Abstract
We tested the hypothesis that superoxide signaling within aortic perivascular adipose tissue (PVAT) contributes to large elastic artery stiffening in old mice. Young (4–6 months), old (26–28 months), and old treated with 4-Hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPOL), a superoxide scavenger (1 mm in drinking water for 3 weeks), male C57BL6/N mice were studied. Compared with young, old had greater large artery stiffness assessed by aortic pulse wave velocity (aPWV, 436 ± 9 vs. 344 ± 5 cm s-1) and intrinsic mechanical testing (3821 ± 427 vs. 1925 ± 271 kPa) (both P < 0.05). TEMPOL treatment in old reversed both measures of arterial stiffness. Aortic PVAT superoxide production was greater in old (P < 0.05 vs. Y), which was normalized with TEMPOL. Compared with young, old controls had greater pro-inflammatory proteins in PVAT-conditioned media (P < 0.05). Young recipient mice transplanted with PVAT from old compared with young donors for 8 weeks had greater aPWV (409 ± 7 vs. 342 ± 8 cm s-1) and intrinsic mechanical properties (3197 ± 647 vs. 1889 ± 520 kPa) (both P < 0.05), which was abolished with TEMPOL supplementation in old donors. Tissue-cultured aortic segments from old in the presence of PVAT had greater mechanical stiffening compared with old cultured in the absence of PVAT and old with PVAT and TEMPOL (both, P < 0.05). In addition, PVAT-derived superoxide was associated with arterial wall hypertrophy and greater adventitial collagen I expression with aging that was attenuated by TEMPOL. Aging or TEMPOL treatment did not affect blood pressure. Our findings provide evidence for greater age-related superoxide production and pro-inflammatory proteins in PVAT, and directly link superoxide signaling in PVAT to large elastic artery stiffness.
Highlights
Aging is the major risk factor for cardiovascular diseases (CVD), as nearly 90% of incident CV events occur in adults over 55 years of age (Go et al, 2013)
It is unknown whether the production of superoxide production and proinflammatory proteins from Perivascular adipose tissue (PVAT) is increased with aging, and whether superoxide signaling in PVAT contributes to large artery stiffening with age
Large elastic artery stiffness was greater in old compared with young control mice based on aortic pulse wave velocity, the clinical gold standard measure (Sutton-Tyrrell et al, 2005; Mitchell et al, 2010) (Fig. 1A), and ex vivo intrinsic mechanical stiffness (Fig. 1B)
Summary
Aging is the major risk factor for cardiovascular diseases (CVD), as nearly 90% of incident CV events occur in adults over 55 years of age (Go et al, 2013). Accepted for publication 8 December 2013 arteries) is a strong, independent predictor of cardiovascular events with aging (Sutton-Tyrrell et al, 2005; Mitchell et al, 2010), and superoxidedependent oxidative stress and inflammation are key mechanisms by which large elastic arteries stiffen with age (Kim et al, 2009; Sindler et al, 2011; Fleenor et al, 2012). Visceral white adipose tissues from older mice demonstrate greater oxidative stress, which may lead to greater pro-inflammatory cytokine and chemokine secretion (Findeisen et al, 2011; Padilla et al, 2013). It is unknown whether the production of superoxide production and proinflammatory proteins from PVAT is increased with aging, and whether superoxide signaling in PVAT contributes to large artery stiffening with age
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