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R W Wissler

Publications and source records attributed to R W Wissler.

At least 19 recordsLinked to original sources
PubMed1992

Theories and new horizons in the pathogenesis of atherosclerosis and the mechanisms of clinical effects.

In this report, I relate some of the major new concepts of the cellular and humoral pathological changes of atherosclerosis to the many observations that have been made recently in the clinicopathological study of the Pathobiological Determinants of Atherosclerosis in Youth, in some of the more human lesion-related animal models, and in epidemiological studies. An effort is made to explain the transition from the many important gross findings to the microscopical, immunohistochemical, and micromorphometric observations that have been made in a number of recent large-scale autopsy studies that are still under way in a number of countries.

Animals↗
PubMed1991

Update on the pathogenesis of atherosclerosis.

The major components of atherosclerotic plaque, ultimately responsible for clinical effects, are deposited lipids--mostly cholesteryl esters and cholesterol, derived largely from the lower-density lipoproteins of the blood--and proliferated, modified arterial smooth muscle cells with their synthesized connective tissue products. Advanced plaques vary widely in the proportion of the two components, but evidence indicates that lipid deposition--especially of lipoprotein elements--often occurs in the lesion-prone intimal areas of the artery prior to the buildup of smooth muscle cells. The 1980s were remarkably productive for investigators who study the pathogenesis of atherosclerosis. We now know of the many forms of lower-density lipoproteins, i.e., low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL), some of which are more likely to be associated with accelerated atherosclerosis and some of which are more likely to be influenced by diet. Among these forms of LDL and VLDL are LDL-1, beta-VLDL, and Lp(a). Work has been reported implicating various alterations of endothelial function in the permeability of the arterial endothelial barrier in the transport of these low-density, cholesterol-rich macromolecules. Of possibly greater interest is the developing evidence that such proliferation-stimulating molecules as platelet-derived growth factor (PDGF) can be produced by a number of cells likely to be involved in the progression of atherosclerotic plaque. In addition to platelets, these include activated monocytes and monocyte-derived macrophages, injured endothelial cells, and smooth muscle cells, which can undergo an autocrine conversion to PDGF synthesis--possibly stimulated by LDL from hyperlipidemic serum. Leukotrienes and other endothelium-associated regulatory molecules may also take part in the paracrine and autocrine mechanisms of stimulating smooth-muscle-cell proliferation. Additional recent developments that have led to a better understanding of atherosclerotic pathogenesis have occurred. The first is evidence of the involvement of oxidized LDL and its apolipoprotein B in atherogenesis. Research indicates that antioxidants have a suppressive effect on atherogenesis when oxidized LDL has been involved in lesion development. The data linking the development of autoimmune reactions to these oxidatively altered lipoproteins are also impressive. Further, there is increasing evidence that atherogenesis in nonhuman primates and in people in whom chronic sustained circulating immune complexes are involved is likely to be accelerated, even when few or no classic risk factors are present. These lesions appear to represent a distinct microarchitectural form of concentric and transmural atherosclerosis that is better classified as "atheroarteritis."

Adolescent↗
PubMed1990

Can atherosclerotic plaques regress? Anatomic and biochemical evidence from nonhuman animal models.

For at least 60 years, spotty and poorly documented evidence has suggested that atherosclerotic disease in humans might be reversible. Little direct evidence was available until researchers demonstrated that rather advanced atherosclerotic lesions in experimental animals could show marked improvement after blood-lipid-reducing regimens that were often combined with other measures, such as increased ambient oxygen and estradiol therapy. In fact, this combination was used in this laboratory to produce one of the first effective regression studies in the rabbit model. In more recent studies in this laboratory, abundant evidence has been obtained that the advanced, eccentric, largely intimal lesions produced in the rhesus monkey are substantially reversible, and the much more inflammatory, concentric, and often transmural atheroarteritis induced by the same atherogenic ration in the cynomolgus monkeys is much more resistant to effective and beneficial regression. This unusual reaction appears to be due to the circulating immune complexes that participate in the pathogenesis of atherosclerosis in these cynomolgus monkeys, as well as possibly in a number of humans. The evidence for this phenomenon, as well as the varying effects of the lesions induced with contrasting food fats, is summarized in this presentation. Some of the time-related effects of varying interventions when the lesions are studied at 4-month intervals in rhesus and cynomolgus monkeys are also discussed. Other factors that may influence regression are also considered.

