Unpredictable Chronic Mild Stress Promotes Atherosclerosis in High Cholesterol–Fed Rabbits

Objectives Chronic psychological stress is associated with an increased risk of atherosclerosis in humans. Experimental studies using various stress models have yielded controversial results. This study investigated the effects of unpredictable chronic mild stress (UCMS) on atherogenesis in New Zealand white rabbits. Methods Rabbits were fed with a cholesterol-enriched (1%) diet for 4 to 16 weeks, with or without concomitant UCMS treatment. Atherosclerosis was assessed in the abdominal aorta by serial sectioning and morphological analysis. Expressions of inflammatory factors were measured with immunohistochemistry and quantitative polymerase chain reaction. Serum nitrate/nitrite levels were determined with Griess assay, and corticosterone and inflammatory markers were determined using enzyme-linked immunosorbent assay. Results High-cholesterol feeding resulted in hypercholesterolemia and formation of atherosclerotic plaques in the aorta. UCMS exposure significantly increased the plaque size (p = .003) and decreased the plaque stability (decreased the contents of collagen and smooth muscle and increased the amount of macrophage and matrix metalloproteinases). The proatherogenic effects of UCMS were unrelated to changes in serum cholesterol level but accompanied by increased blood pressure (p < .001) and vascular inflammation (up-regulation of tumor necrosis factor α, C-reactive protein, and monocyte chemoattractant protein 1, all p values < .01). Serum concentrations of nitrate/nitrite were lower in UCMS-treated animals (p = .01). Vessels from UCMS-treated animals exhibited augmented phosphorylation of p38 and c-Jun N-terminal kinase and activation of nuclear factor κB. Conclusions Chronic psychological stress may contribute to the development of atherosclerosis by enhancing vascular inflammation and decreasing endothelial nitric oxide bioavailability. Abbreviations UCMS = unpredictable chronic mild stress CRP = C-reactive protein TNF-α = tumor necrosis factor α MCP-1 = monocyte chemoattractant protein 1 MIF = macrophage migration inhibitory factor eNOS = endothelial nitric oxide synthase TC = total cholesterol LDL-C = low-density lipoprotein cholesterol JNK = c-Jun N-terminal kinase ND = normal diet HD = high-cholesterol diet MMP = matrix metalloproteinase NF-κB = nuclear factor κB