SSCI Meeting Highlights: Oxidative Stress and Cardiology Injury Symposium
Oxidized Low-Density Lipoprotein and Atherosclerosis Implications in Antioxidant Therapy

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Abstract

Low-density lipoprotein (LDL)-cholesterol is important for cellular function, but in high concentrations, it can lead to atheroma formation. Over the past several decades, it has become abundantly evident that the oxidized form of LDL-cholesterol (ox-LDL) is more important in the genesis and progression of atherosclerosis than native unmodified LDL-cholesterol. Ox-LDL leads to endothelial dysfunction, an initial step in the formation of an atheroma. Ox-LDL acts via binding to a number of scavenger receptors (SR), such as SR-A1, SR-A2 and lectin-like oxidized low-density lipoprotein receptor (LOX-1). Ox-LDL can upregulate expression of its own receptor LOX-1 on endothelial cells and activate these cells. In addition, ox-LDL promotes the growth and migration of smooth muscle cells, monocytes/macrophages and fibroblasts. Ox-LDL also leads to the generation of reactive oxygen species that in physiologic concentrations combat invasion of the body by noxious agents, but when in excess, can lead to a state of oxidative stress. There is evidence for the presence of oxidative stress in a host of conditions such as atherosclerosis and aging. In this review, we discuss the role of oxidative stress, ox-LDL and LOX-1 in atherogenesis and the reasons why the traditional approaches to limit oxidant stress have not been successful.

Section snippets

ATHEROMA FORMATION

The first step in atherogenesis is the formation of fatty streaks, which are small subendothelial deposits of monocyte-derived macrophages rich in ox-LDL. Ox-LDL is taken up by specialized receptors on endothelial cells and induces endothelial activation and injury.3 The initial damage to endothelial cells by ox-LDL results in the expression of adhesion molecules leading to recruitment of monocyte and their migration to subendothelial layers. These monocytes differentiate into macrophages in

FORMATION OF OX-LDL

Ox-LDL is a more potent pro-atherosclerotic mediator than native unmodified LDL.4 Several reactive oxygen species (ROS) can initiate lipid peroxidation leading to activation of native unmodified LDL resulting in the formation of ox-LDL. These include reactions involving multiple enzyme systems like nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (generates superoxide anion),5 mitochondrial electron transport enzymes,6 xanthine oxidase,7 lipoxygenase,8 cyclooxygenase,9

OX-LDL AND ATHEROSCLEROSIS

Ox-LDL plays a central proatherogenic role in the arterial wall13., 14., 15. (Table 1; Figure 1). Kita et al35 established the importance of ox-LDL in atherosclerosis by using antioxidant probucol in atherosclerosis-prone hyperlipidemic Wanatable heritable hyperlipidemic rabbits. This study showed the significance of oxidative state in atherogenesis. Now, it is well known that ox-LDL–induced pro-oxidant state is present in all stages of atherosclerosis from beginning to the acute thrombotic

ROLE OF LOX-1 IN ATHEROGENESIS

Ox-LDL acts via binding to a number of scavenger receptors (SR), such as SR-A1, SR-A2 and LOX-1. Lately, LOX-1, a type II membrane protein ox-LDL receptor with a C-type lectin-like extracellular domain and a short cytoplasmic tail has gained much importance in the effects of ox-LDL on endothelial biology because these cells primarily express LOX-1 as receptor for ox-LDL.16., 38., 39. This receptor was initially identified in endothelial cells, but later was also found to be expressed in

INTERACTION BETWEEN OX-LDL AND ANG II

Both Ang II and ox-LDL are important factors in inducing endothelial dysfunction and injury. Ang II, which is highly expressed in the growing atheroma, shares many of the properties of ox-LDL (Table 2; Figure 1). The effects of Ang II seem to be mediated by activation of its type 1 receptor (AT1R).61 There is ample experimental evidence that ox-LDL upregulates AT1R mRNA via NADPH oxidase-mitogen-activated protein kinase-nuclear factor-kappaB pathway and that Ang II in a positive feedback

Angiogenesis

There is much interest in the process of angiogenesis in atherosclerosis that may have important clinical consequences. Dandapat et al24 showed that small concentrations of ox-LDL (<5 μg protein/mL) promote capillary tube formation by inducing low levels of ROS release via LOX-1–mediated activation of NADPH oxidase-mitogen-activated protein kinases-nuclear factor-kappaB-vascular endothelial growth factor pathway. Progressive angiogenesis in a primary atherosclerotic lesion may cause plaque

EVIDENCE OF OXIDATIVE STRESS IN HUMANS

A host of studies have shown evidence for increased oxidant stress in all risk factors for atherosclerosis, including diabetes mellitus, hypertension, dyslipidemia, smoking, hyperhomocysteinemia and obesity.2., 75., 76. Here, we mention some of the studies that indicate increased oxidant load in these patients:

  • 1.

    There is increased oxidation of LDL-cholesterol in subjects with subclinical or clinical atherosclerosis.

  • 2.

    The ox-LDL levels in serum are increased in patients with ischemic heart disease

USE OF ANTIOXIDANTS IN HUMANS

Numerous cellular antioxidant systems exist to defend against the oxidant stress and to maintain the normal redox balance of cells in our body. ROS are cleared from cells by enzymatic and nonenzymatic systems. Enzymatic systems include superoxide dismutases,87., 88. catalase88 and glutathione peroxidase.89., 90. The nonenzymatic systems include alpha tocopherol (vitamin E), ascorbic acid (vitamin C), glutathione and uric acid. Because ROS are widely involved in progression of atherosclerosis,

WHY HAVE ANTIOXIDANT STRATEGIES FAILED IN HUMANS?

The reasons for the absence of the beneficial effects of antioxidants in disease states related to atherosclerosis are many-fold and essentially unknown. Some of the following may be plausible reasons for the absence of beneficial effect:

  • 1.

    Antioxidants may need to be used for long time for the desired effects to be manifest.

  • 2.

    Antioxidants may need to be given before the disease process starts or becomes established.

  • 3.

    Antioxidants, such as vitamin E, may become oxidized and lose their efficacy as

CONCLUSIONS ON THE ROLE OF OXIDATION HYPOTHESIS IN ATHEROGENESIS

Oxidant load, present in coronary artery disease risk factors, induces adverse effects on different cells of arterial walls resulting in atherosclerosis. Oxidant species oxidize n-LDL, and ox-LDL acts on cells of the arterial wall via LOX-1 and other scavenger receptors. Oxidant species and ox-LDL transform monocytes into macrophages and then foam cells. ROS also induce platelet activation, a common event in the precipitation of an ischemic event. Accordingly, ROS inhibitory strategies may be

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    Presented as a State-of-the-Art Lecture at the Southern Society for Clinical Investigation Cardiovascular Club Session, February 18, 2011, New Orleans, LA.

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