Hazra Sugata, Henson Grant D, Morgan R Garrett, Breevoort Sarah R, Ives Stephen J, Richardson Russell S, Donato Anthony J, Lesniewski Lisa A
Department of Internal Medicine, University of Utah, Salt Lake City, UT, United States.
Department of Exercise and Sport Science, University of Utah, Salt Lake City, UT, United States.
Exp Gerontol. 2016 Oct;83:165-70. doi: 10.1016/j.exger.2016.08.007. Epub 2016 Aug 11.
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 (29months, n=13) compared to young (6months, 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., 4wks). 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±52cm/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.
微小RNA（miRs）是一类小的非编码RNA，是衰老和心血管疾病的重要调节因子。MiR-92a在血管发育生长和肿瘤发生过程中起重要作用，其两个假定靶点，肿瘤坏死因子α受体1（TNFR1）和1型胶原蛋白，在与年龄相关的动脉功能障碍中发挥作用。我们推测，miR-92a表达降低会导致以血管内皮功能障碍和大动脉僵硬度增加为特征的与年龄相关的动脉功能障碍。与年轻人相比，老年人动脉中miR-92a降低了39%（逆转录聚合酶链反应，p<0.05）。同样，在已建立的血管衰老模型B6D2F1小鼠中，老年（29个月，n=13）小鼠主动脉中的miR-92a比年轻（6个月，n=11）小鼠降低了40%。为了确定miR-92a降低是否会导致动脉功能障碍；使用抗miR（腹腔注射，4周）在年轻小鼠体内抑制miR-92a。抗miR治疗与TNFR1伴随增加48%（蛋白质免疫印迹法检测，p<0.05）、1型胶原蛋白增加19%（免疫组织化学检测，p<0.01）以及对乙酰胆碱（ACh，10(-9)至10(-4)M）反应的内皮依赖性舒张功能降低（最大舒张：93±1对73±5%，p<0.01）有关。用一氧化氮（NO）合酶抑制剂L-NAME（10(-4)M）治疗表明，抗miR治疗后ACh舒张功能受损是由于NO生物利用度降低所致。抑制miR-92a还会增加动脉僵硬度（脉搏波速度，309±13对484±52cm/s，p<0.05）。总之，这些结果表明，实验性降低动脉中的miR-92a部分模拟了动脉衰老表型，我们推测调节miR-92a可能提供一种治疗策略来改善与年龄相关的动脉功能障碍。
