Yucatan miniature swine as a model for diet-induced atherosclerosis.

Nine female Yucatan miniature swine, a breed not previously evaluated for their potential usefulness as a model for experimental atherosclerosis studies, were fed a high-fat, high-cholesterol diet for 10-12 months. These swine and 4 control (low-fat, low-cholesterol-fed) swine underwent a complete necropsy at the end of this period to characterize the atherosclerosis both by gross and microscopic examination. Cholesterol feeding led to elevated serum cholesterol levels and the development of accelerated atherosclerosis.

Atherogenic hyperlipoproteinemia. The cellular and molecular biology of plasma lipoproteins altered by dietary fat and cholesterol.

Diets high in saturated fat and cholesterol cause alterations in the plasma lipoproteins, and these alterations cause certain of the lipoproteins to deliver cholesterol to the cells of the arterial wall. Other changes in lipoprotein are induced as an attempt to compensate for the delivery of cholesterol to cells. Atherosclerosis results when influx of cholesterol into the arterial wall exceeds egress of cholesterol from the tissues.

Two independent lipoprotein receptors on hepatic membranes of dog, swine, and man. Apo-B,E and apo-E receptors.

We have reported previously that canine livers possess two distinct lipoprotein receptors, an apoprotein (apo)-B,E receptor capable of binding the apo-B-containing low density lipoproteins (LDL) and the apo-E-containing cholesterol-induced high density lipoproteins (HDLc), and an apo-E receptor capable of binding apo-E HDLc but not LDL. Both the apo-B,E and apo-E receptors were found on the liver membranes obtained from immature growing dogs, but only the apo-E receptors were detected on th hepatic membranes of adult dogs. In this study, the expression of the apo-B,E receptors, as determined by canine LDL binding to the hepatic membranes, was found to be highly dependent on the age of the dog and decreased linearly with increasing age.

Familial dysbetalipoproteinemia. Abnormal binding of mutant apoprotein E to low density lipoprotein receptors of human fibroblasts and membranes from liver and adrenal of rats, rabbits, and cows.

Patients with familial dysbetalipoproteinemia (F. Dys.), also called familial type 3 hyperlipoproteinemia, are homozygous for a mutant allele, Ed, that specifies an abnormal form of apoprotein (apo) E, a prominent constituent of remnant lipoproteins derived from very low density lipoproteins (VLDL) and chylomicrons.

Functional unit of the low density lipoprotein receptor of fibroblasts: a 100,000-dalton structure with multiple binding sites.

The low density lipoprotein (apoprotein B,E) receptors of fibroblasts bind plasma lipoproteins that contain either the B (apo-B) or E (apo-E) apoproteins. These include the low density lipoproteins (LDL) containing apo-B and certain high density lipoproteins containing apo-E (e.g.

Lipoprotein binding to canine hepatic membranes. Metabolically distinct apo-E and apo-B,E receptors.

Hepatic membranes from adult dog livers have receptors which bind to lipoproteins containing the E apoprotein (the apo-E HDLc) but lack specific receptors for the apo-B-containing low density lipoproteins (LDL). Scatchard analysis of direct binding data for 125I-apo-E-HDLc revealed nonlinearity of the binding which could be resolved into two components, suggesting the presence of two separate binding sites. The binding site for apo-E HDLc that possessed the highest affinity (Kd = 0.

Chylomicron metabolism during dietary-induced hypercholesterolemia in dogs.

The metabolism of [1-3H]retinol- and [4-14C]cholesterol-labeled chylomicrons was studied in normal and cholesterol-fed dogs in order to estimate the relative contribution of chylomicron remnant cholesterol to diet-induced hypercholesterolemia. The plasma t 1/2 of intravenously administered Sf greater than 400 chylomicrons, Sf 20-400 chylomicrons, and whole lymph doubly labeled with [1-3H]retinol and [4-14C]cholesterol was not significantly prolonged in hypercholesterolemic recipients. When Sf greater than 400 chylomicrons were administered intravenously, 90% of the radioactivity was cleared from the plasma of both normal and cholesterol-fed dogs within 1 hr and 68 +/- 18% appeared in the liver within approximately 2 hr in normal dogs and 4 hr in hypercholesterolemic dogs.

Acetoacetylated lipoproteins used to distinguish fibroblasts from macrophages in vitro by fluorescence microscopy.

We have developed a procedure for labeling lipoproteins with the fluorescent probe 3,3'-dioctadecylindocarbocyanine (Dil) and have used Dil-labeled native and acetoacetylated lipoproteins to differentiate macrophages from fibroblasts in mixed cell culture. Lipoproteins labeled with this probe were suitable for the direct viewing of their binding and internalization by cells in vitro. The labeling technique has been applied to human low density lipoproteins (LDL) and to two canine cholesterol-induced lipoproteins: apo-E HDLc, which contain only the E apoprotein (apo-E), and beta-migrating, very low density lipoproteins (beta-VLDL), which contain apo-B and apo-E.

Effect of arterial stretch on transmural albumin and Evan's blue dye transport.

The influence of arterial wall circumferential stretch (lambda) on the 32-min diffusive mural uptake of 125I-albumin and of Evan's blue dye (EBD) across the injured endothelial surface was studied in the intimal-medial preparation of the canine descending thoracic aorta (DTA). Albumin uptake (MA nmol/cm2) was measured by standard gamma counting techniques and the corresponding EBD uptake (ME) by the reflectance method. MA and ME were measured at a physiological stretch (lambda = 1.

