Low dose tunicamycin enhances atherosclerotic plaque stability by inducing autophagy
| Autor: | Hai-Chang Wang, Le Zhang, Ling Tao, Rongqing Zhang, Jianhua Hu, Yingmei Zhang, Jian Yuan, Hao Yan, Ying Ma, Congye Li, Zhaole Ji, Meijuan Ma, Yan Li, Min Liu, Li-Qiang Song |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Apolipoprotein E medicine.medical_specialty Pathology Programmed cell death Biochemistry Mice 03 medical and health sciences chemistry.chemical_compound Downregulation and upregulation Internal medicine Autophagy medicine Animals Mice Knockout Pharmacology Mice Inbred BALB C Chemistry Tunicamycin Endoplasmic reticulum Fibrous cap Endoplasmic Reticulum Stress Plaque Atherosclerotic 030104 developmental biology Endocrinology medicine.anatomical_structure Apoptosis |
| Zdroj: | Biochemical Pharmacology. 100:51-60 |
| ISSN: | 0006-2952 |
| Popis: | After decades of indolent progression, atherosclerosis may cause unheralded events, such as myocardial infarction, acute coronary syndrome and stroke due to sudden rupture of atherosclerotic plaques, and pharmacologically modulating plaque stability would reduce the risk of cardiovascular diseases. Endoplasmic reticulum stress (ERS) is responsible for the vulnerability of plaques. However, the underlying mechanism has not been fully elucidated. In this work, ApoE(-/-) mice underwent perivascular carotid collar placement surgeries or sham operations were given higher (3.0mg/kg) and lower (0.3mg/kg) doses of tunicamycin (TM), and plaque stability was evaluated. It was shown that lower TM-treated animals exhibited reduced plaque areas and necrotic cores as well as fibrous cap thickness accompanied by a lower percentage of infiltrates and foam cells than the sham-operated and higher TM treated animals. Lower TM had a profound inhibitory effect on plasma inflammatory response and lipid profile in atherosclerotic ApoE(-/-) mice. In addition, we found that the ApoE(-/-) mice presented higher autophagy activity in response to lower TM administration while apoptosis was reduced. An in vitro study in murine macrophages revealed that lower TM could markedly reduce lipid uptake and accumulation and cell apoptosis while significantly upregulated the expression of Atg7. However, higher TM had adverse effects. Finally, mild induction of ERS by lower TM inhibits AKT-TSC-mTOR cascades to increase cellular autophagy. However, high TM failed to enhance autophagy and equilibrate elevated CHOP-mediated cell death in spite of the inhibition of AKT-TSC-mTOR signaling. In conclusion, lower TM stabilized plaques by activating autophagy through AKT-TSC-mTOR signaling. |
| Databáze: | OpenAIRE |
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