Lowdensity lipoprotein oxidation modification and retention

As illustrated in Figure 5, remodeled and modified LDL particles accumulate in the intima below the vascular endothelium. Oxidized LDL (oxLDL) forms as minimally modified LDL (mmLDL) is subject to oxidation by a variety of chemical oxidants and enzymes. Both oxLDL and mmLDL are cytotoxic to cells and inhibit the migration of the macrophage out of the extravascular space. Several proinflammatory oxidative enzymes have been implicated in this process, including: 5-lipoxygenase (5-LO), 15-lipoxygenase (15-LO), and myeloperoxidase (MPO). Hypochlorous acid (HOCl) and RNS generated from MPO cause chemical modifications to the apoB protein by introducing specific changes in tyrosine and cysteine residues.18 MPO-mediated HOCl also oxidizes the polyunsaturated fatty acids contained in the LDL lipid core. Elevated plasma levels of MPO have been positively correlated with an increased cardiovascular risk, while individuals with MPO deficiency display a significantly reduced risk.18

Similarly, 5-LO and 15-LO also oxidize unsaturated fatty acids bound to surface PL, generating oxidized PL (oxPL) or oxidize polyunsaturated arachidonic acids found within or released from the mmLDL particle by the action of PLA2, creating a number of reactive fatty acid hydroperoxide species. These hydroperoxides act as a source of damaging free radicals by propagating radical chain reactions within the tissue. OxPL species are found in both early- and late-stage atheroma tissue, suggesting that they contribute to all phases of disease progression.19 The transformation of arachidonic acid by 5-LO initiates the leukotriene biochemical cascade (Figure 6) that produces the powerful

Figure 5 An illustrated model of atherosclerosis as an inflammatory disease. Modified LDL is oxidized by MPO and ROS (red circles), activating endothelial cells to express cell adhesion molecules and recruit monocytes and Tcells. Oxidized LDL induces cytokine and chemokine (blue diamonds) expression to magnify the inflammatory response, leading to macrophage activation and more ROS production. The activated macrophages secrete other inflammatory mediators, accumulate additional lipid, and develop into foam cells. ROS and inflammatory mediators induce SMC activation and migration. (Reprinted with permission by Keith Kasnot.)

Figure 5 An illustrated model of atherosclerosis as an inflammatory disease. Modified LDL is oxidized by MPO and ROS (red circles), activating endothelial cells to express cell adhesion molecules and recruit monocytes and Tcells. Oxidized LDL induces cytokine and chemokine (blue diamonds) expression to magnify the inflammatory response, leading to macrophage activation and more ROS production. The activated macrophages secrete other inflammatory mediators, accumulate additional lipid, and develop into foam cells. ROS and inflammatory mediators induce SMC activation and migration. (Reprinted with permission by Keith Kasnot.)

chemoattractant, LTB4, which plays a key role in SMC migration. Both oxPL and oxLDL are injurious to the endothelial lining, increase the secretion of superoxide anion, and activate the endothelial cells to express surface cell adhesion molecules, notably vascular cell adhesion molecule-1 (VCAM-1). Cell adhesion molecules act as coreceptors for VLA-4 integrins found on the surfaces of monocytes and T cells. The resulting specific interaction between cell adhesion molecules and integrins captures the rolling leukocytes and facilitates their localization and recruitment through the endothelial lining. Similarly, activated monocytes, macrophages, and SMC secrete ROS and RNS in response to oxLDL and oxPL, thus perturbing the delicate redox balance of the surrounding tissue.

Activated endothelial cells and monocytes secrete both chemokines20 (e.g., monocyte chemoattractant protein-1 (MCP-1)) and several common proinflammatory cytokines (e.g., tumor necrosis factor alpha, (TNF-a)). Whereas MCP-1 is secreted into the bloodstream, fractalkine (CX3CL1) is a membrane-bound chemokine and adhesion molecule, expressed on the activated endothelium. Both MCP-1 and fractalkine act as powerful chemotactic agents that recruit more monocytes/macrophages and T cells to the atherosclerotic site. TNF-a activates VCAM-1 expression and contributes to the maintenance of the inflammatory cascade.

As more cholesterol-rich mmLDL particles are taken up by phagocytosis or endocytosis within the monocytes, the intracellular cholesterol concentration increases as FC is converted to cholesteryl ester through the action of ACAT-2 within the macrophage. The resulting activated macrophages, which are transformed into developing foam cells, secrete proteases, inflammatory cytokines, and ROS to promote the inflammatory response. Many of these same inflammatory mediators also induce profound changes to the fibrous cap covering the mature lesion. These mediators induce the expression of matrix-degrading metalloproteinases that weaken the overlying extracellular matrix and create a lesion more susceptible to rupture. Both plasma MPO18 levels and the expression of 5-LO21 within atheroma have been positively correlated with increased vulnerability to plaque instability and rupture.

The altered redox state due to inflammation at the atherosclerotic site also changes HDL functionality. For example, apoA-I is a specific target for MPO-catalyzed oxidation of HDL, producing chemical modifications of key tyrosine residues. These changes significantly reduce the capability of the oxidized HDL particle to participate in ABCA1-mediated cholesterol efflux from macrophages.16'18 MPO dramatically alters the delicate balance between

Phospholipids in cellular membranes Phospholipase A2

Was this article helpful?

0 0
Your Heart and Nutrition

Your Heart and Nutrition

Prevention is better than a cure. Learn how to cherish your heart by taking the necessary means to keep it pumping healthily and steadily through your life.

Get My Free Ebook


Post a comment