FIBROSIS IN HYPERTENSION

Abstract

Objective: Hypertension is associated with perivascular inflammation and increased collagen deposition in adventitia. MicroRNAs (miR) are a novel mechanism for gene expression regulation and play a pivotal role in a wide range of pathological processes such as vascular fibrosis.The role and mechanism of miRs in this irreversible process are still unknown. Design and method: 3-months-old C57BL/6, miR-214KO and wild type littermates were treated with angiotensin II (AngII, 490ng/kg/min; n = 6–10) or control buffer for 14 days. Perivascular adipose tissues (PVAT) from C57BL/6 animals were analysed using TaqMan_Rodent_microRNA_Arrays. Histological studies, wire myography, lucigenin enhanced luminometry and cytometrical analysis was conducted. Statistical analysis was performed using ANOVA or t-test. Data are expressed as a meanSEM. Results: Out of 381 miRs, 16 were significantly overexpressed in C57BL/6 AngII animals after global normalisation. Mir-214 was the only significantly overexpressed miR with 8-fold induction (p < 0.001) in hypertensive animals after Bonferroni correction. miR214 was also increased the serum of hypertensive animals (p < 0.05). AngII infusion in miR-214KO animals did not alter blood pressure elevation, when compared to WT mice. Mir-214KOs exhibited diminished peri-aortic fibrosis upon AngII hypertension (44779 ± 2491 vs.78805 ± 8696 μm, p < 0.001). Vascular studies revealed improved endothelial function (69 ± 10 vs. 22 ± 4%, p < 0.001 by repeated measures ANOVA) and protection against oxidative stress in AngII miR-214KO aortas (66 ± 7 vs. 118 ± 19 RLU/sec/mg, p < 0.001), while these parameters were not altered in mesenteric arteries. Moreover, miR-214-KO animals were protected from VSMC hypertrophy observed in WT hypertensive animals. Recruitment of T cells into aortic PVAT was abolished in KO hypertensive animals in comparison to control (192 ± 65 vs. 603 ± 164 cell/mg; p < 0.05). This was observed in relation to both CD4 + and CD8 + T cells (107 ± 32 vs. 360 ± 108; p < 0.05, 69 ± 20 vs. 209 63cell/mg; p < 0.05, respectively). Interestingly AngII hypertension was associated with with 4-fold increase of miR-214 expression in the circulating peripheral blood T cells. Conclusions: AngII infusion changes miR profile in murine PVAT. MiR-214 has a major role in modulation of aortic fibrosis, vascular function and recruitment of T cells into PVAT. In the future, MiR-214 may be used as a biomarker or a potential target in vascular fibrosis prevention.