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Biomedical subjects

R Ross

Publications and source records attributed to R Ross.

At least 163 records · Page 9Linked to original sources
PubMed1993

Glucocorticoid inhibits thrombin-induced expression of platelet-derived growth factor A-chain and heparin-binding epidermal growth factor-like growth factor in human aortic smooth muscle cells.

Proliferation of smooth muscle cells (SMCs) in atherosclerosis may be modulated by several growth regulatory molecules. At least two mitogens for SMCs, platelet-derived growth factor (PDGF) A-chain and heparin-binding epidermal growth factor-like growth factor (HB-EGF), can be produced by SMCs themselves and may stimulate smooth muscle proliferation in an autocrine or paracrine fashion. We examined the effects of thrombin, which may be generated at the site of vascular injury during atherogenesis, and the potent anti-inflammatory glucocorticoid, dexamethasone (DEX), on the expression of the genes encoding these two growth factors. Since both PDGF A-chain and HB-EGF have affinity for heparin, we also examined the effect of thrombin and DEX on the release of heparin binding mitogenic activity from SMCs. Treatment of SMCs with thrombin resulted in increases both in the level of the PDGF-A and HB-EGF transcripts in the cells, as well as in released heparin-binding growth factor activity. DEX inhibits the thrombin-stimulated release of mitogenic activity in a dose-dependent manner. An enzyme-linked immunoadsorbent assay showed that DEX inhibits both constitutive and thrombin-stimulated release of PDGF-AA. DEX also decreases both constitutive and thrombin-stimulated mRNA levels for PDGF A-chain and HB-EGF and destabilizes the transcripts for both growth factors. A nuclear run-on assay revealed that DEX acts, in addition, to inhibit constitutive and thrombin-stimulated transcription of the PDGF A-chain and HB-EGF genes. Thus, these findings indicate that expression of PDGF A-chain and HB-EGF may be regulated by thrombin and glucocorticoid at the transcription level. Our results are consistent with the involvement of thrombin-induced growth factor expression in neointimal SMC proliferation and suggest the possibility that intimal proliferation may be attenuated by glucocorticoids.

Aorta, Thoracic↗
PubMed1993

The pathogenesis of atherosclerosis: a perspective for the 1990s.

Atherosclerosis, the principal cause of heart attack, stroke and gangrene of the extremities, is responsible for 50% of all mortality in the USA, Europe and Japan. The lesions result from an excessive, inflammatory-fibroproliferative response to various forms of insult to the endothelium and smooth muscle of the artery wall. A large number of growth factors, cytokines and vasoregulatory molecules participate in this process. Our ability to control the expression of genes encoding these molecules and to target specific cell types provides opportunities to develop new diagnostic and therapeutic agents to induce the regression of the lesions and, possibly, to prevent their formation.

Animals↗
PubMed1993

Adipose tissue distribution measured by magnetic resonance imaging in obese women.

This study had two objectives: 1) to establish magnetic resonance imaging (MRI) as a tool for measuring subcutaneous and visceral adipose tissue (AT) distribution in obese women, and 2) to assess the relationship between selected anthropometric variables and MRI-measured AT. Fifteen healthy obese women aged 35.0 +/- 9.8 y (mean +/- SD) with a body mass index of 36.4 +/- 7.1 and a waist-to-hip ratio of 0.91 +/- 0.05 participated in the study. The mean difference for repeated measures of subcutaneous and visceral AT area at L4-L5 was 1.1% (P = 0.15) and 5.5% (P = 0.14), respectively. Large interindividual differences were observed for total (30.2-81.7 L), subcutaneous (27.1-76.8 L), and visceral AT volume (0.9-5.5 L). Subcutaneous and visceral AT represented 92.3% and 6.3% of the total AT volume, respectively. Hip (r2 = 0.96) and waist (r2 = 0.88) circumferences were significant predictors of subcutaneous AT volume. The combination of body weight, age, and height explained 89% of the variance in visceral AT volume. These results demonstrate that MRI provides reliable measures of subcutaneous and visceral AT distribution in obese women.

Adipose Tissue↗
PubMed1993

Retinal tolerance to intravitreal perfluoroethylcyclohexane liquid in the rabbit.

