Statins induce plaque regression characterized by reduced macrophage content in humans, but the underlying mechanisms remain speculative. Studying the translational APOE*3-Leiden.CETP mouse model with a humanized lipoprotein metabolism, we find that systemic cholesterol lowering by oral atorvastatin or dietary restriction inhibits monocyte infiltration, and reverses macrophage accumulation in atherosclerotic plaques. Contrary to current believes, none of (1) reduced monocyte influx (studied by cell fate mapping in thorax-shielded irradiation bone marrow chimeras), (2) enhanced macrophage egress (studied by fluorescent bead labeling and transfer), or (3) atorvastatin accumulation in murine or human plaque (assessed by mass spectrometry) could adequately account for the observed loss in macrophage content in plaques that undergo phenotypic regression. Instead, suppression of local proliferation of macrophages dominates phenotypic plaque regression in response to cholesterol lowering: the lower the levels of serum LDL-cholesterol and lipid contents in murine aortic and human carotid artery plaques, the lower the rates of in situ macrophage proliferation. Our study identifies macrophage proliferation as the predominant turnover determinant and an attractive target for inducing plaque regression.
Purpose To compare long-term efficacy and biocompatibility of the 5 most commonly applied LDL-apheresis techniques using a specifically modified calculation method of the area under the curve (AUC) for laboratory parameters. Design Retrospective long-term analysis of 20 patients with homozygous or severe heterozygous familial hypercholesterolemia. Procedures The following 5 extra-corporeal LDL-apheresis methods were compared: IMAL (Immuno Adsorption of Lipoproteins), DSA (Dextran Sulphate Adsorption), HELP (Heparin Induced Extra-corporeal LDL Precipitation), DALI (Direct Adsorption of Lipoproteins), MDF (Membrane Differential Filtration). Main outcome measures AUC derived plasma concentrations (CAUC) of lipoproteins between two apheresis procedures and their long-term course. Comparison of biocompatibility and efficacy concerning the LDL-C target of < 2.6 mmol/L of 5 apheresis techniques. Progression of atherosclerosis in patients with severe hypercholesterolemia. Main findings The means of AUC derived average plasma concentrations (CAUC) of all treatment intervals were for LDL-C and the LDL/HDL ratio as follows: IMAL (5.59 mmol/L; ratio 4.1), DSA (3.03 mmol/L; ratio 2.0), HELP (4.06 mmol/L; ratio 2.2), DALI (3.83 mmol/L; ratio 3.3), MDF (3.26 mmol/L; ratio 3.2). Coronary heart disease and cardiac events (myocardial infarction, PTCA/ stent implantation, CABG) progressed in only 2 patients whereas atherosclerosis manifestations (sclerosis abdominal aorta, carotid artery stenosis, peripheral vascular disease) worsened in 13 patients. Mean ergometric capacity improved from 112 to 118 Watt. Conclusions All 5 apheresis methods (IMAL, DSA, HELP, DALI, MDF) proved to be safe and suitable for long-term treatment in patients with severe hypercholesterolemia. The introduction of the CAUC revealed that the target of LDL-C < 2.6 mmol/L was not achieved with regard to the time averaged concentration (CAUC).
Objective Interferon regulatory factor (IRF) 5 is a transcription factor known for promoting M1 type macrophage polarization in vitro . Given the central role of inflammatory macrophages in promoting atherosclerotic plaque progression, we hypothesize that myeloid cell-specific deletion of IRF5 is protective against atherosclerosis. Methods Female Apoe –/– Lysm Cre/+ Irf5 fl/fl and Apoe −/− Irf5 fl/fl mice were fed a high-cholesterol diet for three months. Atherosclerotic plaque size and compositions as well as inflammatory gene expression were analyzed. Mechanistically, IRF5-dependent bone marrow-derived macrophage cytokine profiles were tested under M1 and M2 polarizing conditions. Mixed bone marrow chimeras were generated to determine intrinsic IRF5-dependent effects on macrophage accumulation in atherosclerotic plaques. Results Myeloid cell-specific Irf5 deficiency blunted LPS/IFNγ-induced inflammatory gene expression in vitro and in the atherosclerotic aorta in vivo . While atherosclerotic lesion size was not reduced in myeloid cell-specific Irf5 -deficient Apoe –/– mice, plaque composition was favorably altered, resembling a stable plaque phenotype with reduced macrophage and lipid contents, reduced inflammatory gene expression and increased collagen deposition alongside elevated Mertk and Tgfβ expression. Irf5- deficient macrophages, when directly competing with wild type macrophages in the same mouse, were less prone to accumulate in atherosclerotic lesion, independent of monocyte recruitment. Irf5 -deficient monocytes, when exposed to oxidized low density lipoprotein, were less likely to differentiate into macrophage foam cells, and Irf5 -deficient macrophages proliferated less in the plaque. Conclusion Our study provides genetic evidence that selectively altering macrophage polarization induces a stable plaque phenotype in mice.
The conventional techniques for the preparation of reconstituted high-density lipoprotein (rHDL) are hampered by long process times, the need for large amounts of starting material, and harsh preparation conditions. Here, we present a novel rHDL preparation method to overcome these challenges. Furthermore, we propose a dual mode of action for rHDL loaded with the immunosuppressant drug everolimus (Eve-rHDL) in the context of atherosclerosis and cardiovascular disease. Methods: We use dual centrifugation for rHDL nanoparticle preparation and characterize the physicochemical properties by NS-TEM, N-PAGE, DLS, AF4, and HPLC. In addition, we determine the biological efficacy in human and murine cell culture with regard to cellular uptake, cholesterol efflux, and proliferation. Results: We confirm the characteristic particle size of 10 nm, discoidal morphology, and chemical composition of the rHDL preparations and identify dual centrifugation as an ideal method for cost-effective aseptic rHDL manufacturing. rHDL can be prepared in approx. 1.5 h with batch sizes as little as 89 µL. Moreover, we demonstrate the cholesterol efflux capacity and anti-proliferative activity of Eve-rHDL in vitro. The anti-proliferative effects were comparable to free Eve, thus confirming the suitability of rHDL as a capable drug delivery vehicle. Conclusion: Eve-rHDL shows great efficacy in vitro and may further be employed to target atherosclerotic plaques in vivo. Highly effective anti-atherosclerotic therapy might be feasible by reducing both inflammatory-and lipid burden of the plaques. Dual centrifugation is an ideal technique for the efficient application of the rHDL platform in cardiovascular disease and beyond.
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