PubMed Health⌕ Search

Biomedical subjects

R Preston Mason

Publications and source records attributed to R Preston Mason.

27 records · Page 2Linked to original sources
PubMed2004

Sulfone COX-2 inhibitors increase susceptibility of human LDL and plasma to oxidative modification: comparison to sulfonamide COX-2 inhibitors and NSAIDs.

Clinical investigations have demonstrated a link between use of the sulfone cyclooxygenase-2 (COX-2) inhibitor, rofecoxib, and increased risk for atherothrombotic events. This increased risk was not observed for a sulfonamide COX-2 inhibitor (celecoxib), indicating a potential non-enzymatic mechanism for rofexocib. To test this hypothesis, we compared the independent effects of COX-2 inhibitors on human LDL oxidation, an important contributor to atherosclerotic cardiovascular disease. The results showed that rofecoxib (100 nM) significantly decreased (>40%, p<0.001) the lag time for LDL conjugated diene formation and increased levels of thiobarbituric-acid-reactive-substances (TBARS) in vitro. The pro-oxidant activity of rofecoxib was dose-dependent and attenuated by 70% (p<0.001) with the antioxidant, Trolox. Rofecoxib and etoricoxib (100 nM) also caused a marked increase (>35%, p<0.001) in non-enzymatic generation of isoprostanes, as measured by mass spectroscopy. Addition of rofecoxib to fresh human plasma reduced the oxygen radical antioxidant capacity (ORAC) by 34% (p<0.0001). By contrast, other selective (celecoxib, valdecoxib, meloxicam) and non-selective COX inhibitors (ibuprofen, naproxen, diclofenac) had no significant effect on LDL oxidation rates or plasma ORAC values, even at suprapharmacologic levels. X-ray diffraction analysis showed that sulfone COX-2 inhibitors interact differently with membrane phospholipids, suggesting a physico-chemical basis for the pro-oxidant activity. These results demonstrate that sulfone COX-2 inhibitors increase the susceptibility of biological lipids to oxidative modification through a non-enzymatic process. These findings may provide mechanistic insight into reported differences in cardiovascular risk for COX-2 inhibitors.

Animals↗
PubMed2004

The antioxidant effects of statins.

Oxidative stress contributes to the initiation and the development of atherosclerotic plaques and adversely influences myocardial integrity. Statins interfere with oxidation in several ways that may contribute to reducing the atherogenic process. In addition to direct antioxidant effects, statins reduce circulating oxidized low-density lipoproteins (oxLDL) and inhibit their uptake by macrophages. They also reduce circulating markers of oxidation such as F2-isoprostane and nitrotyrosine. Statins inhibit oxidant enzymes activity such as that of reduced nicotinamide adenine dinucleotide phosphate (NAD[P]H) oxidase and myeloperoxidase and up-regulate the activity of antioxidant enzymes such as catalase and paraoxonase. They reduce endothelial dysfunction mainly by their ability to enhance endothelial nitric oxide bioavailability, which is achieved by several mechanisms. The antioxidant properties of statins extend to organ protection especially the myocardium and the lungs.

Animals↗
PubMed2003

Cholesterol crystallization and macrophage apoptosis: implication for atherosclerotic plaque instability and rupture.

The presence of abundant cholesterol crystals symbolizes the disorder of cholesterol metabolism during the development of atherosclerosis. Examination of cultured human THP-1 macrophages treated with the cholesterol oxide, 7-ketocholesterol, revealed a concentration- and time-dependent increase in formation of cholesterol crystals in the cells. Radioisotope labeling and X-ray diffraction confirmed the presence of 7-ketocholesterol crystalline domains (d space 35.8A). Under the normal cell culture condition (5% CO(2), 37 degrees ), incubation with 7-ketocholesterol induced moderate levels of apoptosis. Elevating temperature from 37 to 40 degrees markedly reduces formation of the crystals in the macrophages. Meanwhile, at high temperatures, significantly increased numbers of apoptotic cells were detected in the cells treated with 7-ketocholesterol but not in those with native free cholesterol. These results suggest that hyperthermia inhibits cholesterol crystallization and promotes apoptotic effects of oxysterols on macrophages.

Apoptosis↗
PubMed2003

Direct evidence for cholesterol crystalline domains in biological membranes: role in human pathobiology.

This review will discuss the use of small-angle X-ray diffraction approaches to study the organization of lipids in plasma membranes derived from two distinct mammalian cell types: arterial smooth muscle cells and ocular lens fiber cells. These studies indicate that cholesterol at an elevated concentration can self-associate and form immiscible domains in the plasma membrane, a phenomenon that contributes to both physiologic and pathologic cellular processes, depending on tissue source. In plasma membrane samples isolated from atherosclerotic smooth muscle cells, the formation of sterol-rich domains is associated with loss of normal cell function, including ion transport activity and control of cell replication. Analysis of meridional diffraction patterns from intact and reconstituted plasma membrane samples indicates the presence of an immiscible cholesterol domain with a unit cell periodicity of 34 A, consistent with a cholesterol monohydrate tail-to-tail bilayer, under disease conditions. These cholesterol domains were observed in smooth muscle cells enriched with cholesterol in vitro as well as from cells obtained ex vivo from an animal model of atherosclerosis. By contrast, well-defined cholesterol domains appear to be essential to the normal physiology of fiber cell plasma membranes of the human ocular lens. The organization of cholesterol into separate domains underlies the role of lens fiber cell plasma membranes in maintaining lens transparency. These domains may also interfere with cataractogenic aggregation of soluble lens proteins at the membrane surface. Taken together, these analyses provide examples of both physiologic and pathologic roles that sterol-rich domains may have in mammalian plasma membranes. These findings support a model of the membrane in which cholesterol aggregates into structurally distinct regions that regulate the function of the cell membrane.

