Submitted on November 17, 2008
Revised on February 11, 2009
Accepted on February 25, 2009
Atherosclerotic Plaque Disruption Induced by Stress and Lipopolysaccharide in Apolipoprotein E Knockout Mice
Mei Ni1, Yan Wang2, Mei Zhang3, Peng-Fei Zhang, Shi-Fang Ding, Chun Xi Liu4, Xiao Ling Liu, Yu Xia Zhao2, and Yun Zhang5*
1 The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University Qilu Hospital
2 The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Shandong University Qilu Hospital, Jinan, Shandong, China
3 Qilu Hospital Shandong University
4 The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health
5 QiLu Hospital, Shandong, University
* To whom correspondence should be addressed. E-mail: zhangyun{at}sdu.edu.cn.
To establish an animal model with disruptions of atherosclerotic plaques, ninety-six male apolipoprotein E knockout (apoE-/-) mice were randomly divided into stress group, lipopolysaccharide (LPS) group, stress+LPS group and control group (n=24, each). All mice were fed a high-fat diet throughout the experiment and carotid atherosclerotic lesions were induced by placement of a constrictive perivascular collar. Four weeks after surgery, mice in the LPS and stress+LPS groups were intraperitoneally injected with LPS (1 mg/kg, twice per week, for 8 weeks). Eight weeks after surgery, mice in the stress and stress+LPS groups were treated with intermittent physical stress (electric foot-shock and noise stimulation) for 4 weeks. Morphologic analysis revealed a plaque disruption rate of 16.7% in control, 34.8% in LPS, 54.2% in stress and 60.9% in stress+LPS groups. The disruption rates in stress and stress+LPS groups were both significantly higher than those of controls (P=0.007 and P=0.002, respectively). Luminal thrombosis secondary to plaque disruption was observed only in the stress+LPS group. Both stress and LPS stimulation significantly decreased fibrous cap thickness and increased macrophage and lipid contents in plaques. Moreover, the combination of stress and LPS stimulation further lowered cap thickness and enhanced accumulation of macrophages and expression of inflammatory cytokines and matrix metalloproteinases. Stress activated the sympathetic nervous system as manifested by increased blood pressure and flow velocity. Plasma fibrinogen levels were remarkably elevated in the stress and stress+LPS groups. In conclusion, stress and LPS co-stimulated apoE-/- mice provide a useful model for studies of plaque vulnerability and interventions.
