miR-181b regulates vascular stiffness age dependently in part by regulating TGF- square signaling

• Published in: PloS one 2017-03, Vol.12 (3)
• Main Authors: Hori, Daijiro, Dunkerly-Eyring, Brittany, Nomura, Yohei, Biswas, Debjit, Steppan, Jochen, Henao-Mejia, Jorge, Adachi, Hideo, Santhanam, Lakshmi, Berkowitz, Dan E, Steenbergen, Charles
• Format: Article
• Language: English
• ISSN: 1932-6203
• DOI: 10.1371/journal.pone.0174108

Background Endothelial dysfunction and arterial stiffening play major roles in cardiovascular diseases. The critical role for the miR-181 family in vascular inflammation has been documented. Here we tested whether the miR-181 family can influence the pathogenesis of hypertension and vascular stiffening. Methods and results qPCR data showed a significant decrease in miR-181b expression in the aorta of the older mice. Eight miR-181a1/b1-/- mice and wild types (C57BL6J:WT) were followed weekly for pulse wave velocity (PWV) and blood pressure measurements. After 20 weeks, the mice were tested for endothelial function and aortic modulus. There was a progressive increase in PWV and higher systolic blood pressure in miR-181a1/b1-/- mice compared with WTs. At 21 weeks, aortic modulus was significantly greater in the miR-181a1/b1-/- group, and serum TGF-[Beta] was found to be elevated at this time. A luciferase reporter assay confirmed miR-181b targets TGF-[Beta]i (TGF-[Beta] induced) in the aortic VSMCs. In contrast, wire myography revealed unaltered endothelial function along with higher nitric oxide production in the miR-181a1/b1-/- group. Cultured VECs and VSMCs from the mouse aorta showed more secreted TGF-[Beta] in VSMCs of the miR-181a1/b1-/- group; whereas, no change was observed from VECs. Circulating levels of angiotensin II were similar in both groups. Treatment with losartan (0.6 g/L) prevented the increase in PWV, blood pressure, and vascular stiffness in miR-181a1/b1-/- mice. Immunohistochemistry and western blot for p-SMAD2/3 validated the inhibitory effect of losartan on TGF-[Beta] signaling in miR-181a1/b1-/- mice. Conclusions Decreased miR-181b with aging plays a critical role in ECM remodeling by removing the brake on the TGF-[Beta], pSMAD2/3 pathway.