Lipoproteins In Atherosclerosis Research Articles

Role of oxidized human plasma low density lipoproteins in atherosclerosis: effects on smooth muscle cell proliferation.

The effects of oxidized human plasma low density lipoproteins (Ox-LDL) on the proliferation of cultured aortic smooth muscle cells was studied, employing viable cell counting, [3H] thymidine incorporation into DNA, and the release of lactate dehydrogenase (LDH) into the medium. Oxidized LDL (prepared by incubation of LDL with copper sulfate) exerted a concentration-dependent stimulation (2 fold, compared to control) of aortic smooth muscle cell proliferation at low concentrations (0.1 micrograms-10 micrograms/ml medium). On the other hand, at high concentrations (25-200 micrograms/ml), Ox-LDL produced a pronounced decrease in viable cells, a decrease in the incorporation of [3H] thymidine into DNA, and an increase in the release of LDH in the medium. In this report, the previously postulated biological roles of oxidized-LDL in atherosclerosis are discussed in view of these findings.

Oxygen radicals and atherosclerosis

There is increasing evidence that lipids, especially those in low density lipoprotein, may be oxidised during the development of atherosclerotic lesions. The lipid-laden "foam cells" of atherosclerosis are macrophages, which are known to produce oxygen radicals in their microbicidal role. The same process could result in oxidation of lipid or lipoprotein in atherosclerosis. In human atherosclerotic lesions, many of the macrophage foam cells also contain ceroid, an insoluble polymer formed by oxidation of mixtures of lipid and protein. Using in vitro systems, we have studied the possibility that macrophages may be responsible for the oxidation of lipid and/or lipoprotein. Experiments are described in which mouse peritoneal macrophages and human monocyte-derived macrophages have been shown to oxidise cholesteryl linoleate, added to the cultures in the form of an artificial lipoprotein, with the production of soluble oxidised lipids, including oxidised sterols, and, in the case of mouse peritoneal macrophages, abundant ceroid. The oxidation was inhibited by radical scavengers. Oxidised sterols are cytotoxic. It is thus conceivable that oxidised sterols produced by monocyte-macrophages may lead to necrosis and progression of the lesion. Possibilities for prevention of this oxidation are discussed.

Role of biologically modified low-density lipoprotein in atherosclerosis

It has been proposed that low-density lipoprotein (LDL) may become very atherogenic if it undergoes a cell-mediated oxidative modification within the arterial wal. Recently, several lines of evidence have been reported that indicate that such oxidative reactions occur in vivo and that oxidized LDL accumulates in lesions. In addition, it has been shown that treatment of spontaneously atherosclerotic Watanabe heritable hyperlipidemic rabbits with probucol, a very potent antioxidant, inhibits formation or progression of early lesions, suggesting a pathogenic role for oxidized LDL in atherogenesis.

Drug therapy and the prevention of atherosclerosis in humans

The results of the World Health Organization Cooperative Trial, the Coronary Drug Project, the Coronary Primary Prevention Trial and the Helsinki Heart Study indicate that clinical expression of coronary artery disease can be delayed with pharmacologic modification of plasma lipoproteins. Change in coronary artery disease can be semiquantitated by repeat arteriograms. Three randomized clinical trials indicate that rate of progression of atherosclerosis, as defined by arteriography, can be reduced, and existing lumen obstruction decreased. Tendon xanthomas occur in hypercholesterolemia, and reduction in xanthoma size with drug therapy suggests an improved atherosclerotic disease state. The clinician has a variety of pharmacologic therapies available. The role of bile acid-binding resins, fibric acid derivatives, hydroxymethylglutaryl coenzyme A reductase inhibitors, nicotinic acid and antioxidants is each unique. Understanding the role of lipoproteins in atherosclerosis will help in selecting the most appropriate therapy for each individual patient. Medications not designed for their lipoprotein effects can significantly alter lipoproteins. Medications, such as nonselective β blockers, can alter low-density lipoprotein (LDL) subclass distribution with no change in LDL cholesterol content. Such changes may eradicate part of the beneficial cardiovascular effect of β blockade therapy. In the future, therapeutic choices may depend in part on lipoprotein abnormalities such as lipoprotein (a), apolipoprotein E isoforms, hyperapobetalipoproteinemia, or small, large and modified LDL.

