Aging influences multiple incidices of oxidative stress in the aortic media of the Fischer 344/NNia × Brown Norway/BiNia rat

Abstract

Here, we determine the influence of aging on multiple markers of oxidative stress in the aorta of adult (6-month), aged (30-month) and very aged (36-month) Fischer 344/NNiaHSdxBrown Norway/BiNia (F344/NxBN) rats. Compared to adults, increases in as determined by oxidation of hydroethidine (HE) to ethidium (Et) were increased 79.7+/-7.0% in 36-month aortae and this finding was highly correlated with increases in medal thickness (r=0.773, p<0.01) and total protein nitration (r=0.706, p<0.01) but not Ki67, a marker for cell proliferation. Regression analysis showed that increases in aortic superoxide anion (O.-2) with aging were significantly correlated with changes in the expression and/or regulation of proteins involved in metabolic (AMPK-alpha), signaling (mitogen activated protein kinases (MAPKs) along with c-Src), apoptotic (Bax, Bcl-2, Traf-2) and transcriptional (NF-kappaB) activities. These results suggest that the aging F344/NxBN aorta may be highly suited for unraveling the molecular events that lead to age-associated alterations in aortic oxidative stress.

Aortic Aging in the Fischer 344 / NNiaHSd × Brown Norway / BiNia Rat

“…Nonetheless, and like that observed in aging humans, aging in the F344BN is characterized by an increase in tunica media thickness (3,6,24). Similar findings have been demonstrated in the aging female F344BN.…”

“…Recent evidence that supports this theory within the aging F344BN has shown that age-associated increases in (⋅O 2 − ) and oxidative protein damage occur in the aorta by the 30 month of age (6). The same investigation also revealed that Bax and Bcl-2, regulators of cell viability and apoptosis, were highly correlated with increases in ROS, suggesting a compensatory mechanism for maintaining cell viability in the presence of ROS accumulation (6). In addition, the expression levels of mitogen-activated protein kinase (MAPK) and c-SRC family proteins were also affected by the accumulation of ROS (6).…”

“…The free radical theory of aging suggests that aging occurs due to gradual accumulation of free radical damage to biomolecules (21,27). Recent evidence that supports this theory within the aging F344BN has shown that age-associated increases in (⋅O 2 − ) and oxidative protein damage occur in the aorta by the 30 month of age (6). The same investigation also revealed that Bax and Bcl-2, regulators of cell viability and apoptosis, were highly correlated with increases in ROS, suggesting a compensatory mechanism for maintaining cell viability in the presence of ROS accumulation (6).…”

“…Recent studies using the F344BN rat (6,16,17) has found no evidence of age-associated pathology such as intimal fibrosis, fibrolipid plaques, or ulceration in histological cross-sections of the male 6-, 30-, or 36-month age-groups, suggesting that these animals do not exhibit age-associated atherosclerosis (Table 1). Nonetheless, and like that observed in aging humans, aging in the F344BN is characterized by an increase in tunica media thickness (3,6,24).…”

Endothelium-dependent vasorelaxation to the AMPK activator AICAR is enhanced in aorta from hypertensive rats and is NO and EDCF dependent

“…Since AMPK may also play a role in facilitating the generation of NO and vasodilation of vascular smooth muscle, it is conceivable that exogenous activation of AMPK may be able to improve vasomotor function by stimulating processes that are otherwise impaired in diseased arteries. Interestingly, depressed AMPK activation, or AMPK dysregulation, has been observed in arteries of rodent models where vascular dysfunction exists, including in streptozotocin-induced diabetes (55), Zucker diabetic fatty rats (2), aged rats (47), and Otsuka Long Evans Tokushima Fatty (OLETF) rats (34). In pilot work, we determined that basal AMPK activation is also blunted in aorta of spontaneously hypertensive rats (SHR; a genetic model of essential hyperten-sion and vasomotor dysfunction) compared with levels in normotenisve control Wistar-Kyoto rats (WKY).…”