Cholesterol is a structural component of the cell, indispensable for normal cellular function, but its excess often leads to abnormal proliferation, migration, inflammatory responses and/or cell death. To prevent cholesterol overload, ATP-binding cassette (ABC) transporters mediate cholesterol efflux from the cells to apolipoprotein A-I (ApoA-I) and to the ApoA-I-containing high-density lipoprotein (HDL)1-3. Maintaining efficient cholesterol efflux is essential for normal cellular function4-6. However, the role of cholesterol efflux in angiogenesis and the identity of its local regulators are poorly understood. Here we show that ApoA-I binding protein (AIBP) accelerates cholesterol efflux from endothelial cells (EC) to HDL and thereby regulates angiogenesis. AIBP/HDL-mediated cholesterol depletion reduces lipid rafts, interferes with VEGFR2 dimerization and signaling, and inhibits VEGF-induced angiogenesis in vitro and mouse aortic neovascularization ex vivo. Remarkably, Aibp regulates the membrane lipid order in embryonic zebrafish vasculature and functions as a non-cell autonomous regulator of zebrafish angiogenesis. Aibp knockdown results in dysregulated sprouting/branching angiogenesis, while forced Aibp expression inhibits angiogenesis. Dysregulated angiogenesis is phenocopied in Abca1/Abcg1-deficient embryos, and cholesterol levels are increased in Aibp-deficient and Abca1/Abcg1-deficient embryos. Our findings demonstrate that secreted AIBP positively regulates cholesterol efflux from EC and that effective cholesterol efflux is critical for proper angiogenesis.
Oxidative stress is a well-known etiologic factor in the development of cardiovascular disease. Oxidation of lipoproteins, and in particular of low density lipoprotein, is a necessary if not obligatory mechanism for the generation of macrophage-derived foam cells, the first major initiating factor in the development of an atherosclerotic plaque. Oxidation of lipoproteins does not result in the generation of a single, defined molecular species, but of a variety of oxidation-specific epitopes, such as oxidized phospholipids and malondialdehyde-lysine epitopes. Unique monoclonal antibodies have been developed to bind these well-defined epitopes, and have been used in in vitro assays to detect them on circulating lipoproteins present in plasma. This article will summarize the accumulating clinical data of one oxidation-specific biomarker, oxidized phospholipids (OxPL) on apoB-100 lipoproteins. Elevated levels of OxPL/apoB predict the presence and progression of coronary, femoral and carotid artery disease, are increased following acute coronary syndromes and percutaneous coronary intervention, and predict the development of death, myocardial infarction, stroke and need for revascularization in unselected populations. OxPL/apoB levels are independent of traditional risk factors and the metabolic syndrome, and enhance the risk prediction of the Framingham Risk Score. The OxPLs measured in this assay reflect the biological activity of the most atherogenic lipoprotein(a) (Lp(a)) particles, reflected in patients with high plasma Lp(a) levels with small apo(a) isoforms. The predictive value of OxPL/apoB is amplified by Lp(a) and phospholipases such as lipoprotein-associated phospholipase A2 and secretory phospholipase A2, which are targets of therapy in clinical trials. This assay has now been validated in over 10,000 patients and efforts are underway to make it available to the research and clinical communities.
