Atherosclerosis no longer a bland lipidstorage disease

Only a few decades ago the prevailing postulate regarding the pathogenesis of atherosclerosis predicated a proliferation of smooth muscle cells (SMCs) leading to a fibrous stenotic lesion that surrounded a "necrotic core" of deposited cholesterol and cholesteryl esters (1). A combination of observations on experimental atherosclerosis and study of human atherosclerotic lesions has added to this traditional model of atherogenesis by encompassing inflammatory processes. Early after initiation of a diet enriched in cholesterol and saturated fat, sites in the arteries of experimental animals begin to recruit inflammatory leukocytes from the blood (2). The normal endothelial cell (EC) either in situ or in the laboratory resists adhesive interactions with leukocytes derived from blood. How ever, cultured ECs stimulated by proinflammatory cytokines express on their surface adhesion molecules that capture leukocytes and bind them to the endothelial surface. Soon after initiation of a hypercholesterolemic diet, the arteries of susceptible animal species display augmented expression of a variety of leukocyte adhesion molecules, including vascular cell adhesion molecule-1 (VCAM-1) and P-selectin. In rabbits that consume an atherogenic diet, expression of the adhesion molecule VCAM-1 precedes the accumulation of leukocytes in the intima (3). Atherosclerotic mice expressing a mutated form of VCAM-1 that inhibits its leukocyte-binding function show blunted atherosclerotic lesion formation (4). Interestingly, VCAM-1 binds just those types of white blood cells found in early atherosclerotic lesions in both experimental animals and humans, i.e., mononuclear phagocytes and T-lymphocytes. Thus, the transition of the normal artery to the nascent atherosclerotic lesion fundamentally depends on the recruitment of blood leukocytes to initiate and later perpetuate an inflammatory response.

Once bound to the endothelial surface, the leukocyte requires a chemoattractant signal to direct its migration into the subendothelial intimal layer, the site of the atherosclerotic lesion. Multiple proinflammatory cytokines probably participate in this process. First and foremost, monocyte chemoattractant protein-1 (MCP-1) promotes transmigration ofmono-nuclear leukocytes. Intrinsic vascular wall cells, endothelium, and smooth muscle can produce MCP-1. Observations in experimental and human atherosclerotic lesions have documented overexpression of MCP-1 compared to normal arteries. Experiments in genetically altered mice have shown that loss of MCP-1 function, or that of its receptor chemokine receptor-2, can inhibit experimental atherogenesis (5,6). Other chemoattractant cytokines such as fractalkine and interleukin (IL)-8 may also direct the migration of adherent leukocytes during atherogenesis (7,8). In combination, these observations highlight the importance of chemoattractant cytokines as participants in the atherosclerotic process.

Once resident in the arterial intima, mononuclear phagocytes change their character and acquire the characteristics of foam cells. After penetrating into the intima, the blood monocyte expresses scavenger receptors, allowing it to take up modified lipoproteins that accumulate in the subendothelial space. The scavenger receptors evade the usual homeostatic suppression by excessive cholesterol characteristic ofthe classic low-density lipoprotein (LDL) receptor. This untrammeled ability to take up lipoproteins leads to the formation of lipid-laden macrophages known as foam cells, the hallmark of the early atherosclerotic lesion, also known as the fatty streak. Macrophages within the artery wall can also divide and elaborate reactive oxygen species and proinflammatory cytokines that can sustain and amplify intimal inflammation (9,10). Several proinflammatory mediators likely participate in signaling proliferation and activation of the macrophages present in the plaque. One prominent candidate, macrophage colony-stimulating factor (M-CSF), clearly plays a pathogenic role in experimental atherosclerosis. Animals that lack M-CSF show impaired lesion formation in response to atherogenic diets (11,12). This inhibition of atherogenesis occurs despite an increase in plasma cholesterol levels. Human and experimental atherosclerotic plaques overexpress M-CSF (13,14). In vitro, M-CSF can serve as a comitogen for macrophages and stimulate the expression of scavenger receptors by these inflammatory cells (13). Taken together, these observations provide strong evidence for the participation ofinflammatory cells and mediators that attract and stimulate them in atherogenesis (Fig. 1A-D).

Fatty streaks alone do not threaten human health. Rather, clinical events arising from more complicated atherosclerotic lesions often evolve from fatty streaks. This transition

Fig. 1. (A) Normal human artery, including endothelial surface lining lumen, underlying intimal layer, and subjacent tunica media. (B) The endothelial cells exposed to inflammatory mediators express leukocyte adhesion molecules, indicated by the frondlike structures on their lumenal surface. These adhesion molecules engage cognate receptors onblood leukocytes, tethering them and causing them to attach to the endothelial surface.

Fig. 1. (A) Normal human artery, including endothelial surface lining lumen, underlying intimal layer, and subjacent tunica media. (B) The endothelial cells exposed to inflammatory mediators express leukocyte adhesion molecules, indicated by the frondlike structures on their lumenal surface. These adhesion molecules engage cognate receptors onblood leukocytes, tethering them and causing them to attach to the endothelial surface.

from fatty streak to fibro-fatty lesion involves the participation of SMCs. The normal human coronary arterial intima contains resident SMCs. The tunica media that underlies the intimal layer ofarteries contains abundant SMCs. Inflammatory mediators can promote the migration of medial SMCs into the intima. Inflammatory mediators can also heighten the expression of growth factors such as platelet-derived growth factor (PDGF) and forms

Fig. 1. ( C) Chemoattractant cytokines such as MCP-1, fractalkine, and IL-8 signal leukocytes to penetrate through the endothelial layer into the intima by diapedesis. (D) Once resident in the intima, blood monocytes express scavenger receptors, engulf lipoprotein particles, and become foam cells, the hallmark of the fatty streak, the precursor of complicated atherosclerotic lesions. Macrophages in the plaque can also replicate. Inflammatory mediators such as M-CSF can promote scavenger receptor production and proliferation of the lesional macrophages within atheromata.

of fibroblast growth factor that can augment SMC migration and proliferation. Interruption ofinflammatory signaling pathways such as the CD40 ligand (CD40L)-CD40 dyad can limit the formation of fibrous plaques, a key component of the progression of atherosclerotic lesions. Indeed, interruption of CD40 signaling in animals with established atherosclerotic lesions can halt the progression of lesions (15,16). These observations sup port the participation of inflammatory signaling pathways in the progression phase of atherogenesis.

Was this article helpful?

0 0
Lower Your Cholesterol In Just 33 Days

Lower Your Cholesterol In Just 33 Days

Discover secrets, myths, truths, lies and strategies for dealing effectively with cholesterol, now and forever! Uncover techniques, remedies and alternative for lowering your cholesterol quickly and significantly in just ONE MONTH! Find insights into the screenings, meanings and numbers involved in lowering cholesterol and the implications, consideration it has for your lifestyle and future!

Get My Free Ebook


Post a comment