Recently, ATP-binding cassette transporter A1 (ABCA1), the defective molecule in Tangier disease, has been shown to stimulate phospholipid and cholesterol efflux to apolipoprotein A-I (apoA-I); however, little is known concerning the cellular cholesterol pools that act as the source of cholesterol for ABCA1-mediated efflux. We observed a higher level of isotopic and mass cholesterol efflux from mouse peritoneal macrophages labeled with [ 3 H]cholesterol/acetyl low density lipoprotein (where cholesterol accumulates in late endosomes and lysosomes) compared with cells labeled with [3 H]cholesterol with 10% fetal bovine serum, suggesting that late endosomes/lysosomes act as a preferential source of cholesterol for ABCA1-mediated efflux. Consistent with this idea, macrophages from Niemann-Pick C1 mice that have an inability to exit cholesterol from late endosomes/lysosomes showed a profound defect in cholesterol efflux to apoA-I. In contrast, phospholipid efflux to apoA-I was normal in Niemann-Pick C1 macrophages, as was cholesterol efflux following plasma membrane cholesterol labeling. These results suggest that cholesterol deposited in late endosomes/lysosomes preferentially acts as a source of cholesterol for ABCA1-mediated cholesterol efflux.

Objective-The key initial step in atherogenesis is the subendothelial retention of apolipoprotein B-containing lipoproteins. Acid sphingomyelinase (acid SMase), an enzyme present extracellularly within the arterial wall, strongly enhances lipoprotein retention in model systems in vitro, and retained lipoproteins in human plaques are enriched in ceramide, a product of SMase. We now sought to test a direct causative role for acid SMase in lipoprotein retention and atherogenesis in vivo. T he key initial step in early atherogenesis is the retention, or trapping, of apoB-lipoproteins within the subendothelium of focal susceptible regions of the arterial tree. [1][2][3] Retained and modified lipoproteins provoke a series of biological responses that can explain all subsequent features of early atherogenesis. 1,2 Lipoprotein retention within prelesional segments initially involves direct binding of positively charged domains on apoB to negatively charged elements of arterial matrix, chiefly proteoglycans. 4,5 In later stages, lipoprotein retention can be enhanced further by size-related trapping of large lipoproteins in the subendothelium and by uptake by subendothelial macrophages (below). Moreover, lesional cells secrete additional molecules, such as sphingomyelinase and lipoprotein lipase, that are proposed to shift the molecular basis for further lipoprotein retention while also substantially accelerating retention and hence lesion progression. Thus, understanding the molecular mechanisms of subendothelial lipoprotein retention in prelesional and then lesional arteries is a critical goal of atherogenesis research.Previous work has suggested a number of factors that can influence subendothelial lipoprotein retention, including (1) the concentration of circulating atherogenic lipoproteins; (2) endothelial permeability; (3) the nature and amounts of proretentive molecules within the subendothelial space, notably proteoglycans and lipoprotein lipase (LpL), which bridges lipoproteins to matrix; and (4) structure and composition of the lipoproteins, which can be altered by enzymatic and nonenzymatic processes within the subendothelial space. [1][2][3] A large number of studies in vitro implicate the secretory form of acid sphingomyelinase (S-SMase) in proretentive modifications of atherogenic lipoproteins. S-SMase arises from the acid SMase (Asm) gene, which also gives rise to lysosomal acid SMase. 6 S-SMase is secreted by cell types Correlative support for a role of S-SMase in atherogenesis per se has been provided by several human and animal atherosclerosis studies. For example, extracellular acid SMase is present in human and murine atherosclerotic lesions, 16 and aggregated lipoproteins extracted from human atheromata are specifically enriched in ceramide, indicating hydrolysis by sphingomyelinase. 12 Moreover, recent work has demonstrated an association between high SM content in circulating lipoproteins, which enhances S-SMase-mediated hydrolysis, and increased risk for aortic atherosclerosis in mice and coronary...

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Patients presenting with platypnea-orthodeoxia syndrome can be treated successfully with a percutaneous intervention often requiring a variety of devices. Those requiring a non-PFO-type device had a greater prevalence of an aneurysmal septum, shorter primum septal overlap with the secundum septum, and greater septal angulation with the midline.

