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Endothelium and acute coronary syndromes.

The vascular endothelium is the inner lining of blood vessels and serves as an important autocrine/paracrine organ that regulates vascular wall contractile state and cellular composition (1,2). Because of its strategic location between the circulation and the vascular wall, the endothelium interacts with both cellular and hormonal mediators from these two compartments. There is growing evidence that endothelial dysfunction, which is often defined as the decreased synthesis, release, and/or activity of endothelial-derived nitric oxide (NO), [1] is an important factor leading to atherosclerosis and acute coronary syndromes (3,4). This realization, in part, is because the lack of NO in atherosclerotic vessels contributes to impaired vascular relaxation (5,6), platelet aggregation (7), increased vascular smooth muscle proliferation (8), and enhanced leukocyte adhesion to the endothelium (9,10). Indeed, vasoconstriction, platelet activation, and thrombosis caused by the rupture of atherosclerotic plaques are primary features of acute coronary syndromes (11,12).

In addition to endothelial dysfunction, another important feature of atherosclerotic vessels is endothelial cell activation (13,14). The activated endothelium expresses cell-surface adhesion molecules such as vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule-1, and endothelial-leukocyte adhesion molecule (E-selectin), which facilitate the attachment of circulating leukocytes to the endothelium (15). Monocyte adhesion to the vessel wall and its subsequent differentiation into macrophages are crucial events leading to the development of macrophage-derived foam cells in atherosclerotic plaques (16,17). Cytokines, oxidized low-density lipoproteins (ox-LDL), and infectious agents such as cytomegalovirus and Chlamydia pneumonia promote vascular oxidation and inflammation, which lead to endothelial cell activation (18-21). Thus, endothelial dysfunction and activation caused by coronary risk factors and vascular inflammation are the basis for the development of atherosclerotic lesions and acute coronary syndromes (Fig. 1).

Endothelial Function

The endothelium produces vasoactive substances in response to environmental factors such as blood flow, oxygen tension, and receptor-mediated stimulants (Table 1) (22-24). Endothelial function is usually determined by vessel diameter, vascular contractility, or blood flow in response to endothelium-dependent agonists such as acetylcholine or bradykinin. Changes in vessel diameter are determined by angiography or ultrasonography, whereas alterations in blood flow or vascular resistance are determined by forearm or lower extremity strain-gauge plethysmography. Vascular contractility is measured by force transducers in an in vitro bioassay organ chamber.

Endothelium-dependent vascular relaxation is predominantly mediated by NO, and to lesser degrees, by prostacyclin and activators of ATP- and calcium-sensitive potassium channels (i.e., hyperpolarizing factor). Endothelium-derived vasoconstrictitioe substances include endothelin (ET)-1 and thromboxane A2. The balance between these opposing endothelium-derived vasoactive substances under nonpathological and pathological conditions ultimately determines the contractile and perhaps the mitogenic state of the underlying vascular smooth muscle.

[FIGURE 1 OMITTED]

Endothelium-derived NO or a closely-related molecule was initially described as endothelium-derived relaxing factor (EDRF) (25-27). The activity of endothelium-derived NO plays an important physiological role in the regulation of blood pressure and blood flow and has been widely used as a clinical marker of endothelial function. Endothelial dysfunction or the lack of EDRF is often associated with cardiovascular diseases such as hypertension, atherosclerosis, and congestive heart failure (28-30). The mechanism by which NO causes vasodilation is well known and occurs through the stimulation of soluble guanylyl cyclase activity in vascular smooth muscle. However, there is growing evidence that NO may exert other effects on the cardiovascular system independent of cyclic GMP (31,32). As a result, the functional roles of NO in the cardiovascular system have expanded beyond those of a vasodilator.

NO is synthesized in many cell types from the conversion of L-arginine to L-citrulline (33). At least three distinct NO synthases (NOSs) have been identified and found to produce various amounts of NO under different conditions (Table 2) (34-36). For example, both the neuronal (Type I nN05) and endothelial (Type III eN05) isoforms are calcium-dependent and produce low concentrations of NO constitutively; whereas, sustained, high concentrations of NO are produced by macrophages or smooth muscle (Type II iN05) only after induction by certain cytokines. Such unique differences in the regulation and localization of these NOSs may underlie their importance and contributions in the cardiovascular system.

