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

• DOI: 10.1253/circj.cj-18-0700
• Publication Date: 2019-01-17T22:31:10Z
• Authors: 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
• Keywords: Inflammation; 0301 basic medicine; Mice, Knockout, ApoE; Macrophages; NF-kappa B; Biological Transport; Atherosclerosis; Lipid Metabolism; Mice; 03 medical and health sciences; Cholesterol; Pregnancy; Animals; Humans; Pregnancy-Associated Plasma Protein-A; Female; Aorta

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.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.