Percutaneous removal of large tricuspid valve vegetations is a safe and effective alternative for patients with TVE who carry high-surgical risk. © 2017 Wiley Periodicals, Inc.

Abstract-The apoE knockout (E0) mouse is one of the most widely used animal models of atherosclerosis, and there may be similarities to chylomicron remnant-induced atherosclerosis in humans. Although the lesions of these mice contain large numbers of cholesteryl ester (CE)-laden macrophages (foam cells), E0 plasma lipoproteins are relatively weak inducers of cholesterol esterification in macrophages. Previous in vivo work has suggested that arterial wall sphingomyelinase (SMase) may promote atherogenesis in the E0 mouse, perhaps by inducing subendothelial lipoprotein aggregation and subsequent foam cell formation. The goal of the present study was to test the hypothesis that the modification of E0 lipoproteins by SMase converts these lipoproteins into potent inducers of macrophage foam cell formation. When dϽ1.063 E0 lipoproteins were pretreated with SMase and then incubated with E0 macrophages, cellular CE mass and stimulation of the cholesterol esterification pathway were increased Ϸ5-fold compared with untreated lipoproteins. SMase-treated E0 lipoproteins were more potent stimulators of cholesterol esterification than either E0 lipoproteins in the presence of lipoprotein lipases or oxidized E0 lipoproteins. The uptake and degradation of SMase-treated E0 lipoproteins by macrophages were saturable and specific and substantially inhibited by partial proteolysis of cell-surface proteins. Uptake and degradation were diminished by an anti-apoB antibody and by competition with human S f 100-400 hypertriglyceridemic VLDL, raising the possibility that a receptor that recognizes apoB-48 might be involved. In conclusion, SMase-modification of E0 lipoproteins, a process previously shown to occur in lesions, may be an important mechanism for foam cell formation in this widely studied model of atherosclerosis. Moreover, the findings in this report may provide important clues regarding the atherogenicity of chylomicron remnants in humans.

Atheroma macrophages internalize large quantities of lipoprotein-derived lipids. While most emphasis has been placed on cholesterol, lipoprotein-derived fatty acids may also play important roles in lesional macrophage biology. Little is known, however, about the trafficking or metabolism of these fatty acids. In this study, we first show that the cholesterol-fatty acyl esterification reaction, catalyzed by acyl-CoA:cholesterol acyltransferase (ACAT), competes for the incorporation of lipoprotein-derived fatty acids into cellular phospholipids. Furthermore, conditions that inhibit trafficking of cholesterol from late endosomes/lysosomes to the endoplasmic reticulum (ER), such as the amphipathic amine U18666A and the Npc1؉/؊ mutation, also inhibit incorporation of lipoprotein-derived fatty acids into phospholipids. The biological relevance of these findings was investigated by studying the suppression of agonist-induced prostaglandin E 2 (PGE 2 ) and leukotriene C 4 /D 4 /E 4 production during lipoprotein uptake by macrophages, which has been postulated to involve enrichment of cellular phospholipids with non-arachidonic fatty acids (NAAFAs). We found that eicosanoid suppression was markedly enhanced when ACAT was inhibited and prevented when late endosomal/lysosomal lipid trafficking was blocked. Moreover, PGE 2 suppression depended entirely on acetyl-LDL-derived NAAFAs, not on acetyl-LDL-cholesterol, and was not due to decreased cPLA 2 activity per se. These data support the following model: lipoprotein-derived NAAFAs traffic via the NPC1 pathway from late endosomes/lysosomes to a critical pool of phospholipids. In competing reactions, these NAAFAs can be either esterified to cholesterol or incorporated into phospholipids, resulting in suppression of eicosanoid biosynthesis. In view of recent evidence suggesting dysfunctional cholesterol esterification in late lesional macrophages, these data predict that such cells would have highly suppressed eicosanoid synthesis, thus affecting eicosanoid-mediated cell signaling in advanced atherosclerosis.

Biventricular DCC can augment end-systolic pressure with no added costs of M&f1;O2. Under ejecting conditions, this augmentation of ventricular contracting ability manifests as increases in stroke volume. Thus, DCC represents a feasible alternative form of ventricular assist, and devices that support the heart in this manner should be further explored.