The complete cDNA and amino acid sequence of human apolipoprotein B-100.

We have determined the complete sequence of apolipoprotein (apo) B-100 cDNA. It is 14.1 kilobases in length and codes for a 4563-amino acid protein, including a 27-amino acid signal peptide and a 4536-amino acid mature protein. Further, we identified 2366 residues of apoB-100 by direct sequence analysis of apoB-100 tryptic peptides. The mature peptide is characterized by high hydrophobicity (0.916 kcal/residue) and predicted beta-sheet content (21%). Dot matrix analysis revealed the presence of many long internal repeats in apoB-100. The mature peptide contains 25 cysteine residues, 12 of which are in the N-terminal 500 residues. Twenty potential N-linked glycosylation sites were identified, of which 13 were proven to be glycosylated, and 4 were found not to be glycosylated by direct analysis of tryptic peptides. Our findings on apoB structure provide a basis for future experimentation on the role of apoB-100-containing lipoproteins in atherosclerosis.

1] Introduction to the plasma lipoproteins

Current knowledge of the structure and function of lipoproteins and apolipoproteins and of the enzymes and receptors that mediate lipoprotein–lipid transport is making it possible to define discrete steps of lipoprotein metabolism at the molecular level. This chapter describes the plasma lipoproteins and the association of individual apolipoproteins with specific classes of lipoproteins from the surface properties of lipoprotein particles. The coupling of cellular regulatory mechanisms to the processes of intracellular lipoprotein biosynthesis and catabolism is beginning to yield to the powerful tools of contemporary cell and molecular biology. This chapter shows that a myriad of methods have been brought to bear upon the biology of the plasma lipoproteins. The policies of granting agencies have helped to increase communication and collaboration among investigators. Included in this interaction have been clinical scientists and pathologists whose important contributions have not been described in this survey of lipoprotein structure and metabolism. The chapter indicates that the current state of the field is conducive both to further understanding of normal processes and of the role of lipoproteins in atherosclerosis.

Molecular cloning and expression of partial cDNAs and deduced amino acid sequence of a carboxyl-terminal fragment of human apolipoprotein B-100.

Apolipoprotein (apo) B-100 cDNAs were identified in a human liver cDNA library cloned in the expression vector lambda gt11. The beta-galactosidase-apoB-100 fusion protein was detected by two independently produced low density lipoprotein polyclonal antisera and by three apoB-100 monoclonal antibodies that crossreact with apoB-74. It was not recognized by two apoB-100 monoclonal antibodies that crossreact with apoB-26. The longest clone, lambda B8, was completely sequenced. It contains a 2.8-kilobase DNA fragment containing the codons for the carboxyl-terminal 836 amino acid residues of apo-B-100, as well as the 3' untranslated region of apoB-100 mRNA. We have thus mapped apoB-74 to the carboxyl-terminal portion of apoB-100. The deduced amino acid sequence of the cloned DNA matches the sequences of 14 apoB-100 peptides determined in our laboratory. Minor differences in amino acid sequence were noted in three of the peptides, suggesting polymorphism of apoB-100 at the protein and DNA levels. Secondary structure predictions reveal an unusual pattern for apolipoproteins, consisting of beta-structure (24%), alpha-helical content (33%), and random structure (30%). Ten amphipathic helical regions of 10-24 residues were identified. This carboxyl-terminal fragment of apoB-100 is considerably more hydrophobic than other apolipoproteins with known structure. Its lipid binding regions might include stretches of highly hydrophobic beta-sheets as well as amphipathic helices. Our findings on apoB structure might be important for understanding the role of apoB-100-containing lipoproteins in atherosclerosis.

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.

