Disruption of low density lipoprotein receptor pathway under microinflammation accelerates the progression of vascular calcification in hemodialysis patients / 中华肾脏病杂志

ABSTRACT

Objective To investigate whether low density lipoprotein receptor (LDLr) pathway involves in the progression of vascular calcification (VC) in hemodialysis patients under microinflammation.Methods Twenty-eight hemodialysis patients were divided into control and inflammation group according to plasma C-reactive protein level.Surgically removed tissues from radial artery of patients receiving arteriovenostomy were used in experiments.Foam cell formation and calcification deposition were observed by hematoxylin-eosin (HE) and alizarin red S staining respectively.VC-related protein expression,such as bone morphogenetic proteins-2 (BMP-2),collagen Ⅰ,alkaline phosphatase (ALP),and LDLr and its related nuclear factor of transcriptional regulation,such as sterol regulatory element binding protein-2 (SREBP-2) and SREBP cleavage-activating protein (SCAP),were detected by immunohistochemistry and immunofluorescence staining.Results HE and alizarin red S staining showed that there were parallel increased foam cell formation and calcium deposit in continuous cross-sections of radial arteries in inflammation group compared to control group,which were closely correlated with increased protein expressions of LDLr,SREBP-2,BMP-2,and collagen Ⅰ as shown by immunohistochemical and immunofluorescent staining.Confocal microscopy confirmed that inflammation enhanced the translocation of SCAP/SREBP-2 complex from endoplasmic reticulum to Golgi,thereby activating LDLr gene transcription.Inflammation increased protein expression of ALP and reduced protein expression of alpha-smooth muscle actin,contributing to the phenotype conversion of vascular smooth muscle cells in calcified vessels from the fibroblastic to the osteogenic,which were the main cell components in VC.Further analysis showed that the disruption of LDLr pathway induced by inflammation was positively correlated with the enhanced expression of BMP-2 and collagen Ⅰ (r=0.782,P＜0.01; r=0.644,P＜0.05).Conclusion Inflammation accelerates the progression of VC in hemodialysis patients through the disruption of LDLr feedback regulation.