Chronic aerobic exercise opposes age‐ and high fat diet‐associated vascular endothelial dysfunction: relation to IKKβ and AMPK

Abstract

Age and high fat, ie. Western, diet (WD) are associated with inflammation and impaired endothelium‐dependent dilation (EDD), whereas aerobic exercise has opposite effects. Activation of the pro‐inflammatory signaling molecule inhibitor of kappa B kinase beta (IKKβ), as modulated by adenosine monophosphate activated protein kinase (AMPK), may contribute to these differential effects. Old (O: 29‐31 mo) B6D2F1 mice fed either normal chow (NC) or WD (40% fat, 8 weeks) either were sedentary (SED) or performed voluntary wheel running (VR). In SED, carotid artery EDD to acetylcholine was reduced after WD (max dilation: 62 ± 8 vs. NC: 76 ± 2%, P < 0.05) and this was associated with increased aortic IKKβ activation (phosphorylated (pSer177/181):total IKKβ: 2.1 ± 0.8 vs. 0.5 ± 0.1 AUs, P = 0.01) and reduced AMPK activation (pThr172:total AMPKα: 0.7 ± 0.1 vs. 1.0 ± 0.1 AUs, P = 0.05). VR improved EDD in both NC (96 ± 2%, P < 0.01) and WD (91 ± 7%, P < 0.05) fed mice, while reducing IKKβ activation by ~60% (P < 0.01 in NC, P = 0.1 in WD) and increasing AMPK activity by 30‐40% (P = 0.1 in NC, P < 0.05 in WD). Here we demonstrate that habitual voluntary aerobic exercise may reverse age‐ and WD‐associated vascular endothelial dysfunction by increasing AMPK activity and inhibiting IKKβ‐linked pro‐inflammatory signaling.NIH AG013038, AG006537, AG015897, AG022241, AG000279