Lipoprotein immunogenetics and atherosclerosis.

The discovery of the first human lipoprotein polymorphism by Allison and Blumberg [Lancet i:634-637, 1961] and the availability of alloimmune sera stimulated us to begin immunogenetic studies on swine in search of lipoprotein diversity and its relationship to biological functions. We found considerable lipoprotein polymorphism, complexity, and heterogeneity in this species. These results and the correlation between immunogenetically defined lipoprotein type and arterial lipidosis in swine, fed a high fat diet, are discussed. Immunogenetic studies of lipoproteins, initiated more recently in rhesus monkeys, will be reviewed also. Preliminary data show similarities between these two species with regard to polymorphism, complexity, phenotypic expression of lipoprotein genes and, most importantly, their serological relationship to human lipoproteins. We also note immunogenetic studies on lipoproteins done by other investigators, or in other species. Brief remarks on implications of the lipoproteins in atherosclerosis, their general classification, immunological properties, and immunological methods used in their study precede the immunogenetic presentation.

Recent advances in experimental and molecular pathology: Influx, Synthesis, and Transport of Arterial Lipoproteins in Atherosclerosis

Recent advances in experimental and molecular pathology: Influx, Synthesis, and Transport of Arterial Lipoproteins in Atherosclerosis

THE INFLUENCE OF GONADAL HORMONES ON SERUM LIPIDS AND LIPOPROTEINS: STUDIES IN NORMAL AND HYPOGONADAL SUBJECTS

Excerpt Clinicians have known for almost 200 years that the manifestations of coronary atherosclerosis are much more frequent in men than in women. Numerous autopsy studies have disclosed the disea...

A study of myocardial infarction in women.

Excerpt It is well known that myocardial infarction occurs much more commonly in men than in women. Almost all reports on coronary artery disease in the female emphasize a history of diabetes or hy...

THE FAMILIAL OCCURRENCE OF HYPERTENSION AND CORONARY ARTERY DISEASE, WITH OBSERVATIONS CONCERNING OBESITY AND DIABETES

Excerpt I. INTRODUCTION It is commonly thought that certain families are afflicted with high blood pressure, strokes and heart attacks with unwarranted frequency and to a severe degree. Sudden deat...

Observations on atherosclerosis of the coronary arteries in males under the age of 46; a necropsy study with special reference to somatotypes.

Excerpt Recent studies on establishing criteria for the prediction of the development of coronary artery disease, investigations relating to the development of coronary artery disease in certain so...

The role of lipids and lipoproteins in atherosclerosis.

A THEROSCLEROSIS is generally considered to be the major disease of this era. Its consequences in the coronary, cerebral, and peripheral arteries, in the form o£ ocelu- sive phenomena, are responsible for more death and disability than any other disease. In spite of much study and research there is still no agreement con- cerning the sequence of pathogenetic events, etiol- ogy, or treatment of atheroselerosis. The not-too- rare oceurrence of coronary artery ocelusions (almost always a consequence of atheroselerosis) in young men from 20 to 40 years of age testifies to the fallacy of the idea, still prevalent, that atheroselerosis is a problem of the aged or senile. For the male it is a 1 This work was supported (in part) by the Atomic Energy Commission and the United States Public Health Service. The authors wish to acknowledge with gratitude the gener- ous and invaluable advice and assistance given by Profs. Hardin B. Jones and John H. Lawrence. A THEROSCLEROSIS is generally considered to be the major disease of this era. Its consequences in the coronary, cerebral, and peripheral arteries, in the form o£ ocelu- sive phenomena, are responsible for more death and disability than any other disease. In spite of much study and research there is still no agreement con- cerning the sequence of pathogenetic events, etiol- ogy, or treatment of atheroselerosis. The not-too- rare oceurrence of coronary artery ocelusions (almost always a consequence of atheroselerosis) in young men from 20 to 40 years of age testifies to the fallacy of the idea, still prevalent, that atheroselerosis is a problem of the aged or senile. For the male it is a