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

• Published in: PloS one Vol. 12; no. 3; p. e0174108
• 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, Flavell, Richard A, Das, Samarjit
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 21.03.2017; Public Library of Science (PLoS)
• Subjects: Aging; Aging - genetics; Anesthesiology; Angiotensin; Angiotensin II; Angiotensin II - blood; Animals; Antihypertensive Agents - pharmacology; Aorta; Aorta - cytology; Biology and Life Sciences; Blood; Blood pressure; Blood Pressure - drug effects; Blood Pressure - genetics; Breast cancer; Cardiovascular disease; Cardiovascular diseases; Cardiovascular Diseases - physiopathology; Critical care; Endothelial Cells - pathology; Extracellular matrix; Extracellular Matrix - genetics; Extracellular Matrix - pathology; Growth factors; Heart diseases; Heart surgery; Hypertension; Hypertension - drug therapy; Hypertension - genetics; Hypertension - pathology; Immunohistochemistry; Inflammation; Losartan - pharmacology; Male; Medicine; Medicine and Health Sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; MicroRNAs; MicroRNAs - genetics; Nitric oxide; Nitric Oxide - biosynthesis; Pathogenesis; Pathology; Physical Sciences; Pressure measurement; Pressure measurements; Research and Analysis Methods; Rodents; Signaling; Smad2 protein; Smad2 Protein - metabolism; Smad3 Protein - metabolism; Smooth muscle; Stiffening; Stiffness; Transforming Growth Factor beta - metabolism; Vascular Stiffness - genetics; Wave velocity
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0174108

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. 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. Decreased miR-181b with aging plays a critical role in ECM remodeling by removing the brake on the TGF-β, pSMAD2/3 pathway.