To evaluate the use of perfluoroethylcyclohexane (PFE) liquid during vitreoretinal surgery, retinal tolerance was tested by electroretinographic (ERG) and histologic study of rabbit eyes undergoing intravitreal placement of PFE for 48 hours. When PFE occupied the vitreous cavity, ERG amplitudes were decreased, probably because of electrical insulation by the liquid. Immediately after removal of the liquid, elevations of a and b waves occurred. Further improvements in the waveforms were recorded when tested between 5 days and 2 months after PFE removal, such that the eyes injected with PFE exhibited ERG amplitudes comparable to contralateral control eyes and preoperative eyes. Histologic examination of the eyes 2 months after PFE removal also revealed normal morphologic features. Small residual amounts of PFE produced no adverse histologic changes after 6 months. When PFE remained intravitreally for longer than 1 week, dispersion of the liquid and preretinal accumulation of macrophages occurred, and in inferior retina, distortions of photoreceptor outer segments and narrowing of outer plexiform layer were observed in the rabbit model.

Animals↗
PubMed1993

Radiofrequency modification of atrioventricular conduction by selective ablation of the low posterior septal right atrium in a patient with atrial fibrillation and a rapid ventricular response.

A case is presented of a 58-year-old woman with atrial fibrillation and uncontrolled ventricular responses up to 180 beats/min despite therapy with digoxin. Radiofrequency energy was applied to the low posteroseptal right atrium in an attempt to modify "slow fiber" conduction. This resulted in a decrease in ventricular rate from 125 to 50 beats/min. Follow-up Holter monitor demonstrated an average heart rate of 64 beats/min (range 43-112). On exercise tolerance test, the maximum heart rate was 126. Modification of the low posterosepta right atrium may prove to be an alternative to AV node or His bundle ablation and pacemaker implantation in patients with poorly controlled atrial fibrillation and rapid ventricular response. The mechanism by which this approach was effective may be ablation of slow conducting AV nodal fibers with a short refractory period.

Atrial Fibrillation↗
PubMed1993

Smooth muscle cells and the pathogenesis of the lesions of atherosclerosis.

In this review we have tried to identify the characteristic features of SMCs in developing lesions of atherosclerosis and the extracellular factors that may be involved in regulating these altered features. Though the list seems long and complex there is probably a great deal of interplay among the different regulatory mechanisms. The function and activities of SMCs in the artery are dependent on the milieu created by the surrounding cells and the components of the extracellular matrix. In the normal, uninjured media of the artery, SMC phenotype and function seem to be in large part determined by the extracellular matrix in which they are embedded and by diffusible factors, in particular from endothelial cells. Endothelial cell injury, infiltration of monocytes and lymphocytes, and ultimately, thrombosis and platelet release, as seen in developing lesions of atherosclerosis, dramatically alter the balance of growth-regulatory and vasoactive factors present in the local environment. These extracellular factors (table and figure) can alter both SMC phenotype, and thus responsiveness, and SMC migration, proliferation, and synthesis of the extracellular matrix. A better understanding of how specific factors mediate these responses, should make it possible to determine the ways in which the SMC response can be modulated. Though growth regulatory molecules seem to be key to this process, the challenge for the future is to understand their regulation in the environment of the artery wall and the interplay between growth-regulatory molecules, extracellular matrix, and vasoactive agents.

Arteriosclerosis↗
PubMed1993

Role of endogenous platelet-derived growth factor in arterial smooth muscle cell migration after balloon catheter injury.

The process of intimal thickening after de-endothelializing injury to the rat carotid artery is dependent on the migration of smooth muscle cells from the media. Recent reports have suggested that platelet-derived growth factor may be an important mediator of migration after injury. We have addressed this issue by directly determining smooth muscle cell migration in injured arteries of animals depleted of platelets and after administration of an antibody that blocks platelet-derived growth factor. Because there is a reported association between plasminogen activator synthesis and smooth muscle cell migration, we assayed the activity levels of plasminogen activators after arterial injury and also assessed the effect of a plasmin inhibitor on migration. The data suggest that platelet-derived growth factor, released by platelets at sites of arterial injury, is an endogenous mediator of smooth muscle cell migration; that plasmin generation, catalyzed by tissue-type plasminogen activator, is necessary for migration; and that one way in which platelet-derived growth factor may act is by stimulation of the synthesis of tissue-type plasminogen activator by smooth muscle cells.

Animals↗
PubMed1993

Regional expression of the platelet-derived growth factor and its receptors in a primate graft model of vessel wall assembly.

Healing baboon polytetrafluoroethylene grafts express PDGF mRNA in the neointima. Perfusates of graft segments also contain PDGF-like mitogenic activity. To extend these findings, we studied the expression and regional distribution of the PDGF protein isoforms and their receptors in this prosthetic graft model. By immunohistochemistry, as well as ELISA and Western blot analysis of tissue extracts, both PDGF-A and PDGF-B were identified in macrophages within the interstices of the synthetic material. In contrast, the neointima contained predominantly PDGF-A localized to the endothelial surface and the immediate subjacent smooth muscle cell layers. Tissue extracts of neointima and graft material were mitogenic for baboon aortic smooth muscle cells in culture; nearly all of this proliferative activity was blocked by a neutralizing anti-PDGF antibody. PDGF receptor beta-subunit mRNA and protein were easily detectable in the neointima and graft material. PDGF receptor alpha-subunit mRNA was also observed in the graft matrix and at lower levels in the neointima. This pattern of ligand and receptor expression further implicates locally produced PDGF as a regulator of neointimal smooth muscle cell growth in this model. The coexpression of ligand and receptor in the macrophage-rich matrix also suggests that PDGF may participate in the foreign body response.

