The Cell Biology of Atherosclerosis Heart Attacks and Strokes

In this concluding section we examine the relation between lipid metabolism and atherosclerosis, the most common cause of heart attacks and strokes. Atherosclerosis accounts for 75 percent of deaths due to cardiovascular disease in the United States. Advances in our understanding of the molecular mechanisms underlying lipid metabolism and its regulation are having an enormous effect on the treatment and prevention of this major health problem.

Frequently called cholesterol-dependent clogging of the arteries, atherosclerosis is characterized by the progressive deposition of lipids, cells, and extracellular matrix material in the inner layer of the wall of an artery. The resulting distortion of the artery's wall can lead, either alone or in combination with a blood clot, to major blockage of blood flow. Thus, to understand the cellular basis of atherosclerosis, we need to first briefly consider the structure of an artery. I

Specialized epithelial cells called endothelial cells form a thin layer, the endothelium, that lines the blood vessel wall immediately adjacent to the lumen through which the blood flows (Figure 18-19a). Beneath the endothelium are several concentric layers of extracellular matrix and cells that make up the artery wall: the intima, composed largely of amorphous collagens, proteoglycans, and elastic fibers; the media, a well-organized layer of smooth muscle cells whose contraction controls the diameter of the vessel lumen and thus influences blood pressure; and the adventitia, a layer of connective tissue and cells that forms the interface between the vessel and the tissue through which it runs.

Under normal circumstances, the plasma (the fluid part of blood) and many types of blood cells flow smoothly and rapidly through the lumen of an artery, a type of movement termed laminar flow. When an infection or traumatic damage occurs within the walls of an artery or in the underlying tissue, a complex series of events permits white blood cells (leukocytes) to initially adhere loosely to the luminal surface of the artery wall and roll, propelled by the laminar flow of the surrounding plasma (see Figure 6-30). Subsequently, adhesion molecules mediate firm attachment of the white cells to the endothelium and their movement across the endothe-lium into the wall. Within the artery wall, white blood cells called monocytes differentiate into macrophages, which fight infection in a number of ways. For instance, macrophages and other leukocytes release proteins and small molecules

(a) Normal artery wall

(b) Fatty streak stage

(a) Normal artery wall

(b) Fatty streak stage

Endothelium

Intima

Foam Rolling And Blood Clots

Media (smooth muscle cells)

Macrophage foam cell formation

White blood cells Rolling white adhere and migrate blood cell Blood flow into artery wall to fight infection

Endothelium

Intima

Adventitia

Media (smooth muscle cells)

Macrophage foam cell formation

(c) Atheroslerotic plaque stage

Fibrous cap formation

(d) Rupture of endothelium and occlusive blood clot formation

(c) Atheroslerotic plaque stage

(d) Rupture of endothelium and occlusive blood clot formation

Fibrous cap formation

Macrophage foam Formation of cell accumulation necrotic core

Occlusive blood clot

Macrophage foam Formation of cell accumulation necrotic core

Occlusive blood clot

▲ FIGURE 18-19 Major stages in the onset and progression of atherosclerosis in the artery wall. (a) The anatomy of a normal artery wall, which is composed of concentric layers of cells and extracellular matrix, is shown. White blood cells adhere to the endothelium, roll along it, and then migrate into an artery wall to fight infection (see Figure 6-30). (b) When plasma LDL is high or plasma HDL is low, or both, macrophages in the intima can accumulate lipoprotein cholesterol, generating foam cells filled with cholesteryl ester droplets (see Figure 18-20). Accumulation of foam cells produces a fatty streak in the vessel wall that is only visible microscopically. (c) Continued generation that directly attack bacteria and other pathogens. The cells also secrete proteins that help recruit additional monocytes and other immune cells (e.g., T lymphocytes) to join in the fight. Macrophages also engulf and destroy pathogens, damaged macromolecules, and infected or dead body cells. When the infection has been cured, damaged tissue is repaired and the remaining macrophages and other leukocytes move out of the artery wall and reenter the circulation.

As we will see, atherosclerosis is an "unintended" consequence of this normal physiological inflammatory response, which is designed to protect against infection and tissue damage. For this reason and because atherosclerosis most often strikes late in life after the prime reproductive years, there appears to have been little evolutionary selec-

of foam cells and migration of smooth muscle cells from the media into the intima is followed by cell death, producing an advanced atherosclerotic plaque. This plaque consists of a necrotic core of lipids (including needlelike cholesterol crystals) and extracellular matrix overlain by a fibrous cap of smooth muscle cells and matrix. (d) As an atherosclerotic plaque grows into the lumen of the artery, it disrupts and reduces the flow of blood. In some cases, the plaque alone can fully occlude the artery. In many cases, the fibrous cap ruptures, inducing formation of a blood clot that can fully occlude the artery. [Adapted from R. Russell, 1999, N. Engl. J. Med. 340(2):115.]

tive pressure against the disease. Thus, although atherosclerosis has an enormous negative influence on modern human populations, its high incidence in well-fed, long-lived persons is not surprising.

