PMID- 30662023 OWN - NLM STAT- MEDLINE DCOM- 20200330 LR - 20220409 IS - 1347-4820 (Electronic) IS - 1346-9843 (Linking) VI - 83 IP - 3 DP - 2019 Feb 25 TI - Pregnancy-Associated Plasma Protein-A Accelerates Atherosclerosis by Regulating Reverse Cholesterol Transport and Inflammation. PG - 515-523 LID - 10.1253/circj.CJ-18-0700 [doi] AB - 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 LXRalpha, 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-alpha, and interleukin-1beta through the nuclear factor kappa-B (NF-kappaB) 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. FAU - Tang, Shi-Lin AU - Tang SL AD - Department of Intensive Care Unit, the First Affiliated Hospital of University of South China. FAU - Zhao, Zhen-Wang AU - Zhao ZW AD - 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. FAU - Liu, Shang-Ming AU - Liu SM AD - Department of Intensive Care Unit, the First Affiliated Hospital of University of South China. FAU - Wang, Gang AU - Wang G AD - 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. FAU - Yu, Xiao-Hua AU - Yu XH AD - 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. FAU - Zou, Jin AU - Zou J AD - 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. FAU - Wang, Si-Qi AU - Wang SQ AD - 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. FAU - Dai, Xiao-Yan AU - Dai XY AD - Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University. FAU - Fu, Min-Gui AU - Fu MG AD - Department of Biomedical Science and Shock/Trauma Research Center, School of Medicine, University of Missouri-Kansas City. FAU - Zheng, Xi-Long AU - Zheng XL AD - Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences and the Fifth Affiliated Hospital, Guangzhou Medical University. AD - Department of Biochemistry and Molecular Biology, The Libin Cardiovascular Institute of Alberta, The University of Calgary, Health Sciences Center. FAU - Zhang, Da-Wei AU - Zhang DW AD - Department of Pediatrics and Group on the Molecular and Cell Biology of Lipids, University of Alberta. FAU - Fu, Hui AU - Fu H AD - Department of Intensive Care Unit, the First Affiliated Hospital of University of South China. FAU - Tang, Chao-Ke AU - Tang CK AD - 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. LA - eng PT - Journal Article DEP - 20190118 PL - Japan TA - Circ J JT - Circulation journal : official journal of the Japanese Circulation Society JID - 101137683 RN - 0 (NF-kappa B) RN - 97C5T2UQ7J (Cholesterol) RN - EC 3.4.24.- (Pregnancy-Associated Plasma Protein-A) SB - IM MH - Animals MH - Aorta/metabolism/pathology MH - Atherosclerosis/*etiology/pathology MH - Biological Transport MH - Cholesterol/*metabolism MH - Female MH - Humans MH - Inflammation/*etiology MH - Lipid Metabolism/drug effects MH - Macrophages/metabolism MH - Mice MH - Mice, Knockout, ApoE MH - NF-kappa B/metabolism MH - Pregnancy MH - Pregnancy-Associated Plasma Protein-A/pharmacology/*physiology OTO - NOTNLM OT - Atherosclerosis OT - Inflammation OT - Pregnancy-associated plasma protein-A OT - Reverse cholesterol transport EDAT- 2019/01/22 06:00 MHDA- 2020/03/31 06:00 CRDT- 2019/01/22 06:00 PHST- 2019/01/22 06:00 [pubmed] PHST- 2020/03/31 06:00 [medline] PHST- 2019/01/22 06:00 [entrez] AID - 10.1253/circj.CJ-18-0700 [doi] PST - ppublish SO - Circ J. 2019 Feb 25;83(3):515-523. doi: 10.1253/circj.CJ-18-0700. Epub 2019 Jan 18.