Animals↗
PubMed1993

Human atherosclerosis. IV. Immunocytochemical analysis of cell activation and proliferation in lesions of young adults.

The accumulation of smooth muscle cells is a major phenomenon associated with the pathogenesis of lesions of atherosclerosis. Smooth muscle cell proliferation in response to the release of growth factors from neighboring cells, both smooth muscle and macrophages, is one mechanism postulated to account for the increasing numbers of smooth muscle cells as atherosclerotic lesions progress. Indeed, we recently demonstrated the B chain of platelet-derived growth factor (PDGF-B), a potent smooth muscle mitogen, within macrophages in monkey and human lesions of atherosclerosis. To further test the hypothesis that smooth muscle proliferation and/or activation (eg, expression of major histocompatibility complex proteins) plays a role in the early development of these lesions, we applied antibodies to PDGF-B, HLA-DR (a marker of cell activation), and proliferating-associated marker) on a series of early human atherosclerotic lesions from young adults in conjunction with cell-type-specific antibodies. Smooth muscle cells had previously been demonstrated to comprise a major fraction of the cell population in these lesions. In a continuing study of early and intermediate lesions of individuals ranging in age from 15 to 34 years, PDGF-B was detected within macrophages in 2 of 15 lesions. There was no evidence of HLA-DR expression by the smooth muscle cell population in any of the lesions. PCNA-positive cells comprised less than 2% of the cells in the lesions, and the majority of these were blood-borne cells (macrophages and/or lymphocytes), although a small fraction of the PCNA-positive cells were identified as smooth muscle. Concurrent PCNA and 5'-bromodeoxyuridine studies of peripheral blood monocytes demonstrated the presence of significant numbers of cells positive for these proliferation-related markers. It is concluded that the growth factor PDGF-B may have a role in regulating cell proliferation in early human fatty streaks, but the number of proliferating smooth muscle cells is relatively small, and there is no evidence of smooth muscle cell activation, as judged by HLA-DR positivity, in these lesions.

Adolescent↗
PubMed1993

Atherosclerosis: current understanding of mechanisms and future strategies in therapy.

The lesions of atherosclerosis represent a protective, inflammatory-fibroproliferative response against the different agents that can cause the disease. If the injury continues chronically over a sufficiently long period of time, and if opportunity is not given for restitution of normal architecture in the artery wall, lesions may progress to a point at which clinical sequelae develop. On the other hand, as demonstrated by Brown et al, Kane et al, and Blankenhorn et al, the advanced lesions of atherosclerosis can be shown to regress. A quantitative, statistical analysis of angiograms in patients who are aggressively treated with lipid-lowering agents, such as HMGCoA reductase inhibitors has clearly shown this to be the case. Thus, it is entirely conceivable that this chronic, excessive, inflammatory, and fibroproliferative response can be reversed, given sufficient opportunity for the factors that have led to the endothelial and arterial wall injury causing these events to be taken into hand and modified.

Angioplasty, Balloon↗
PubMed1992

Platelet-derived growth factor B-chain-like immunoreactivity in the developing and adult rat brain.

Platelet-derived growth factors (PDGFs) are growth-regulatory molecules that stimulate chemotaxis, proliferation and increased metabolism, primarily of connective tissue cells. In our previous paper, we have demonstrated the ubiquitous localization of PDGF B-chain-containing proteins in neurons and expression of transcripts for PDGF A-chain, B-chain and the two forms of the PDGF receptor in the brains of non-human primates. In the present study, the cellular localization of PDGF B-chain in developing and adult rat brains was analyzed using immunocytochemistry with a PDGF B-chain-specific monoclonal antibody. Intense PDGF B-chain immunoreactivity (PDGFB-I) was distributed around the continuously regenerating primary olfactory neurons at all stages of development from embryo to adult. The major part of PDGFB-I associated with neurons appeared some time after birth and increased with age. PDGFB-I appeared in several nerve fiber systems during earlier stages of development and gradually decreased with age. In conjunction with other data showing the existence of functional PDGF receptor beta-subunits in the neurons, these data suggest a possible role for PDGF B-chain as a neurotrophic or neuroregulatory factor in both developing and mature brains.

Animals↗