Experimental Atherogenesis Research Articles

An appraisal of cholesterol feeding in experimental atherogenesis

D IETARY LIPIDS are widely considered to be the major environmental agent responsible for severe atherosclerosis in populations of technologically developed countries, and the arterial lipid deposition induced in rabbits by the chronic administration of cholesterol or egg yolk’** is thought to support this view. Though lipid lesions can be produced by a high-fat diet alone and even by diets containing 14% to 20% vegetable fat3’4 or specific proteins associated with hypercholesterolemia,5-7 cholesterol-rich diets remain the principal means of inducing hypercholesterolemia, with the vascular lesions so produced accepted as atherosclerotic*-‘3 and the diets themselves regarded as atherogenic. However, with further knowledge and improved ultrastructural techniques, review of the model and its applicability is advisable to alert those interested in atherogenesis to the differences between diet-induced and spontaneous lesions despite known similarities. The Henle-Koch postulates,i4-i6 which stressed the importance of reproducing the same morbid condition in experimental animals to validate an etiologic agent, has been regarded as the epitome of scientific logic and method. A few authors have alleged that cholesterol-fed animals comply with the principles of Koch’s postulates,“.l’.‘8 but many acknowledge that feeding rabbits a cholesterol-rich diet does not reproduce atherosclerosis as it occurs in rnan.19-” Nevertheless the diet-induced lipid-containing lesions are still considered atherosclerotic by very many investigators.‘0~23~27-5’ In the light of new knowledge the Henle-Koch postulates have required modification for some diseases, and specific criteria applicable to experimental atherogenesis have been proposed27,52: (1) The experimental procedure must reproduce or be comparable to those conditions existing in man. (2) The sequence of pathologic changes in the vessel wall must be similar to that in man. (3) The experimental lesion must be similar to human atherosclerosis morphologically and topographically. (4) The complications of the disease, ie, intimal tears, ulceration, mural dissection, thrombosis, and aneurysmal dilatation, must result when severe lesions are produced. Application of these criteria will ensure maintenance of scientific standards and failure to comply, invalidation of the experimental model. Heedful of these criteria, this review is concerned with the pathology of diet-induced lesions with particular reference to the rabbit.

Participation of the endothelium in the development of the atherosclerotic plaque

In the past decade, initiated by the response-to-injury hypothesis of Ross and Glomset, the endothelium has been implicated in atherogenesis but as a passive participant--more involved through its absence than its presence. The hypothesis stated that endothelial desquamation due to an undefined injury led to platelet adhesion to the exposed basement membrane, and infiltration of serum lipoproteins. The subsequent release from the platelet alpha-granule of a potent smooth muscle cell mitogen and chemoattractant--the platelet-derived growth factor (PDGF)--was postulated to cause the intimal proliferative response that is known to be important in atherosclerotic plaque development. Recent evidence from several laboratories indicates that the endothelium has the potential to play a more active role in plaque development than simply contributing to pathological sequelae resulting from the loss of the nonthrombogenic surface provided by the endothelium. First, the endothelial cell (EC) is the site of attachment, and possibly activation, of blood-borne monocytes which enter the vessel wall as an early event in experimental atherogenesis. We have obtained in vitro evidence that the expression of monocyte binding sites on the surface of EC is a regulatable process and that increased EC turnover and certain exogenous agents acting on EC cause increased monocyte adhesion. Similar events may be responsible for focal adhesion of monocytes to the endothelium in vivo following hypercholesterolemia. Secondly, EC in culture are capable of chemically modifying low density lipoprotein (LDL) by a free radical oxidation process that renders the LDL toxic to proliferating cells and recognizable to the scavenger receptor of monocyte-derived macrophages. Thus, by oxidation of LDL, the EC have the potential to play an active role both in the formation of lipid-laden foam cells and in the accumulation of necrotic tissue which are hallmarks of the atherosclerotic lesion. Thirdly, cultured EC have been recently shown to secrete multiple mitogens for cultured smooth muscle cells. One of these mitogens appears to be closely related, if not identical, to PDGF using the criteria of receptor binding and biochemical and immunological similarity. Production of growth factors by EC is a regulatable process that is stimulated by exogenous agents such as endotoxin and phorbol esters which cause severe injury to cultured EC. Such a regulatory mechanism may participate in the in vivo proliferation of vascular SMC during the atherosclerotic process.(ABSTRACT TRUNCATED AT 400 WORDS)

Histochemical detection and quantification of macrophages in rhesus and cynomolgus monkey atherosclerotic lesions.