Animals↗
PubMed1990

An update on the pathogenesis of atherosclerosis (principles of prevention, intervention, retardation, and regression).

The major life-threatening ischemic events in heart and brain are precipitated by the plaque. Thrombosis in the muscular arteries and rupture of the large elastic arteries usually follows fracture or ulceration of the plaque's fibrous cap. The smooth muscle cell (SMC) participates in many aspects of the atherosclerotic process: lipid uptake, synthesis of plaque components, and cell proliferation. The latter is a particularly significant aspect of the disease. High serum cholesterol levels stimulate proliferation of arterial medical cells; lower-density lipoproteins (LDL and B-VLDL) induce ingress and storage of cholesteryl ester in the arterial intima. These effects are inhibited by high-density lipoproteins (HDL). Endothelial injury may be an important part of the pathogenesis of some atherosclerotic plaques because powerful growth factors liberated from circulating monocytes, injured endothelial cells, and platelets, actively stimulate SMC proliferation, even when other risk factors are absent.

Animals↗
PubMed1990

Aneurysm formation in experimental atherosclerosis: relationship to plaque evolution.

To determine whether aneurysms form in experimental diet-induced atherosclerosis, we reviewed our experience with cynomolgus monkeys (n = 268) and rhesus monkeys (n = 175) fed an atherogenic diet for various lengths of time. Many animals in long-term experiments were fed "regression" diets and cholestyramine to lower cholesterol levels after lesions were established. No aneurysms were found in animals on normal diet. There were no aneurysms in 252 animals fed an atherogenic diet with or without regression for 12 months or less. However, aneurysms formed in 13% of cynomolgus monkeys (4 of 31) and 1% (1 of 107) rhesus monkeys on an atherogenic regimen for 16 to 24 months. Four of the five animals with aneurysms were on a regression diet and cholestyramine for 4 to 12 months. The fifth was fed the atherogenic diet for 20 months without subsequent regression. Aneurysms were prominent and involved the thoracic and abdominal aorta, innominate artery, carotid arteries, iliac and femoral arteries, and formed in areas most involved with plaque formation in both species. Histologic evidence was found of thinning of the media and atrophy with loss of normal architecture. The higher incidence of aneurysms in cynomolgus monkeys was associated with greater media destruction than was noted in the rhesus. These data support the thesis that aneurysm formation is a manifestation of atherosclerosis. In primate atherosclerosis, aneurysms form only after prolonged exposure to the atherogenic regimen, even in the presence of declining serum cholesterol levels. Matrix fibers in plaques may provide structural support to the aortic wall where there is underlying atrophy of the media. With time or declining serum cholesterol levels or both, plaques may atrophy leaving an aortic wall too thin to support increasing mural tension, leading to aneurysmal enlargement.

Animals↗
PubMed1989

The rat as an experimental animal.

The development and characterization of many inbred, congenic, and recombinant strains of rats in recent years has led to the detailed genetic description of this species, especially in regard to its major histocompatibility complex. This information has contributed substantially to the study of comparative genetics and has greatly enhanced the utility of the rat in a variety of areas of biomedical research. This article focuses on the use of the rat in immunogenetics, transplantation, cancer-risk assessment, cardiovascular diseases, and behavior.

Animals↗
PubMed1989

Effects of feeding fish oil on the properties of lipoproteins isolated from rhesus monkeys consuming an atherogenic diet.

This study examined plasma lipids and lipoproteins of rhesus monkeys fed fish oil incorporated into a highly atherogenic diet containing saturated fat and cholesterol. The animals were fed diets containing 2% cholesterol and either 25% coconut oil (group I), 25% fish oil/coconut oil (1:1; group II), or 25% fish oil/coconut oil (3:1; group III) for 12 months (n = 8/group). Adding menhaden fish oil to the diet increased plasma eicosapentaenoic acid and docosahexaenoic acid and decreased plasma linoleic acid in animals fed the fish oil containing diets. Plasma concentrations of all lipoprotein fractions were decreased in the fish oil groups. VLDL isolated from group I animals exhibited beta-mobility on agarose gels but the VLDL from groups II and III animals did not. The group I VLDL was more highly enriched in cholesteryl ester than was VLDL from groups II and III. Group I LDL had a small but significant increase in cholesteryl ester content compared to group III LDL. No differences in HDL composition were observed in the 3 groups. At least 6 times less apo E was recovered in VLDL, IDL, and LDL from group III animals than from group I animals. Assuming 1 molecule of apo B per lipoprotein particle, there were 50% fewer VLDL, IDL, and LDL particles in group III than in group I animals. Group III also had significantly lower molar ratios of apo E/apo B in VLDL, IDL, and LDL than did group I animals. When VLDL from all 3 groups were incubated with J774 macrophages at equal protein concentrations, only the VLDL from the group I animals stimulated cholesterol esterification. Thus, introducing fish oil into an atherogenic diet reduced the number of VLDL, IDL and LDL particles in plasma by as much as 50%, reduced the cholesteryl ester content of the circulating lipoprotein, and reduced the ability of the VLDL to stimulate cholesterol esterification in macrophages.

