Superoxide‐lowering therapy with TEMPOL reverses arterial dysfunction with aging in mice

BS Fleenor, DR Seals, ML Zigler, AL Sindler - Aging cell, 2012 - Wiley Online Library
BS Fleenor, DR Seals, ML Zigler, AL Sindler
Aging cell, 2012Wiley Online Library
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 …
Summary
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.
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