MiR-181b regulates vascular stiffness age dependently in part by regulating TGF-β signaling

Daijiro Hori, Brittany Dunkerly-Eyring, Yohei Nomura, Debjit Biswas, Jochen Steppan, Jorge Henao-Mejia, Hideo Adachi, Lakshmi Santhanam, Dan E. Berkowitz, Charles Steenbergen, Richard A. Flavell, Samarjit Das

Research output: Contribution to journalArticle

Abstract

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-β was found to be elevated at this time. A luciferase reporter assay confirmed miR-181b targets TGF-βi (TGF-β 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-β 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-β 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-β, pSMAD2/3 pathway.

Original languageEnglish (US)
Article numbere0174108
JournalPloS one
Volume12
Issue number3
DOIs
StatePublished - Mar 2017

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Hori, D., Dunkerly-Eyring, B., Nomura, Y., Biswas, D., Steppan, J., Henao-Mejia, J., Adachi, H., Santhanam, L., Berkowitz, D. E., Steenbergen, C., Flavell, R. A., & Das, S. (2017). MiR-181b regulates vascular stiffness age dependently in part by regulating TGF-β signaling. PloS one, 12(3), [e0174108]. https://doi.org/10.1371/journal.pone.0174108