Zhen-Wang Zhao1, Min Zhang1, Ling-Yan Chen1, Duo Gong1, Xiao-Dan Xia1, Xiao-Hua Yu1, Si-Qi Wang1, Xiang Ou2, Xiao-Yan Dai3, Xi-Long Zheng4, Da-Wei Zhang5, Chao-Ke Tang6. 1. Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, Medical Research Experiment Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, China. 2. Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, Medical Research Experiment Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, China; Department of Endocrinology, The First Hospital of Changsha, Changsha, Hunan 410005, China. 3. Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 511436, China. 4. Department of Biochemistry and Molecular Biology, The Libin Cardiovascular Institute of Alberta, The University of Calgary, Health Sciences Center, 3330 Hospital Dr. N.W., Calgary, Alberta T2N 4N1, Canada. 5. Department of Pediatrics and Group on the Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada. 6. Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, Medical Research Experiment Center, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, University of South China, Hengyang, Hunan 421001, China. Electronic address: tangchaoke@qq.com.
Abstract
BACKGROUND AND AIMS: Recent studies have suggested that heat shock protein 70 (HSP70) may play critical roles in cardiovascular disease. However, the effects of HSP70 on the development of atherosclerosis in apoE-/- mice remain largely unknown. This study was to investigate the role and potential mechanism of HSP70 in atherosclerosis. METHODS: HSP70 was overexpressed in apoE-/- mice and THP-1-derived macrophages with lentiviral vectors. Oil Red O, hematoxylin-eosin, and Masson staining were performed to evaluate atherosclerotic plaque in apoE-/- mice fed the Western type diet. Moreover, immunostaining was employed to detect the expression of relative proteins in aortic sinus. Reporter gene and chromatin immunoprecipitation were performed to analyze the effect of Elk-1 on the promoter activity of ABCA1 and ABCG1; [3H] labeled cholesterol was used to assess the capacity of cholesterol efflux and reverse cholesterol transport (RCT). RESULTS: Our results showed that HSP70 increased lipid accumulation in arteries and promoted the formation of atherosclerotic lesion. The capacity of cholesterol efflux was reduced in peritoneal macrophages isolated from HSP70-overexpressed apoE-/- mice. The levels of ABCA1 and ABCG1 expression were also reduced in the peritoneal macrophages and the aorta from apoE-/- mice in response to HSP70. The c-Jun N-terminal kinase (JNK) and ETS transcription factor (Elk-1) played a critical role in HSP70-induced downregulation ABCA1 and ABCG1. Further, HSP70 reduced RCT from macrophages to plasma, liver, and feces in apoE-/- mice. CONCLUSIONS: HSP70 promotes the progression of atherosclerosis in apoE-/- mice by suppressing the expression of ABCA1 and ABCG1 through the JNK/Elk-1 pathway.
BACKGROUND AND AIMS: Recent studies have suggested that heat shock protein 70 (HSP70) may play critical roles in cardiovascular disease. However, the effects of HSP70 on the development of atherosclerosis in apoE-/- mice remain largely unknown. This study was to investigate the role and potential mechanism of HSP70 in atherosclerosis. METHODS:HSP70 was overexpressed in apoE-/- mice and THP-1-derived macrophages with lentiviral vectors. Oil Red O, hematoxylin-eosin, and Masson staining were performed to evaluate atherosclerotic plaque in apoE-/- mice fed the Western type diet. Moreover, immunostaining was employed to detect the expression of relative proteins in aortic sinus. Reporter gene and chromatin immunoprecipitation were performed to analyze the effect of Elk-1 on the promoter activity of ABCA1 and ABCG1; [3H] labeled cholesterol was used to assess the capacity of cholesterol efflux and reverse cholesterol transport (RCT). RESULTS: Our results showed that HSP70 increased lipid accumulation in arteries and promoted the formation of atherosclerotic lesion. The capacity of cholesterol efflux was reduced in peritoneal macrophages isolated from HSP70-overexpressed apoE-/- mice. The levels of ABCA1 and ABCG1 expression were also reduced in the peritoneal macrophages and the aorta from apoE-/- mice in response to HSP70. The c-Jun N-terminal kinase (JNK) and ETS transcription factor (Elk-1) played a critical role in HSP70-induced downregulation ABCA1 and ABCG1. Further, HSP70 reduced RCT from macrophages to plasma, liver, and feces in apoE-/- mice. CONCLUSIONS:HSP70 promotes the progression of atherosclerosis in apoE-/- mice by suppressing the expression of ABCA1 and ABCG1 through the JNK/Elk-1 pathway.