C‐reactive protein promotes atherosclerosis by increasing LDL transcytosis across endothelial cells

Abstract

BACKGROUND AND PURPOSEThe retention of plasma low-density lipoprotein (LDL) particles in subendothelial space following transcytosis across the endothelium is the initial step of atherosclerosis. Whether or not C-reactive protein (CRP) can directly affect the transcytosis of LDL is not clear. Here we have examined the effect of CRP on transcytosis of LDL across endothelial cells and have explored the underlying mechanisms. EXPERIMENTAL APPROACHEffects of CRP on transcytosis of FITC-labelled LDL were examined with human umbilical vein endothelial cells and venous rings in vitro and, in vivo, ApoE -/-mice. Laser scanning confocal microscopy, immunohistochemistry and Oil Red O staining were used to assay LDL. KEY RESULTSCRP increased transcytosis of LDL. An NADPH oxidase inhibitor, diphenylene iodonium, and the reducing agent, dithiothreitol partly or completely blocked CRP-stimulated increase of LDL transcytosis. The PKC inhibitor, bisindolylmaleimide I and the Src kinase inhibitor, PP2, blocked the trafficking of the molecules responsible for transcytosis. Confocal imaging analysis revealed that CRP stimulated LDL uptake by endothelial cells and vessel walls. In ApoE -/-mice, CRP significantly promoted early changes of atherosclerosis, which were blocked by inhibitors of transcytosis. CONCLUSIONS AND IMPLICATIONSCRP promoted atherosclerosis by directly increasing the transcytosis of LDL across endothelial cells and increasing LDL retention in vascular walls. These actions of CRP were associated with generation of reactive oxygen species, activation of PKC and Src, and translocation of caveolar or soluble forms of the N-ethylmaleimide-sensitive factor attachment protein.

Baseline High-Sensitivity C-Reactive Protein Predicts Macrovascular and Microvascular Complications of Type 2 Diabetes: A Population-Based Study

“…Hs-CRP directly increases the transcytosis of LDL across endothelial cells and promotes atherosclerosis due to increasing the LDL retention in vascular walls [30]. This is one of the explanations of the contribution of hs-CRP to thrombotic vascular events such as CHD events.…”

C reactive protein and enzymatically modified LDL cooperatively promote dendritic cell-mediated T cell activation

“…C-reactive protein has also been shown to be involved in many aspects of atherosclerosis [27,[38][39][40], with or without the involvement of modified LDL. CRP inhibited cholesterol efflux from foam cells by inhibiting the expression of ABCA1 and ABCG1 while increasing oxidative stress by promoting activation of ERK1/2 and expression of reduced nicotinamide adenine dinucleotide phosphate oxidase subunits [41].…”

“…A complex containing CRP, oxLDL, and β2-glycoprotein I promoted atherosclerosis in diabetic mice by increasing lipid uptake [40]. In ApoE −/− mice, CRP promoted the transcytosis of LDL cross-endothelial cells and vascular wall in a protein kinase C/Src kinase-dependent manner, which resulted in early atherosclerotic changes [38]. CRP bound to eLDL and strongly activated complement pathway [42].…”

A New Pathogenesis of Albuminuria: Role of Transcytosis

“…Bian et al [25] found that CRP could directly enhance LDL transcytosis across endothelial cells and promote accumulation of LDL in the subendothelial space of the human umbilical vein wall, via stimulating ROS production and activating protein kinase C (PKC) and Src kinase [73]. PKC phosphorylates Cav-1 at Ser [37], and Src phosphorylates Cav-1 at Tyr [14,74].…”

“…PKC phosphorylates Cav-1 at Ser [37], and Src phosphorylates Cav-1 at Tyr [14,74]. CRP remarkably increases the expression of Cav-1 and cavin-1 (also known as polymerase I and transcript release factors/PTRF) in membrane raft domains when the caveolae/Cav-1/cavin-1 system participates in the transcellular transport of LDL [25]. These findings suggest that CRP plays an important role in PKC or Src kinase-stimulated transcytosis of LDL and the resultant development of early atherogenesis.…”