Role of NF‐κβ and Oxidative Pathways in Atherosclerosis: Cross‐Talk Between Dyslipidemia and Candesartan

Abstract

Summary Purpose The objective of this study is to assess the effect of the candesartan on the progression of atherosclerosis through the downregulation of NF‐κβ and interference with oxidative pathway. Methods Twenty‐four rabbits were assigned to three groups: control group fed normal diet; induced untreated group fed 1% cholesterol diet; and treated candesartan group also fed 1% cholesterol diet. Plasma lipid profiles were measured, and ELISA for plasma cytokines and chemokine was performed. Analyses of NF‐κβ and VCAM‐1 were performed using Western blotting with RT‐PCR for NF‐κB activity at mRNA. Doppler ultrasound was used to evaluate aortic intima‐media thickness, and atheroma was detected by H&E staining. Immunofluorescent staining was performed to confirm accumulation of monocytes and PMNs. Results Candesartan markedly reduced the levels of the plasma lipid profile including total cholesterol [TC], triglycerides [TG], and LDL‐C, while significantly elevating levels in the plasma HDL‐C, in addition to reducing cytokine (TNF‐α, IL‐6, IL‐1β) and chemokine levels (MCP‐1). Also, it decreased the aortic malondialdehyde (MDA) concentration and elevated the aortic glutathione (GSH) level compared with untreated animals (P < 0.05). The triplex Doppler ultrasound study confirmed that the candesartan attenuated intima‐media thickness at 6 months of study. All candesartan‐treated rabbits showed significantly attenuated atherosclerosis lesions with reduced accumulation of monocytes and had significantly reduced VCAM‐1 expression and NF‐κβ activity. Conclusion Candesartan retards the progression of atherosclerosis via interference with NF‐κβ and oxidative pathways.

The potential therapeutic use of renin–angiotensin system inhibitors in the treatment of inflammatory diseases

“…Torres et al () investigated the effects of candesartan treatment in hypercholesterolemic rabbits and found reduced expression of ICAM‐1 and consequent macrophage accumulation in the sclera and choroid. Hadi et al () have reported that candesartan reduces cytokine (TNF‐α, IL‐6, and IL‐1β) and chemokine levels (MCP‐1) as well as plasma lipid profile including total cholesterol, triglycerides, and LDL‐C, while also increasing plasma HDL‐C levels in treated rabbits. Additionally, candesartan significantly attenuated atherosclerosis lesions via interference with NF‐κB and oxidative pathways (Hadi et al, ).…”

<i>Equisetum sylvaticum</i> base reduces atherosclerosis risk factors in rats fed a high-fat diet

“…It is known that free radicals mediate various signaling pathways that are involved in vascular inflammation and lipid oxidation in atherogenesis (Yancey et al, 2003;Haas and Mooradian, 2011). Oxidative stress is defined as the disturbed balance between cellular levels of free radicals and antioxidant defenses (Hadi et al, 2013). Excessive free radicals attack all types of biomolecules including lipids molecules.…”

Candesartan ameliorates acute myocardial infarction in rats through inducible nitric oxide synthase, nuclear factor-κB, monocyte chemoattractant protein-1, activator protein-1 and restoration of heat shock protein 72

“…In the present study, candesartan was observed to attenuate NF-κB p65 activity in the rat model of acute myocardial infarction. Furthermore, Hadi et al reported that candesartan significantly attenuates atherosclerotic lesions and significantly reduces NF-κB activity in rabbits (34). In addition, Ishrat et al demonstrated that candesartan reduces hemorrhage in rat embolic stroke through a reduction in NF-κB activity (35).…”

“…Candesartan has also been observed to inhibit LPS-induced gene expression through the suppression of MCP-1 protein concentrations in human renal tubular epithelial cells (36). Hadi et al reported that candesartan retards the progression of atherosclerosis via reducing MCP-1, NF-κβ and oxidative pathways (34).…”