A detailed histochemical study of the macrophage involvement during experimental atherogenesis in rhesus and cynomolgus monkeys was performed. Aortic, carotid, and femoral artery lesions were examined in both species after 4, 8, and 12 months of atherogenic diet feeding. Macrophages were identified and quantified in the atherosclerotic lesions using acid lipase, acid esterase, beta-galactosidase, and cytochrome oxidase histochemical procedures. Morphometric quantitation revealed that the cynomolgus monkey arterial lesions were larger and consistently demonstrated a greater number of cells with characteristics of macrophages in the intimal, medial, and adventitial portion of the arteries when compared to the primarily intimal rhesus monkey lesions. Biochemical assays of aortic samples for acid lipase and acid esterase activity also showed consistently higher activities in the cynomolgus samples when compared to the rhesus samples. Average serum cholesterol levels were higher in the cynomolgus monkeys than in the rhesus monkeys, but the differences in the arterial lesions still existed when animals with overlapping cholesterol levels were compared. Macrophages and their associated activities predominated in experimental cynomolgus monkey atherosclerosis when it was compared to the rhesus disease process, which may be an explanation for some of the differences in atherogenesis reported in these two species.

Prostaglandin E2 biosynthesis: changes in rabbit aorta and skin during experimental atherogenesis

The transformation of [1-14C]arachidonic acid into [14C]prostaglandin E2(PGE2) by rabbit aorta and skin was demonstrated by cell-free preparations, and the PGE2 synthetase activity was located mainly in the microsomal fraction (105,000 g pellet) of both tissues. Rabbits fed an atherogenic diet (Purina rabbit chow plus 1% cholesterol and 2% cottonseed oil) developed atheroma in the aortas and skin lesions resembling xanthoma in 6 to 7 months. At the end of this period, increases in the conversion of [1-14C]-arachidonic acid into [14C]PGE2 were observed in microsomal preparations of the intima-media of the aortas (2.5-fold of control) and normal-appearing skin (3.0-fold of control) of the experimental animal. Microsomal preparations of skin lesions particularly had greater ability to form PGE2 (7-fold of control).

On the presence of a concanavalin-A reactive coat over the endothelial aortic surface and its modifications during early experimental cholesterol atherogenesis in rabbits.

In rabbits, guinea pigs, and rats an ultrathin coat containing carbohydrates has been demonstrated in transmission electron microscopy by means of the highly specific Concanavalin-A histochemical reaction over the endothelial aortic surface. In rabbits fed on a hypercholesterolic diet in aortic areas where the Concanavalin-A reactivity of the endothelial surface is lost, an amorphous thick deposit is found.

Physical fitness and coronary heart disease. Some basic views.

The purposes of a physical training program are examined and the evidence for the general and circulatory benefits of physical fitness is discussed. While the proof of benefits is not established, there is sufficient evidence from current studies to justify encouragement of the exercise programs. The evidence that exercise lessens experimental atherogenesis is equivocal. The possibility that physical fitness alters the morbidity and mortality of coronary sclerosis remains conjectural. Whether a physical fitness program would (1) lessen the incidence of intravascular thrombosis or atheromatous ulceration, (2) increase the extent or rate of development of coronary collaterals in man although the evidence in animals is suggestive, (3) improve the performance capacity of the heart, (4) decrease the likelihood of arrhythmias, or (5) result in more efficient bodily responses to the stresses associated with myocardial infarction is not clear or has not been definitely ascertained because of lack of evidence.

Effect of Gastric Resective Surgery on Experimental Atherogenesis

In Rhesus monkeys on a 1 per cent cholesterol diet for periods up to twenty-six months, vagotomy and hemigastrectomy provided no protection against hypercholesterolemia and atherosclerosis; rather in this study the degree of hypercholesterolemia and severity of atherosclerosis were greater in the gastrectomized animals than in control animals on the same diet.

The effect of incubated arteries on estrogenic properties of estradiol-containing media

The aorta, the coronary and the carotid arteries were aseptically removed from cockerels and incubated for 72 hours in nutrient media with and without estradiol. The endocrine activity of the nutrient media was determined by injection into immature female mice. The incubating media from aorta or carotid arteries showed in general no differences from the controls, while estrogenic activity was always decreased after incubation with coronary arteries. The significance of these findings in connection with the modification of experimental atherogenesis by estrogens is discussed. Les aortes, les coronaires et les artères carotides de poulets sont aseptiquement prélevées et incubées 72 heures dans un milieu nutritif avec ou sans æstradiol. L'activité hormonale du milieu est ensuite déterminée par injection à la souris femelle immature. L'incubation de faorte ou de la carotide ne modifie pas le milieu par rapport aux temoins. L'incubation des arteres coronaires diminue constamment l'activité æstrogenique du milieu. La signification de ces résultats et leurs rapports avec (influence des æstrogénes sur l'athérogénèse expérimentale sont discutés. Aorta, Coronararterien und Carotiden wurden aseptisch von Hähnchen entnommen und für 72 Stunden in Nährmedien mit und ohne Östradiol inkubiert. Die endokrine Aktivität der Nährf\:ssigkeit wurde an unreifen weiblichen Mäusen durch Injektion geprüft. Die Inkubierungsflüssigkeit der Aorta und der Carotiden zeigte im allgemeinen gegenüber Kontrollen keine Unterschiede, wahrend die östrogene Aktivität des Mediums durch Inkubation von Coronararterien stets herabgesetzt wurde. Es wird die Bedeutung dieser Befunde im Hinblick auf die Modifikation der experimentellen Atherogenese durch Östrogene erörtert.

