Phospholipid Transfer Protein Destabilizes Mouse Atherosclerotic Plaque

Abstract

16Apoptotic macrophages, especially in advanced plaques, promote several processes that contribute to plaque instability. 17 PLTP could augment apoptosis in THP-1 (human acute monocytic leukemia cell line) cell-derived macrophages 18 and PLTP stimulates Janus family kinase 2 phosphorylation, 19 involved in apoptosis in several cells, including macrophages. 20 Therefore, PLTP-related plaque instability may be mediated by macrophage apoptosis.In this study, we evaluated the association of PLTP and atherosclerotic plaque stability under PLTP-deficient and PLTPoverexpression conditions. PLTP deficiency could stabilize plague, and PLTP overexpression had the opposite effect. Furthermore, we explored the underlying mechanisms. Materials and MethodsMaterials and Methods are available in the online-only Data Supplement. Results Adenovirus Can Mediate PLTP Expression in Carotid ArteriesTo evaluate whether intravenous adenovirus transduction could mediate gene expression in carotid arteries, we injected Ad-GFP or Ad-PLTP into apolipoprotein E (ApoE) Objective-Phospholipid transfer protein (PLTP) accelerates the development of atherosclerosis in mouse models. We examined the role of PLTP in atherosclerotic plaque stability. Approach and Results-We prepared apolipoprotein E and PLTP double-knockout (PLTP −/− ApoE −/− ) mice. PLTP deficiency significantly decreased lesion size and reduced monocyte/macrophage infiltration, as well as macrophage apoptosis in lesion areas. Moreover, it increased fibrous content in plaques, which suggests that PLTP may affect atherosclerotic plaque stability. Importantly, PLTP overexpression mediated by adenovirus had the reverse effect. It promoted the accumulation of reactive oxygen species in macrophages, which could lead to cell apoptosis and increased the production of inflammatory cytokines and chemokines. PLTP overexpression could promote receptor-interacting protein 3 recruitment of macrophages in cytoplasm, which could induce reactive oxygen species, thus inducing atherogenesis. Conclusions-PLTP plays an important role in modulating the stability of atherosclerotic plaques. The receptor-interacting protein 3-reactive oxygen species signal pathway could be involved in this PLTP-mediated process. − PLTP Increases AtherosclerosisTo evaluate the effect of PLTP on atherogenesis, we dissected mouse carotid arteries and found plaque area lower in PLTP+Ad-GFP than in ApoE −/− + Ad-GFP arteries. After Ad-PLTP transduction, plaque area was increased in both mouse groups ( Figure 1A and 1D Figure 1C and 1E). Therefore, PLTP accelerated the development of atherosclerotic plaque. PLTP Decreases Atherosclerotic Plaque StabilityWe next sought to determine whether PLTP plays a role in atherosclerotic plaque stability. Figure 2A and 2B).Ad-PLTP transduction significantly decreased collagen and SMC content and increased macrophage content in carotid arteries (P<0.05; Figure 2A and 2B).Plaque vulnerable index was lower for PLTP −/− ApoE −/− than for ApoE −/− mice (P<0.05) but was increased in both groups...

Phospholipid transfer protein: its impact on lipoprotein homeostasis and atherosclerosis

“…In mouse models, it has been demonstrated that global PLTP deficiency reduces atherosclerotic lesion size (63) and the plaque stability (105), while its overexpression shows the opposite effect (106). Global PLTP deficiency in mice is also associated with abdominal aortic aneurysm (80).…”

The role of the lymphatic system in cholesterol transport

“…The result supports the observation of the importance of passive HDL transport ( Kareinen et al, 2015 ). Adenoviral overexpression of PLTP in hepatocytes generates larger particle size (<7.1 nm but larger than lipid-free ApoA1; Ji et al, 2014 ) and also increases atherosclerotic lesion size in PLTP overexpressing ApoE deficient mice ( Zhang et al, 2014 ), although the causal relationship between PLTP and CVD is still under debate ( Vergeer et al, 2010 ; Kim et al, 2015 ). In line with the mechanism proposed by Zhang et al (2014) , the increased HDL particle size resulting from PLTP overexpression impaired RCT ( Samyn et al, 2009 ), perhaps impairing movement of HDL into the interstitium, limiting cholesterol uptake from extravascular spaces like plaque, and ultimately increasing atherosclerotic disease progression.…”

The Role of RIPK1 and RIPK3 in Cardiovascular Disease

“…Finally, mice deficient in phospholipid transfer protein (PLTP), a protein known to correlate with atherosclerosis severity, showed reduced levels of RIPK3 in atherosclerotic plaques in addition to reduced atherosclerotic lesion burden and intra-lesion cell death. Overexpression with a PLTP-containing adenovirus vector conversely increased RIPK3 protein levels detected in murine atherosclerotic plaques, lesion area and intra-lesion cell death [23]. These findings collectively suggest that necroptosis occurs in human atherosclerotic disease and that RIPK1 and RIPK3 contribute to the atherosclerosis pathophysiology.…”