title: Experimental reduction of miR-92a mimics arterial aging.
abstract: 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.
authors: Department of Internal Medicine, University of Utah, Salt Lake City, UT, United States.
authors: Sugata
authors: S
authors: Hazra
authors: Department of Exercise and Sport Science, University of Utah, Salt Lake City, UT, United States.
authors: Grant D
authors: GD
authors: Henson
authors: Department of Internal Medicine, University of Utah, Salt Lake City, UT, United States.
authors: R Garrett
authors: RG
authors: Morgan
authors: Department of Internal Medicine, University of Utah, Salt Lake City, UT, United States.
authors: Sarah R
authors: SR
authors: Breevoort
authors: 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; Veteran's Affairs Medical Center-Salt Lake City, Geriatrics Research and Clinical Center, Salt Lake City, UT, United States.
authors: Stephen J
authors: SJ
authors: Ives
authors: 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; Veteran's Affairs Medical Center-Salt Lake City, Geriatrics Research and Clinical Center, Salt Lake City, UT, United States.
authors: Russell S
authors: RS
authors: Richardson
authors: 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; Department of Biochemistry, University of Utah, Salt Lake City, UT, United States; Veteran's Affairs Medical Center-Salt Lake City, Geriatrics Research and Clinical Center, Salt Lake City, UT, United States.
authors: Anthony J
authors: AJ
authors: Donato
authors: 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; Veteran's Affairs Medical Center-Salt Lake City, Geriatrics Research and Clinical Center, Salt Lake City, UT, United States. Electronic address: Lisa.Lesniewski@utah.edu.
authors: Lisa A
authors: LA
authors: Lesniewski
mesh_terms: D000328:Adult; D000368:Aged; D000375:Aging / Q000235:genetics*; D000818:Animals; D001011:Aorta / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D063177:Pulse Wave Analysis; D015854:Up-Regulation; D059289:Vascular Stiffness
chemical_list: C541874:MIRN92 microRNA, human; D035683:MicroRNAs; C541873:Mirn92 microRNA, mouse; D009569:Nitric Oxide; D019331:NG-Nitroarginine Methyl Ester
keywords: Age related arterial dysfunction; Endothelial dependent dilation; MicroRNA