Abstract
Aging is a risk factor for the development of CVD and is characterized by a reduced vascular reactivity and increased free radical generation (ROS). The uncoupling of oxidative phosphorylation (OXPHOS) reduces ROS generation. We hypothesized that endothelium-dependent (EDD) and endothelium-independent (EIND) dilation is linked to mitochondrial uncoupling. Isometric tension experiments were performed in Fisher 344 (F344, 15–16 months) rat aortic rings. Acetylcholine (Ach, 10 μM, n=13 rings) caused 10% vasodilation (n= 19). The EIND dilation was tested with MAHMA NONO-ate (10μM) and rings responded with 46% (n= 13, P<0.05) relaxation. FCCP (1 μM) a chemical uncoupler of OXPHOS had no effects on neither EDD nor EIND (n=6, ns). Bay 41–2272 (10 μM), stimulator of soluble guanylate cyclase (sGC) improved relaxation to Ach, and arteries responded with 56% (n=6, P<0.05) relaxation; relaxation to MAHMA was at 71% (n=6, P<0.05). The expression of uncoupling protein UCP-2 in heart and aorta of F344 was increased by 30% (3 hearts, 3 aortas, n=2), respectively; the expression of UCP-3 was increased by 3-fold (n=3) in F344 hearts as compare to age matched controls. Taken together, a decline in vascular function is consistent with progressive oxidative stress. The oxidative modification of proteins could be responsible for a lack of activation of a negative feedback via the uncoupling of OXPHOS and reduction in ROS levels.
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