Effects of emotional and physiological stress on plaque instability in apolipoprotein E knockout mice

Abstract

In the present study, we sought to investigate the effects of emotional and physiological stress on plaque instability in atherosclerosis. We used different stress-treated apolipoprotein E (ApoE)-deficient mice, which have been shown to spontaneously develop atherosclerosis with features similar to those seen in humans, as an animal model. Morphology study showed that emotional stress (ES) obviously promoted the development of atherosclerotic plaques and plaque instability evidenced by significantly increasing plaque size, plaque-to-surface ratio and plaque calcification, and enhancing the frequency of large necrotic core and medial erosion compared with control ApoE(-/-) mice (P<0.01). Physiological stress (PS) treatment alone did not affect the plaque stability compared with control ApoE(-/-) mice (P>0.05). However, the combination of ES and PS treatment (CS) initiated much stronger plaque instability compared with ES treatment alone (P<0.01), increased the frequency of thin fibrous caps, and even triggered plaque rupture and buried fibrous cap. Immunohistochemical analysis indicated that both ES and CS treatment led to an increase in the accumulation of macrophages and T cells and a decrease of smooth muscle cells, reflecting an unstable atherosclerotic plaque phenotype, in the atherosclerotic lesions in ApoE(-/-) mice. PS alone did not affect plaque cellular components. Similarly, CS-mediated changes in atherosclerotic plaque composition were stronger than that caused by ES alone (P<0.01). Taken together, ES treatment alone is sufficient to promote plaque instability. PS alone does not affect atherosclerotic plaque development, but can potentiate ES-mediated plaque destabilization.

Acute and chronic psychological stress as risk factors for cardiovascular disease: Insights gained from epidemiological, clinical and experimental studies

“…Furthermore, the expression ratio of matrix degrading enzymes and their inhibitors was less favorable in the chronically stressed mice (Zheng et al, 2014). Interestingly, emotional stress alone or combined with a physical stressor, but not the physical stressor by itself seemed to contribute to lesion progression and destabilization in apoE À/À mice (Zhang et al, 2011). Here, social defeat stress induced by exposing mice to a rat was sufficient to increase atherosclerotic lesion development and this effect was even potentiated when combined with the physical stress of water withdrawal.…”

Impact of Acute and Chronic Psychosocial Stress on Vascular Inflammation

“…Indeed, various experimental evidences demonstrate accelerated atherosclerosis development in chronic stress models ( 83 ). Reports about changes in lesion size are inconsistent ( 9 , 10 ), however, researchers agree that chronic psychosocial stress changes the plaque phenotype toward a more unstable lesion, which includes more plaque inflammatory leukocytes ( 57 , 191 , 192 ), fewer plaque SMCs ( 191 , 192 ), higher expression levels of matrix metalloproteinases ( 57 , 192 ) and, consequently, reduced plaque collagen content ( 192 ) and a thinner fibrous cap ( 118 , 191 ). Of note, standard murine models of atherosclerosis acquire features of unstable plaques but lack plaque rupture or erosion, which frequently occur as the ultimate consequences of atherosclerosis in humans.…”

The sex-dependent response to psychosocial stress and ischaemic heart disease

“…The broadly pro-inflammatory milieu induced by acute and chronic stress and SNS overactivity is pro-atherogenic (607), and the makeup, inflammatory profile and stability of atherosclerotic plaques is stress-sensitive. Chronic stress shifts plaques towards an unstable phenotype, with increased leukocyte and matrix metalloproteinase (608,609) vs. reduced smooth muscle and collagen contents (634), and attrition of the fibrous cap (608). Plaque destabilisation in response to acute stress in ApoE −/− mice (335) involves noradrenaline stimulation of endothelial adhesion molecule expression and chemokine release.…”