Experimental reduction of miR-92a mimics arterial aging

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MicroRNAs (miRs) are small non-coding RNAs that are important regulators of aging and cardiovascular diseases. MiR-92a is important in developmental vascular growth and tumorigenesis and two of its putative targets, tumor necrosis factor alpha receptor 1 (TNFR1) and collagen type 1, play a role in age-related arterial dysfunction. We hypothesized that reduced miR-92a expression contributes to age-related arterial dysfunction characterized by endothelial dysfunction and increased large artery stiffness. MiR-92a is reduced 39% (RT-PCR, p < 0.05) in arteries of older adults compared to young adults. Similarly, there was a 40% reduction in miR-92a in aortas of old (29 months, n = 13) compared to young (6 months, n = 11) B6D2F1 mice, an established model of vascular aging. To determine if reduced miR-92a contributes to arterial dysfunction; miR-92a was inhibited in vivo in young mice using antagomirs (I.P., 4 wks). Antagomir treatment was associated with a concomitant 48% increase in TNFR1 (Western blot, p < 0.05), 19% increase in type 1 collagen (immunohistochemistry, p < 0.01), and a reduction in endothelial dependent dilation (max dilation: 93 ± 1 vs. 73 ± 5%, p < 0.01) in response to acetylcholine (ACh, 10− 9 to 10− 4 M). Treatment with the nitric oxide (NO) synthase inhibitor, L-NAME (10− 4 M), revealed that impaired ACh dilation after antagomir treatment resulted from reduced NO bioavailability. Inhibition of miR-92a also increased arterial stiffness (pulse wave velocity, 309 ± 13 vs. 484 ± 52 cm/s, p < 0.05). Together, these results suggest that experimental reductions in arterial miR-92a partially mimic the arterial aging phenotype and we speculate that modulating miR-92a may provide a therapeutic strategy to improve age-related arterial dysfunction.

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