Increased mitochondrial H2O2 production promotes endothelial NF-kappaB activation in aged rat arteries.
Previous studies have shown that the aging vascular system undergoes pro-atherogenic phenotypic changes, including increased oxidative stress and a pro-inflammatory shift in endothelial gene expression profile. To elucidate the link between increased oxidative stress and vascular inflammation in aging, we compared the carotid arteries and aortas of young and aged (24 mo old) Fisher 344 rats. In aged vessels there was an increased NF-kappaB activity (assessed by luciferase reporter gene assay and NF-kappaB binding assay), which was attenuated by scavenging H(2)O(2). Aging did not alter the vascular mRNA and protein expression of p65 and p50 subunits of NF-kappaB. In endothelial cells of aged vessels there was an increased production of H(2)O(2) (assessed by 5,6-chloromethyl-2',7'-dichlorodihydrofluorescein diacetate-acetyl ester fluorescence), which was attenuated by the mitochondrial uncoupler FCCP. In young arteries and cultured endothelial cells, antimycin A plus succinate significantly increased FCCP-sensitive mitochondrial H(2)O(2) generation, which was associated with activation of NF-kappaB. In aged vessels inhibition of NF-kappaB (by pyrrolidenedithiocarbamate, resveratrol) significantly attenuated inflammatory gene expression and inhibited monocyte adhesiveness. Thus increased mitochondrial oxidative stress contributes to endothelial NF-kappaB activation, which contributes to the pro-inflammatory phenotypic alterations in the aged vaculature. Our model predicts that by reducing mitochondrial H(2)O(2) production and/or directly inhibiting NF-kappaB novel anti-aging pharmacological treatments (e.g., calorie restriction mimetics) will exert significant anti-inflammatory and vasoprotective effects.
Ungvari
Zoltan
Z
Department of Physiology, New York Medical College, Valhalla, NY 10595, USA. zoltan_ungvari@nymc.edu
Orosz
Zsuzsanna
Z
Labinskyy
Nazar
N
Rivera
Aracelie
A
Xiangmin
Zhao
Z
Smith
Kira
K
Csiszar
Anna
A
D000375:Aging / Q000378:metabolism*; D000818:Animals; D002339:Carotid Arteries / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000378:metabolism*; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D015533:Transcriptional Activation / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology
D016328:NF-kappa B; D006861:Hydrogen Peroxide