Arteries↗
PubMed2003

Inhibition of oxidized LDL aggregation with the calcium channel blocker amlodipine: role of electrostatic interactions.

Atherogenic low-density lipoproteins (LDL) are characterized by elevations in cholesterol content and increased electronegativity, factors that contribute to aggregation and foam cell formation. This study was designed to test the effect of the positively charged calcium channel blocker (CCB) amlodipine on the aggregation properties of oxidized LDL lipids. Large unilamellar vesicles (LUVs) (100 nm diameter) labeled with a non-exchangeable marker [3H]cholesteryl hexadecyl ether were prepared with lipids extracted from human LDL following oxidation. The LUVs were shown to bind, in a reversible fashion, to charged diethylaminoethyl Sephadex columns. The addition of amlodipine inhibited binding of the oxidized LDL lipids in a dose-dependent fashion with an IC(50) in the nanomolar range as a result of its high lipophilicity and positively charged amino group (pK(a) of 9.02). The activity of amlodipine was reproduced in model membranes that contained fixed amounts of charged phospholipid (glycerophospholipid) in a concentration-dependent manner. By contrast, drugs lacking a formal positive charge, including CCBs (felodipine, nifedipine, diltiazem, verapamil) and an angiotensin-converting enzyme-inhibitor (ramiprilate) had no effect on the column binding of the modified, electronegative lipids. These effects of amlodipine on LDL lipid aggregation and electrostatic properties may represent a novel antiatherosclerotic mechanism of action.

Amlodipine↗
PubMed2003

Atheroprotective effects of long-acting dihydropyridine-type calcium channel blockers: evidence from clinical trials and basic scientific research.

Atherosclerosis is a systemic disease that can ultimately lead to ischaemia and infarction in the heart, brain and peripheral vasculature. According to the "response to injury" hypothesis, endothelial dysfunction is the early event that allows penetration of lipids and inflammatory cells into the arterial wall, contributing to the development of the atherosclerotic lesion. Endothelial dysfunction is causally related to a variety of risk factors for atherosclerosis, including hyperlipidaemia and hypertension. Agents that restore endothelial function and NO bioavailability have beneficial anti-atherogenic activities and can improve cardiovascular outcomes; this has been observed with angiotensin-converting enzyme (ACE) inhibitors, statins and certain dihydropyridine-type calcium channel blockers (CCBs). In the Prospective Randomised Evaluation of the Vascular Effects of Norvasc Trial (PREVENT), the CCB amlodipine provided significant clinical benefits compared with placebo, including a marked reduction in cardiovascular morbidity and a reduction in the progression of carotid atherosclerosis. As these beneficial effects of amlodipine have not been observed with other dihydropyridine-type CCBs, it has been proposed that this agent has distinct anti-atherosclerotic properties related to its strong lipophilicity and membrane location. Experimental support for this hypothesis has been obtained from various in vitro and in vivo models of atherosclerosis. These findings support a broader therapeutic role for third-generation dihydropyridine-type CCBs in the treatment of atherosclerosis.

Arteriosclerosis↗
PubMed2002

Mechanisms of plaque stabilization for the dihydropyridine calcium channel blocker amlodipine: review of the evidence.

Coronary artery disease (CAD) is the consequence of atherosclerosis, a vascular disorder that is the leading cause of death and disability throughout much of the developed world. Certain cellular changes in the vulnerable atherosclerotic plaque are characterized by a loss of normal calcium regulation. This observation has led to interest in a potential antiatherogenic role for calcium channel blockers (CCBs), independent of their effects on vasodilation. The Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT) demonstrated that treatment with amlodipine, a third-generation CCB, in patients with documented CAD produced marked reductions in cardiovascular events as compared with placebo, without a reduction in coronary luminal loss. Amlodipine therapy was also associated with significant slowing in carotid atherosclerosis, an important surrogate marker for CAD, independent of blood pressure changes. The findings from PREVENT were remarkably consistent with another study known as the Coronary Angioplasty Amlodipine Restenosis Study (CAPARES). A reduction in the progression of carotid atherosclerosis has also been recently reported for lacidipine, another third-generation dihydropyridine CCB. These clinical findings have led to a renewed interest in potential plaque stabilization properties of certain CCBs, as will be systematically reviewed in this article. It is also probable that vascular protective agents, such as amlodipine may work in a synergistic fashion with other established treatments, including HMG-CoA reductase inhibitors, to effectively improve outcomes in patients who are at risk for or have established CAD.

Amlodipine↗