Arterial Inflammation and Cellular Import of Cholesterol Mark the Early Stages of Atherosclerosis

During an inflammatory response, macrophages in the inflamed artery wall can endocytose substantial amounts of cholesterol from lipoproteins, which accumulate within the artery wall under some circumstances (Figure 18-20a). As macrophages convert the imported cholesterol into the ester

Vascular lumen

Vascular lumen

which can mediate the efflux of excess cellular cholesterol to HDL in the intima (5). Thus the amount of cholesterol accumulation is determined by the relative uptake of LDL-derived cholesterol and efflux to HDL. (b) Micrograph of a coronary artery with an atherosclerotic plaque containing many intimal macrophage foam cells (FC) filled with spherical cholesteryl ester lipid droplets (light circles). Some smooth muscle cells also are present and also contain lipid droplets (arrow). [Part (a) adapted from C. K. Glass and J. L. Witztum, 2001, Cell 104:503. Part (b) from H. C. Stary, 2003, Atlas of Atherosclerosis Progression and Regression, 2d ed., Parthenon Publishing, p. 61.]

▲ FIGURE 18-20 Generation of macrophage foam cells in an artery wall. (a) At a site of infection or damage (1), monocytes adhere to and migrate across the activated endothelial cell layer into the intima ( 2|), where they differentiate into macrophages. When plasma LDL levels are high, the concentration of LDL in the intima is high, and some of the LDL is oxidized to oxLDL or otherwise modified (3). Scavenger receptors expressed by macrophages are proposed to bind to and endocytose oxLDL, which is degraded. Its cholesterol accumulates as cholesteryl esters in cytosolic lipid droplets, leading to an accumulation of cholesterol and the formation of foam cells (□). Macrophages also express ABCA1 and SR-BI,

which can mediate the efflux of excess cellular cholesterol to HDL in the intima (5). Thus the amount of cholesterol accumulation is determined by the relative uptake of LDL-derived cholesterol and efflux to HDL. (b) Micrograph of a coronary artery with an atherosclerotic plaque containing many intimal macrophage foam cells (FC) filled with spherical cholesteryl ester lipid droplets (light circles). Some smooth muscle cells also are present and also contain lipid droplets (arrow). [Part (a) adapted from C. K. Glass and J. L. Witztum, 2001, Cell 104:503. Part (b) from H. C. Stary, 2003, Atlas of Atherosclerosis Progression and Regression, 2d ed., Parthenon Publishing, p. 61.]

form, they become filled with cholesteryl ester lipid droplets. The resulting lipid-filled macrophages are called foam cells because the lipid droplets have a foamy appearance (Figure 18-20b). As macrophage foam cells accumulate in an artery wall, they initially form an early fatty streak, the first unique step in atherosclerosis (Figure 18-19b).

The next stage in atherosclerosis is marked by the continued accumulation of macrophage foam cells, proliferation of smooth muscle cells, and migration of these cells from the media into the intima. The smooth muscle cells secrete additional extracellular matrix, and some internalize sufficient amounts of lipoprotein cholesterol to also become foam cells. The initial macroscopically invisible early fatty streak grows bigger as the disease progresses, forming an early atherosclerotic plaque, or atheromatous plaque. Cells within the center of the plaque die, producing a necrotic core containing large amounts of cholesteryl esters and unesterified cholesterol (Figure 18-19c). Cholesterol crystals, readily detected microscopically, commonly form within a more advanced plaque, which is eventually covered by a fibrous cap composed of smooth muscle cells and collagen.

Atherosclerotic Plaques Can Impede Blood Flow, Leading to Heart Attacks and Strokes

As an atherosclerotic plaque expands, it projects farther and farther into the lumen of the vessel, narrowing the lumen and distorting the normal shape of the endothelium lining the vessel. Because blood flow through the affected artery is reduced and disturbed, the rate of delivery of nutrient-rich, oxygenated blood to tissues fed by the artery decreases, a condition known as ischemia. If sufficiently severe, such partial starvation of the heart can cause pain (angina).

If the endothelial lining covering a plaque ruptures, a large platelet and fibrin blood clot (thrombus) can form very rapidly and block or occlude the artery (Figure 18-19d and Figure 18-21). Tissue downstream of an occlusion soon becomes depleted of oxygen (ischemic hypoxia) and energy sources (e.g., fatty acids in the adult heart, glucose in the brain). The extent of damage, including tissue death, caused by a severe occlusion depends on the length of time that the artery is occluded and the size of the affected area. Severe occlusion of a coronary (heart) artery can cause a mj

▲ EXPERIMENTAL FIGURE 18-21 Atherosclerosis narrows and blocks blood flow through coronary arteries. X-ray multi-slice computed tomographic image of a human heart reveals a major occlusion (black arrow) of the left anterior descending artery (LAD, arrow) and a narrowing of a nearby vessel (white arrow) as a block in the stream of blood (seen in the arteries as a white tube). [From K. Nieman et al., 2001, Lancet 357:599.]

heart attack; occlusion of an artery feeding the brain can cause a stroke.

Atherosclerosis can begin at or even before puberty but usually takes decades to develop into overt disease. In some cases, the growth of new blood vessels permits sufficient blood flow to tissue downstream of a plaque so that major tissue damage does not occur. Balloon stretching, removal of plaques, insertion of metal scaffolds (stents), and grafting of a bypass vessel are among the surgical treatments for advanced blockage of coronary arteries.

Your Heart and Nutrition

Your Heart and Nutrition

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