Experimental atherosclerosis and portacaval shunt.

The role of the liver in cholesterol metabolism and experimental atherogenesis is not completely understood. Katz and Stamler¹in their familiar monograph on "Experimental Atherosclerosis" state that, to their knowledge, "no thorough-going studies have been carried out on the influence of hepatic factors on atherogenesis in experimental animals." According to the texts, free cholesterol exists in the blood stream as a result of the breakdown of erythrocytes and other cells and is excreted by the liver in bile—the only body fluid in which it is readily soluble. In addition, the liver may synthesize cholesterol from acetate by a process involving some 26 separate enzymatic reactions. According to Siperstein and Guest,²exogenous cholesterol may exert some control over this synthesis by a feedback mechanism probably blocking the synthesis prior to the formation of squalene. Little else appears to be known of the handling of exogenous cholesterol by the liver.

The role of diet and hormones in the prevention of myocardial infarction.

Article1 November 1955THE RÔLE OF DIET AND HORMONES IN THE PREVENTION OF MYOCARDIAL INFARCTIONLOUIS N. KATZ, M.D., F.A.C.P.LOUIS N. KATZ, M.D., F.A.C.P.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-43-5-930 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptINTRODUCTIONThe rôle of diet and hormones in the prevention of myocardial infarction is not definitely established, but the evidence available today strongly suggests that they do play an important rôle. Their effects are dependent chiefly upon four modes of action:1. An alteration of the personality, motivation and drive of the individual, which may place undue strain upon a vulnerable vasculature and may be the immediate precipitating cause of the infarction.2. The development of hypertension, which accelerates "wear and tear" of the coronary arteries and, in the presence of the atherogenic trigger mechanism, hastens atherosclerosis.3. The development...Bibliography1. KatzStamler LNJ: Experimental atherosclerosis, 1953, Charles C Thomas, Springfield, Illinois. Google Scholar2. KatzPickStamler LNRJ: Atherosclerosis, Mod. Concepts Cardiovas. Dis. 23: 239, 1954. MedlineGoogle Scholar3. StamlerKatzPick JLNR: Nutritional-endocrinological interrelationships in the pathogenesis of hypertension and atherosclerosis over the life span, in Fourth annual report on stress, edited by Hans Selye and Gunnar Heuser, 1954, Acta, Montreal, Canada, p. 245. Google Scholar4. KatzStamlerPickRodbard LNJRS: Dietary and hormonal factors in experimental atherogenesis and blood pressure regulation, Recent Progress in Hormone Research 11: 401, 1955. Google Scholar5. KatzStamlerPick LNJR: The role of the hormones in atherosclerosis, 1954, Proceedings of the Symposium on Atherosclerosis, National Academy of Sciences, National Research Council, Washington, D. C., N.A.S.-N.R.C. Publication 338: 236, 1954. Google Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: *From the Symposium on Acute Myocardial Infarction, presented at the Thirty-sixth Annual Session of The American College of Physicians, Philadelphia, Pennsylvania, April 26, 1955.From the Cardiovascular Department, Medical Research Institute, Michael Reese Hospital, Chicago, Illinois.†This work was supported by the Chicago Heart Association, National Heart Institute, Michael Reese Research Foundation, and by other benefactors, and carried out in collaboration with Dr. Ruth Pick, Dr. Simon Rodbard and Dr. Jeremiah Stamler. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byEffects of Caponization on Body Weight, Atherosclerosis, and Cardiovascular Variables in Hypertensive and Hypotensive Turkey LinesEffects of Estrogen and Progestogen Treatment on the Response of the Aorta of Male Rats to Hypertension: MORPHOLOGICAL AND CHEMICAL STUDIESDie Grundstoffe der NahrungExperimental atherosclerosis as observed in the chickenDie Coronarerkrankungen. Coronarinsuffizienz, Angina pectoris und HerzinfarktAcute myocardial infarction in a city hospitalLIPOPROTEINS IN CORONARY ARTERY DISEASEEarly age of menopause in young women with fatal acute myocardial infarctionThe epidemiology of atherosclerosis among a random sample of clothing workers of different ethnic origins in New York CityTHE DESIGN OF PROPER EXPERIMENTS TO INVESTIGATE CLINICAL ANGINA PECTORIS AND THE IMPORTANCE OF KNOWING THE DETERMINANTS OF CORONARY FLOW IN CONSIDERING THERAPY OF ANGINA PECTORISSex hormone deficiency of adrenal origin in older men and women 1 November 1955Volume 43, Issue 5Page: 930-941KeywordsAtherosclerosisDietHeartHormonesHypertensionInfarctionInsulinMotivationMyocardial infarctionPancreas ePublished: 1 December 2008 Issue Published: 1 November 1955 PDF downloadLoading ...