Animals↗
PubMed1989

Suppression of atherogenesis by nifedipine in the cholesterol-fed rhesus monkey.

Diet-induced atherosclerosis in rhesus monkeys was suppressed in the carotid arteries and thoracic aorta by the calcium antagonist nifedipine given orally for a period of 1 year at a dose of 10 mg b.i.d. The extent of atherosclerosis was determined by quantitative micromorphometric studies. No change in serum blood cholesterol or biochemical composition of the major vessels was detected, but the intimal area and thickness of the atherosclerotic plaques in the carotid arteries of the nifedipine group were markedly less than those found with the control group (p less than 0.05). However, no statistically significant differences were seen in the degree of atherosclerotic involvement of the other major arterial vessels. Although the mechanism is not clear, nifedipine may be useful in the treatment of carotid artery disease.

Animals↗
PubMed1989

Plasma platelet factor 4 response in rhesus monkeys fed coconut oil.

Platelet factor 4 (PF 4), the low molecular weight polypeptide stored in the alpha granule, has been shown to be released from platelets during the process of activation. To examine the effects of known atherogenic food fats on platelet activation, as manifested in circulating PF 4 concentrations, groups of rhesus monkeys were fed diets enriched with varying quantities of different food fats. Plasma PF 4 levels were measured at set intervals during the experimental period. Platelet counts were performed and PF 4 values assayed using the radioligand binding technique. Animals given coconut-oil-enriched diets showed the greatest increase in PF 4 levels; while those fed corn, peanut and soybean-oil-containing rations showed small insignificant fluctuations of plasma PF 4 values. In this study the coconut oil effect on plasma PF 4 values increased with time; diluting the coconut oil with increasing quantities of corn oil led to progressive decreases in these values. These data indicate an increased incidence of platelet activation in animals fed coconut-oil-enriched diets, and suggest that corn oil counteracts this thromboactive effect of coconut oil.

Animal Feed↗
PubMed1988

Brief overview of the mounting evidence that atherosclerosis is both preventable and reversible.

The major life-threatening events in advanced atherosclerosis are precipitated by the plaque. Thrombosis in the muscular arteries and rupture of the large elastic arteries usually follows rupture of the plaque's fibrous cap. The smooth muscle cell (SMC) participates in many aspects of the atherosclerotic process: lipid uptake, synthesis of plaque components, and cell proliferation. The latter is a particularly significant aspect of the disease. High serum cholesterol levels stimulate proliferation of arterial medial cells; low-density lipoproteins (LDL) from hyperlipidemic plaques induce ingress and storage of cholesterol ester. These effects are inhibited by high-density lipoproteins (HDL). Endothelial injury may be an important part of the pathogenesis of some atherosclerotic plaques because powerful growth factors actively stimulate SMC proliferation, even when other risk factors are absent. Utilization of animal models of atherosclerosis, especially nonhuman primate models, has led to great progress in understanding this disease process. In controlled feeding experiments, severe atherosclerosis has been produced in rhesus monkeys by means of a high fat, high cholesterol diet. Animals then placed on a low fat, low cholesterol diet, or given cholestyramine, or a combination of these two approaches, showed a remarkable decrease in the size of their atherosclerotic plaques. Many epidemiologic studies, as well as more recent prospective intervention studies involving bile acid sequestrants, indicate by imaging techniques that plaque regression takes place in humans.

Arteriosclerosis↗
PubMed1988

Quantitative ultrastructural analysis of coronary atherosclerotic involvement in two macaque species.

