Pregnancy-Associated Plasma Protein-A Accelerates Atherosclerosis by Regulating Reverse Cholesterol Transport and Inflammation

Shi-Lin Tang; Zhen-Wang Zhao; Shang-Ming Liu; Gang Wang; Xiao-Hua Yu; Jin Zou; Si-Qi Wang; Xiao-Yan Dai; Min-Gui Fu; Xi-Long Zheng; Da-Wei Zhang; Hui Fu; Chao-Ke Tang

doi:10.1253/circj.CJ-18-0700

Aortic Disease

Pregnancy-Associated Plasma Protein-A Accelerates Atherosclerosis by Regulating Reverse Cholesterol Transport and Inflammation

Shi-Lin Tang, Zhen-Wang Zhao, Shang-Ming Liu, Gang Wang, Xiao-Hua Yu, Jin Zou, Si-Qi Wang, Xiao-Yan Dai, Min-Gui Fu, Xi-Long Zheng, Da-Wei Zhang, Hui Fu, Chao-Ke Tang

Author information

Shi-Lin Tang
Department of Intensive Care Unit, the First Affiliated Hospital of University of South China
Zhen-Wang Zhao
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
Shang-Ming Liu
Department of Intensive Care Unit, the First Affiliated Hospital of University of South China
Gang Wang
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
Xiao-Hua Yu
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
Jin Zou
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
Si-Qi Wang
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
Xiao-Yan Dai
Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University
Min-Gui Fu
Department of Biomedical Science and Shock/Trauma Research Center, School of Medicine, University of Missouri-Kansas City
Xi-Long Zheng
Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University
Department of Biochemistry and Molecular Biology, The Libin Cardiovascular Institute of Alberta, The University of Calgary, Health Sciences Center
Da-Wei Zhang
Department of Pediatrics and Group on the Molecular and Cell Biology of Lipids, University of Alberta
Hui Fu
Department of Intensive Care Unit, the First Affiliated Hospital of University of South China
Chao-Ke Tang
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

Keywords: Atherosclerosis, Inflammation, Pregnancy-associated plasma protein-A, Reverse cholesterol transport

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Supplementary material

2019 Volume 83 Issue 3 Pages 515-523

DOI https://doi.org/10.1253/circj.CJ-18-0700

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Abstract

Background: Recent studies have suggested that pregnancy-associated plasma protein-A (PAPP-A) is involved in the pathogenesis of atherosclerosis. This study aim is to investigate the role and mechanisms of PAPP-A in reverse cholesterol transport (RCT) and inflammation during the development of atherosclerosis.

Methods and Results: PAPP-A was silenced in apolipoprotein E (apoE^−/−) mice with administration of PAPP-A shRNA. Oil Red O staining of the whole aorta root revealed that PAPP-A knockdown reduced lipid accumulation in aortas. Oil Red O, hematoxylin and eosin (HE) and Masson staining of aortic sinus further showed that PAPP-A knockdown alleviated the formation of atherosclerotic lesions. It was found that PAPP-A knockdown reduced the insulin-like growth factor 1 (IGF-1) levels and repressed the PI3K/Akt pathway in both aorta and peritoneal macrophages. The expression levels of LXRα, ABCA1, ABCG1, and SR-B1 were increased in the aorta and peritoneal macrophages from apoE^−/−mice administered with PAPP-A shRNA. Furthermore, PAPP-A knockdown promoted RCT from macrophages to plasma, the liver, and feces in apoE^−/−mice. In addition, PAPP-A knockdown elevated the expression and secretion of monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), tumor necrosis factor-α, and interleukin-1β through the nuclear factor kappa-B (NF-κB) pathway.

Conclusions: The present study results suggest that PAPP-A promotes the development of atherosclerosis in apoE^−/−mice through reducing RCT capacity and activating an inflammatory response.

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