Aortic transmural serum protein transport: effect of concentration, time, and location.

The diffusive transport of certain 125I-labeled purified serum proteins, canine (C), human (H), and porcine (P) serum albumin (A), as well as human high-density lipoprotein (HDL), into the isolated deendothelialized intimal-medial thoracic aortic preparation was measured as a function of protein concentration (c0), intimal surface exposure time (T), and location (z) along the vessel at 21 degrees C. Selected proteins were studied in each of 11 canine preparations and 1 porcine preparation. The resulting uptake (M, nmol/cm2) was measured by direct gamma counting of specially excised fixed tissue specimens, and the transmural concentration distributions [c(xi), nmol/cm3] were calculated from electron probe X-ray microanalysis of the silver distributions across specially prepared microautoradiographs.

Cellular and molecular biology of lipoprotein metabolism in atherosclerosis.

Despite a significant decrease in mortality from cardiovascular disease in the US over the past decade, coronary artery disease, more specifically myocardial infarction, remains the leading cause of death in our country, and in most Westernized countries of the world. The disease process of atherosclerosis causes coronary heart disease; yet, despite considerable progress, much remains to be learned about the basic mechanisms responsible for this disease process. It is the purpose of this paper to review the recent advances that are contributing to our understanding of the important role of plasma lipoproteins in atherosclerosis and the role of dietary fat and cholesterol in altering plasma lipoprotein metabolism.

Immunoregulatory plasma lipoproteins. Role of apoprotein E and apoprotein B.

Plasma lipoproteins containing either the B (apo-B) or E (apo-E) apoproteins, e.g. apo-B low density lipoproteins (LDL) isolated from normolipemic humans and apo-E-containing cholesterol-induced high density lipoproteins (apo-E HDLc) isolated from cholesterol-fed dogs, suppress phytohemagglutinin (PHA)-induced lymphocyte activation and inhibit early events such as mitogen-enhanced 45Ca2+ accumulation and late events such as enhanced DNA synthesis.

Disparities in the interaction of rat and human lipoproteins with cultured rat fibroblasts and smooth muscle cells. Requirements for homology for receptor binding activity.

This study characterizes the interactions of various rat and human lipoproteins with the lipoprotein cell surface receptors of rat and human cells. Iodinated rat very low density lipoproteins (VLDL), rat chylomicron remnants, rat low density lipoproteins (LDL), and rat high density lipoproteins containing predominantly apoprotein E (HDL1) bound to high affinity cell surface receptors of cultured rat fibroblasts and smooth muscle cells. Rat VLDL and chylomicron remnants were most avidly bound; the B-containing LDL and the E-containing HDL1 displayed lesser but similar binding.

Cholesteryl ester synthesis in macrophages: stimulation by beta-very low density lipoproteins from cholesterol-fed animals of several species.

Animals fed cholesterol accumulate several types of cholesterol-rich lipoproteins in their plasma and ultimately develop cholesteryl ester deposition in tissue macrophages. Previous studies in the cholesterol-fed dog have shown that one class of cholesterol-rich lipoproteins. beta-migrating very low density lipoproteins (beta-VLDL, density < 1.

A-IMilano apoprotein. Decreased high density lipoprotein cholesterol levels with significant lipoprotein modifications and without clinical atherosclerosis in an Italian family.

Significant hypertriglyceridemia with a very marked decrease of high density lipoproteins (HDL)-cholesterol levels (7-14 mg/dl) was detected in three members (father, son, and daughter) of an Italian family. The three affected individuals did not show any clinical signs of atherosclerosis, nor was the atherosclerotic disease significantly present in the family. Lipoprotein lipase and lecithin:cholesterol acyltransferase activites were normal or slightly reduced.

A-Imilano apoprotein. Isolation and characterization of a cysteine-containing variant of the A-I apoprotein from human high density lipoproteins.

A recently discovered familial lipoprotein disorder is characterized by reduced plasma levels of high density lipoproteins (HDL) and elevated triglyceride levels. The clinical aspects of this disorder are presented in an accompanying article (Franceschini et al. 1980.

Effect of cholesterol supplementation of diets of thyroidectomized dogs on the fatty acid composition of erythrocyte phospholipids and plasma phosphatidylcholine.

Thyroidectomized foxhounds were fed: (a) a control diet, (b) the control diet supplemented with 15% beef tallow or cottonseed oil, with or without added cholesterol, or (c) the control diet supplemented with beef tallow (15%), safflower oil (1.5%) and cholesterol. After 23 weeks on the diet, the content of the individual phospholipids of the erythrocytes was not altered appreciably.

Quantitative microautoradiography of arteries: comparison of radioactivity to silver.

The local concentration of silver in developed aortic transmural microautoradiographs was compared to the corresponding 125I-labeled albumin radioactivity concentration [ci(x)] in the subjacent tissue. Silver [s(x)] was measured by electron probe X-ray microanalysis (EPA) and the corresponding ci(x) by direct gamma-ray counting. The results show 1) that the relationship between volume-averaged values of radioactivity (ci) and EPA signal (s) is adequately described by ci = Ks, where K is a proportionality constant, and 2) that ci(x) measured by EPA [i.