Ultrastructural analyses were employed to observe and to compare in detail lesions of the coronary artery of cynomolgus and rhesus monkeys. Animals were fed individually with the same atherogenic ration under identical conditions for 4, 8, and 12 months, and controls of each species were fed with a low fat, cholesterol-free ration. Transmission electron microscopic studies of coronary arteries from these animals led to the following conclusions: (1) Synthetic smooth muscle cells (SMC) without lipid and macrophages without lipid appeared more frequently in the cynomolgus lesions than in the rhesus lesions. Furthermore, phenotypic expression of synthetic SMCs in the cynomolgus was more active with greater diversity, while the rhesus showed less phenotypic modulation. Macrophages without lipid appeared frequently in the cynomolgus media. (2) Increased percentages of both synthetic SMCs with lipid and macrophages with lipid were demonstrated in the cynomolgus lesions as compared to those in the rhesus. This indicates that foam cells, including SMC- and macrophage-derived foam cells, are more prevalent in cynomolgus than in rhesus. They are considered to play an important role in atherogenesis. (3) Medial disruption, synthetic SMCs, and macrophages containing lipid appeared more often in cynomolgus media than in rhesus media. (4) There were greater percentages of both synthetic SMCs and macrophages in the intima of the myocardial side of coronary arteries in both species. (5) Approximately 42% of all foam cells in the cynomolgus lesions were derived from SMCs. There were fewer macrophages in rhesus lesions. (6) The difference in expression between the two macaque species reflects different responses of macrophages to medial smooth muscle cell (SMC) components. The configuration of the artery wall could be one of the important indicators of these different expressions.

Animals↗
PubMed1988

Sequential change of DNA synthesis in cultured aortic smooth muscle cells stimulated by hyperlipidemic serum.

Smooth muscle cells from monkey aorta quiescent in 5% calf serum have been shown to be stimulated to renewed proliferation by hyperlipidemic serum or LDL from such serum. This proliferative response evidently is not dependent on platelet-derived growth factor present in our system in large quantities. The least exposure time required for reaction between the mitogen and the cells in order to initiate maximal DNA synthesis by this mechanism was studied using autoradiography. Stationary primary cultures and subcultures from monkey aortic media required at least 4 and 8 hr of contact with hyperlipidemic serum or LDL so that a significant number of cells reentered the mitotic cycle. Compared to the primary culture system, subcultures needed a slightly longer time of contact with serum to initiate DNA synthesis. Since there was no significant difference in labeling index between the primary cultures stimulated by serum for 8 and 48 hr and the subcultures exposed between 6 and 48 hr, it is concluded that a relatively brief stimulation commits the majority of responsive cells to reenter the cycle and initiate DNA synthesis.

Animals↗
PubMed1987

The sympathetic nervous system and atherosclerosis.

Morphometric and chemical changes in the arterial wall were studied after 12 months of diet-induced atherosclerosis in rhesus monkeys treated with either bilateral surgical thoracic sympathectomy or propranolol. There was a marked reduction in the progression of atherosclerosis in the carotid arteries and a moderate reduction in the disease found in the thoracic aorta of monkeys treated initially with a sympathectomy, in comparison to control monkeys fed an atherogenic diet alone. Propranolol at a dose of 40 mg/12 hrs also seemed to reduce the progression of atherosclerosis in the carotid arteries and thoracic aorta, although the differences were less dramatic. There were minimal differences in the extent of atherosclerosis in the abdominal aorta or femoral arteries of animals in either treatment group as compared with the control group. Similarly, the chemical composition of these same major vessels showed no significant differences. Therefore, in the face of severe atherogenic stimuli, chemical or surgical sympathectomy may be useful in controlling atherosclerosis in specific arterial beds.

Animals↗
PubMed1986

Ultrastructural aspects of cynomolgus atherosclerotic carotid artery lesions on cholestyramine 'regression' treatment.

The carotid artery lesions of atherosclerotic cynomolgus monkeys treated with cholestyramine and studied with scanning electron microscopy appeared to be less bulging and largely covered by endothelial cells. With transmission electron microscopy these lesions showed an evident disappearance of cells and of extra- and intracellular lipid; a marked relative increase of fibrous material in the intercellular matrix, chiefly collagen and elastin fibers, was noted.

Animals↗