Oxidation of Low-Density Lipoprotein in Atherosclerosis from Basic Biochemistry to Clinical Studies

Abstract

Although it has been known for long time that atherosclerosis is associated with lipid deposition, only recently it has been accepted that the plasmatic concentration of cholesterol, especially LDL cholesterol, is a risk factor for atherosclerosis. However, chemically modified LDL, but not native LDL, is able to induce the formation of foam cells, the hallmark of atherosclerosis. LDL oxidation is likely to be the most important form of LDL modification in humans. In biochemical terms, LDL oxidation is a free radical driven chain reaction where polyunsaturated fatty acids are converted to lipid peroxides, which easily decompose to many products, including biologically active aldehydes. The assay of LDL oxidation in biological fluids is problematic; direct assays detect a product of LDL oxidation whereas indirect assays give an indicator of LDL oxidation susceptibility. In general, epidemiological studies support the concept that the level of plasmatic lipophilic antioxidants, tocopherols and carotenoids, is low in populations at increased risk for atherosclerosis. However, clinical trials based on vitamin E as antioxidant showed inconclusive results, suggesting that supplementation with vitamin E is not generically recommended for atherosclerotic patients. These results, however, do not contradict that oxidation of lipoprotein is involved in atherosclerosis; rather, this negative outcome raises a number of considerations such as the need for a reliable marker of lipoprotein oxidation in plasma and a more complete information about the physiological triggers of lipoprotein oxidation.

Redox Mechanisms in Blood Vessels

“…The best-characterized of these events is oxidative modification of low-density lipoprotein, which can occur via reaction of ROS with low-density lipoprotein or via direct enzymatic modification by lipoxygenases. 7 Beyond this, ROS can promote inflammation, 8 alter vasomotion, 9 activate matrix metalloproteinases, 10 induce apoptosis, 11 cause platelet aggregation, 12 and stimulate vascular smooth muscle proliferation. 13 All of these events are active in the atherosclerotic lesion and are thought to contribute to vascular lesion formation.…”

Antioxidant Effects of Statins in the Management of Cardiometabolic Disorders

“…Inflammatory markers shown to be elevated in patients with CVD include the levels of C-reactive protein, interleukin-8 (IL8), monocyte chemoattractant protein-1 (MCP1) and tumor necrosis factor-α (TNFα), all of which play a crucial role in recruiting neutrophils,T lymphocytes andmonocytestothevascularwall 36,37) .Inaddition, increasedCD40-CD40ligandinteractionsresultina prothrombotic state 38) , while increased matrix metalloproteinasesleadtoplaquerupture 39) . Manyinflammatoryprocessesareinvolvedinthe productionandactionsofROSbyNAD(P)Hoxidase inthevascularwallcell 9) .Forexample,nuclearfactor (NF)-κB,atranscriptionfactorthatplaysakeyrolein theexpressionof proinflammatorycytokines,ispositivelyregulatedbyROS 40) .Consistentwiththisobservation, dimethyl sulfoxide (DMSO), a scavenger of ROS, inhibits the release of proinflammatory cytokines 41) ,whereasROScontributetotheformationof oxidizedLDL,whichinturnsleadstothedeposition of foam cells in atherosclerotic plaques 10) .Therefore, oxidativestressandinflammationareimportantcausative factors for atherosclerotic vascular diseases, particularlyunderconditionsofdiabetes 42) .…”

“…LDL oxidation is a key player in the initiation American College of Cardiology guidelines recommendtheadministrationofhigh-intensitystatintherapyandextenditsusetoindividualsatriskofvascular disease 8) .Onepossibleeffectofstatinsistheirability to reduce reactive oxygen species (ROS) production and/oractivity,whichhasthepotentialtoinhibitthe development of atherosclerosis, independent of LDL reduction 9,10) . In addition, several studies have demonstrated the antioxidative properties of statins 6,11) , andithaspreviouslybeenshown,bothinvitroandin vivo, that statins inhibit lipid and lipoprotein oxidation, thereby suppressing ROS formation and/or bluntingthedamagingeffectsoftheseradicals 6,12) .…”

“…Oxidatively modified LDL, or oxidized LDL, is involved in the early development of atherosclerotic lesions 14) . Several in vitro studies have shown that lipid-laden foam cells are formed after macrophages take up oxidized LDL 10,28,29) . In addition, the presence of lipid-laden foam cells is a typical feature of vulnerable atherosclerotic lesions.Therefore, the oxidativemodificationofLDLplaysaroleinthedevelopmentofatheroscleroticlesionsviatheformationof foamcells 13) .Recentevidenceindicatesthatmodified apolipoproteinBderivedfromoxidizedLDLaccumulates in foam cells 29) .…”

In vitro and in vivo protective action of ethanolic extract of Triphala on LDL against glycation-oxidation

“…LDL modifications (oxidation and glycation) are strongly related to diabetic complications, atherosclerosis, and other cardiovascular diseases (Lyons, 1993;Hunt, 1991;Li et al, 1996;Picard, 1995). Glycated LDL is more susceptible to oxidation than unglycated LDL, and oxidized LDL is more prone to modification by glycation (Picard, 1995;Albertini et al, 2002). Oxidation of LDL is crucial in plaque formation and onset of atherosclerosis (Steinberg, 1997).…”