SummaryBackgroundThe lipoprotein(a) pathway is a causal factor in coronary heart disease. We used a genetic approach to distinguish the relevance of two distinct components of this pathway, apolipoprotein(a) isoform size and circulating lipoprotein(a) concentration, to coronary heart disease.MethodsIn this mendelian randomisation study, we measured lipoprotein(a) concentration and determined apolipoprotein(a) isoform size with a genetic method (kringle IV type 2 [KIV2] repeats in the LPA gene) and a serum-based electrophoretic assay in patients and controls (frequency matched for age and sex) from the Pakistan Risk of Myocardial Infarction Study (PROMIS). We calculated odds ratios (ORs) for myocardial infarction per 1-SD difference in either LPA KIV2 repeats or lipoprotein(a) concentration. In a genome-wide analysis of up to 17 503 participants in PROMIS, we identified genetic variants associated with either apolipoprotein(a) isoform size or lipoprotein(a) concentration. Using a mendelian randomisation study design and genetic data on 60 801 patients with coronary heart disease and 123 504 controls from the CARDIoGRAMplusC4D consortium, we calculated ORs for myocardial infarction with variants that produced similar differences in either apolipoprotein(a) isoform size in serum or lipoprotein(a) concentration. Finally, we compared phenotypic versus genotypic ORs to estimate whether apolipoprotein(a) isoform size, lipoprotein(a) concentration, or both were causally associated with coronary heart disease.FindingsThe PROMIS cohort included 9015 patients with acute myocardial infarction and 8629 matched controls. In participants for whom KIV2 repeat and lipoprotein(a) data were available, the OR for myocardial infarction was 0·93 (95% CI 0·90–0·97; p<0·0001) per 1-SD increment in LPA KIV2 repeats after adjustment for lipoprotein(a) concentration and conventional lipid concentrations. The OR for myocardial infarction was 1·10 (1·05–1·14; p<0·0001) per 1-SD increment in lipoprotein(a) concentration, after adjustment for LPA KIV2 repeats and conventional lipids. Genome-wide analysis identified rs2457564 as a variant associated with smaller apolipoprotein(a) isoform size, but not lipoprotein(a) concentration, and rs3777392 as a variant associated with lipoprotein(a) concentration, but not apolipoprotein(a) isoform size. In 60 801 patients with coronary heart disease and 123 504 controls, OR for myocardial infarction was 0·96 (0·94–0·98; p<0·0001) per 1-SD increment in apolipoprotein(a) protein isoform size in serum due to rs2457564, which was directionally concordant with the OR observed in PROMIS for a similar change. The OR for myocardial infarction was 1·27 (1·07–1·50; p=0·007) per 1-SD increment in lipoprotein(a) concentration due to rs3777392, which was directionally concordant with the OR observed for a similar change in PROMIS.InterpretationHuman genetic data suggest that both smaller apolipoprotein(a) isoform size and increased lipoprotein(a) concentration are independent and causal risk factors for coronary heart ...
This study documents the first specific therapy, to our knowledge, for lowering apo(a)/Lp(a) levels and their associated OxPL. A more potent effect was documented in mice expressing apo(a) with multiple KIV-2 repeats. Targeting liver expression of apo(a) with ASOs directed to KIV-2 repeats may provide an effective approach to lower elevated Lp(a) levels in humans.
Objectives The goal of this study was to examine the prospective association between oxidation-specific biomarkers, primarily oxidized phospholipids (OxPL) on apolipoprotein B-100-containing lipoproteins (OxPL/apoB) and lipoprotein (a) [Lp(a)], and risk of peripheral artery disease (PAD). As secondary analyses, we examined indirect measures of oxidized lipoproteins, including autoantibodies to malondialdehyde-modified low density lipoprotein (MDA-LDL) and apolipoprotein B-100 immune complexes (ApoB-IC). Background Biomarkers to predict the development of PAD are lacking. OxPL circulate in plasma, are transported by Lp(a), and deposit in the vascular wall and induce local inflammation. Methods The study population included two parallel nested case-control studies of 143 men within the Health Professionals Follow-up Study (1994-2008) and 144 women within the Nurses’ Health Study (1990-2010) with incident confirmed cases of clinically significant PAD, matched 1:3 to controls. Results Levels of OxPL/apoB were positively associated with risk of PAD in men and women: pooled relative risk (RR) 1.37, 95% CI, 1.19-1.58 for each 1-standard deviation increase after adjusting age, smoking, fasting status, month of blood draw, lipids, body mass index, and other cardiovascular disease risk factors. Lp(a) was similarly associated with risk of PAD (pooled adjusted RR, 1.36; 95% CI, 1.18-1.57 for each 1-standard deviation increase). Autoantibodies to MDA-LDL and ApoB-IC were not consistently associated with risk of PAD. Conclusions OxPL/apoB were positively associated with risk of PAD in men and women. The major lipoprotein carrier of OxPL, Lp(a), was also associated with risk of PAD, reinforcing the key role of OxPL in the pathophysiology of atherosclerosis mediated by Lp(a).
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