December 13, 2011Aging Cell132 citationsOpen Access
View Full PaperSuperoxide‐lowering therapy with TEMPOL reverses arterial dysfunction with aging in mice
Key Result
Short-term treatment with TEMPOL restored acetylcholine-stimulated endothelium-dependent dilation (94.5% vs 75.6%) and reversed age-associated increases in aortic pulse wave velocity in older mice.
Structured PICO
Does TEMPOL improve arterial stiffness and endothelial dysfunction in aged mice?
P
Population
32 young and old male C57BL6 mice treated with regular or TEMPOL-supplemented drinking water for 3 weeks to assess arterial aging.
I
Intervention
TEMPOL-supplemented (1mM) drinking water for 3 weeks
C
Comparator
Regular drinking water
O
Outcome
Aortic pulse wave velocity (aPWV) and acetylcholine-stimulated endothelium-dependent dilation (EDD)surrogate
Short-term treatment with the superoxide dismutase mimetic TEMPOL ameliorates large elastic artery stiffening and endothelial dysfunction associated with aging in a mouse model.
Main Result
Absolute Event Rate: 94.5% vs 75.6%
Abstract
To test the hypothesis that the antioxidant enzyme superoxide dismutase (SOD) mimetic TEMPOL improves arterial aging, young (Y, 4-6 months) and old (O, 26-28 months) male C57BL6 mice received regular or TEMPOL-supplemented (1mM) drinking water for 3 weeks (n = 8 per group). Aortic superoxide was 65% greater in O (P < 0.05 vs. Y), which was normalized by TEMPOL. O had large elastic artery stiffening, as indicated by greater aortic pulse wave velocity (aPWV, 508 ± 22 vs. 418 ± 22 AU), which was associated with increased adventitial collagen I expression (P < 0.05 vs. Y). TEMPOL reversed the age-associated increases in aPWV (434 ± 21 AU) and collagen in vivo, and SOD reversed the increases in collagen I in adventitial fibroblasts from older rats in vitro. Isolated carotid arteries of O had impaired endothelial function as indicated by reduced acetylcholine-stimulated endothelium-dependent dilation (EDD) (75.6 ± 3.2 vs. 94.5 ± 2.0%) mediated by reduced nitric oxide (NO) bioavailability (L-NAME) associated with decreased endothelial NO synthase (eNOS) expression (P < 0.05 vs. Y). TEMPOL restored EDD (94.5 ± 1.4%), NO bioavailability and eNOS in O. Nitrotyrosine and expression of NADPH oxidase were ~100-200% greater, and MnSOD was ~75% lower in O (P < 0.05 vs. Y). TEMPOL normalized nitrotyrosine and NADPH oxidase in O, without affecting MnSOD. Aortic pro-inflammatory cytokines were greater in O (P < 0.05 vs. Y) and normalized by TEMPOL. Short-term treatment of excessive superoxide with TEMPOL ameliorates large elastic artery stiffening and endothelial dysfunction with aging, and this is associated with normalization of arterial collagen I, eNOS, oxidative stress, and inflammation.