Mechanism of Ang II involvement in activation of NF-κB through phosphorylation of p65 during aging

Abstract

Angiotensin II (Ang II), a major effector of the renin-angiotensin system, is now recognized as a pro-inflammatory mediator. This Ang II signaling, which causes transcription of pro-inflammatory genes, is regulated through nuclear factor-κB (NF-κB). At present, the molecular mechanisms underlying the effect of aging on Ang II signaling and NF-κB activation are not fully understood. The purpose of this study was to document altered molecular events involved in agerelated changes in Ang II signaling and NF-κB activation. Experimentations were carried out using kidney tissues from Fischer 344 rats at 6, 12, 18, and 24 months of age, and the rat endothelial cell line, YPEN-1 for the detailed molecular work. Results show that increases in Ang II and Ang II type 1 receptor during aging were accompanied by the generation of reactive species. Increased Ang II activated NF-κB by phosphorylating IκBα and p65. Increased phosphorylation of p65 at Ser 536 was mediated by the enhanced phosphorylation of IκB kinase αβ, while phosphorylation site Ser 276 of p65 was mediated by upregulated mitogen-activated and stress-activated protein kinase-1. These altered molecular events in aged animals were partly verified by experiments using YPEN-1 cells. Collectively, our findings provide molecular insights into the pro-inflammatory actions of Ang II, actions that influence the phosphorylation of p65-mediated NF-κB activation during aging. Our study demonstrates the age-related pleiotropic nature of the physiologically important Ang II can change into a deleterious culprit that contributes to an increased incidence of many chronic diseases such as atherosclerosis, diabetes, and dementia.

Toll-like receptor-4 signaling pathway in aorta aging and diseases: “its double nature”

“…Interestingly, also the chymase, another angiotensin-convertase, was found in the wall of aged aorta [69]. Recently, two additional groups [70,71] evidenced that Ang II signaling cascades promote aorta remodeling by Fig. 4.…”

“…This evidence is the result of findings from the Lakatta s' group, using rat models, [62,63], and Šabovic's group [64], who propose administering combination of low-dose fluvastatin and valsartan, as anti-aging drugs. On the other hand, the expression and activity of Ang II, the angiotensin converting enzyme (ACE), the Ang II receptor AT1 receptor within the aorta wall, in particular, in the thickened intima in several species, including humans, are risen as the age progress [62][63][64][65][66][67][68][69][70][71]. Interestingly, also the chymase, another angiotensin-convertase, was found in the wall of aged aorta [69].…”

“…[58] Vascular endothelial dysfunction and apoptosis during aging Monkeys Vascular endothelial dysfunction was present in oldmonkeys without evidence of atherosclerosis, which may be due to endothelial apoptosis and reduced endothelial cell density Wang M. et al [59] Proinflammatory signaling in age-associated arterial remodeling Rats A local proinflammatory signaling loop facilitates adverse age-associated arterial remodeling Song Y. et al [60] Expression inducing expression and/or activity of several pro-inflammatory transcription factors (located downstream to these pathways). Among these, first is the Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) [41,61,71]. Its activation determines the production and release of a myriad of factors, including inflammatory mediators, mitotic and tropic factors, proteoglycans and metalloproteinase (MMP)s (especiallyMMP-2 and -9), and vaso-active molecules.…”

Involvement of the Renin‐Angiotensin System in Atherosclerosis

“…Ang II activates NF-κB via AT1R in vascular cells and mononuclear cells, both in vivo and in vitro [59,60]. The increase Ang II activates NF-κB by phosphorylating IκBα and p65 [61], which induces enhanced matrix metalloproteinase 9 (MMP-9) expression [62]. The AT1R mediates most of the actions of Ang II, but experimental data suggest that AT2R is also involved in Ang II-mediated NF-κB activation in inflammatory cell recruitment [63].…”

Anti-inflammatory Action of Calorie Restriction Underlies the Retardation of Aging and Age-Related Diseases

“…Experimental data suggest that age-related NF-κB activation is affected by AGE-induced NADPH oxidase activation [18]. Recent work from Kim et al [19] has shown that angiotensin II, a major effector of the rennin-angiotensin system, influences the phosphorylation of p65-mediated NF-κB activation during aging. Increased phosphorylation of p65 at Ser 536 was mediated by the enhanced phosphorylation of IKK, while phosphorylation site Ser 276 of p65 was mediated by upregulated MSK-1.…”