Vessels affected by atherosclerosis develop endothelial dysfunction, as indicated by impaired vasomotor function because of loss of endothelium-derived NO activity (25,37). It remains uncertain whether this aspect of endothelial dysfunction serves merely as a marker for atherosclerosis or is an important contributor to the atherogenic process. Growing evidence, however, indicates that NO exerts antiatherogenic and antiinflammatory actions. As previously mentioned, the loss of endothelium-derived NO activity contributes to impaired vascular relaxation (19,37), enhanced platelet aggregation (7,38), increased vascular smooth muscle proliferation (8), and greater endothelial-leukocyte interactions (9, 10,39). Mutant mice lacking endothelial NOS have hypertension and develop greater proliferative and inflammatory vascular response to cuff injury (40,41). Furthermore, inactivation of endothelium-derived NO by superoxide anion ([O.sub.2.sup.-]) limits the bioavailability of NO and leads to nitrate tolerance, vasoconstriction, and hypertension (42,43).

In contrast, in vivo transfer of the endothelial NOS gene into balloon-injured rat carotid arteries decreases intimal smooth muscle cell proliferation (44). Enriching the diets of cholesterol-fed rabbits with L-arginine, the precursor of NO, improves endothelium-dependent relaxation, reduces leukocyte attachment to the endothelial surface, and limits the extent of atherosclerotic lesions (45, 46). Indeed, a single bolus treatment of a NO-generating compound, S-nitrosothiol, inhibits intimal smooth muscle proliferation in the balloon-injured rabbit carotid artery (47). Taken together, these studies suggest that endothelial function as defined by NO production and/or bioavailability may play an important role in suppressing the atherosclerotic process.

Endothelial dysfunction may also be attributed to abnormal or excessive release of vasoconstricting substances such as ET-1 (48). Indeed, circulating concentrations and tissue immunoreactivity of ET-1 are increased in patients with advanced atherosclerosis and acute coronary syndromes (49,50). Whereas NO is vasodilatory and antiproliferative in its effects on the underlying vascular smooth muscle, ET-1 is vasoconstrictive and mitogenic. Exposure to cardiovascular risk factors such as oxidized LDL enhances the production and release of ET-1 (51). Increased ET-1 concentrations in combination with platelet-derived growth factors promote vascular smooth muscle proliferation in the neointima of atherosclerotic lesions (52). Although definitive proof that ET-1 is a primary inducer of atherosclerosis is still elusive, it is highly likely that ET-1 is at least an important contributor to the atherogenic process.

Atherogenic Risk Factors and Endothelial Function

Numerous studies demonstrate that endothelial dysfunction is one of the earliest manifestations of atherosclerosis even in the absence of angiographic evidence of disease (53-55). Conversely, improved endothelial function is one of the earliest clinical markers of atherogenic risk factor modification. There is a strong association between atherogenic risk factors and endothelial dysfunction (Table 3). For example, LDL, especially oxidized LDL, is a potent inhibitor of endothelial function (56). The mechanisms by which LDL inhibits endothelium-derived NO activity include down-regulation of endothelial NOS expression (57), decreased receptor-mediated NO release (58), and NO inactivation via increases in superoxide anion production (59). Indeed, endothelial dysfunction is a hallmark of hypercholesterolemia and rapidly improves with cholesterol reduction (60,61).

Large clinical studies has shown beneficial effects of cholesterol reduction on cardiovascular mortality even in patients with average cholesterol concentrations (62-64). Furthermore, endothelial dysfunction correlates with male gender, increasing age, hypertension, and diabetes mellitus (65-67). The association between atherogenic risk factors and endothelial dysfunction is corroborated by studies demonstrating that endothelial function improves after risk factor modifications such as cholesterol reduction, smoking cessation, and estrogen replacement

therapy (60,61,68,69).

Morphologic and Functional Stages of Atherosclerosis

The current model of atherogenesis is based on the "response to injury[degrees] hypothesis (70). The basic tenet is that injury to the endothelium by local disturbances of blood flow at certain branch points of the arterial tree coupled with systemic factors such as hypercholesterolemia, hyperglycemia, cigarette smoking, and microbial infections initiates a cascade of events that ultimately leads to the development of the atherosclerotic lesion (Fig. 2) (11,12). During the early phase of atherosclerosis, there is absence of gross morphologic changes within the vessel wall, except for isolated macrophages containing minimal oxidized lipid droplets. However, in this early Type I lesion, some activation of endothelial cells and impairment of endothelium-dependent vasodilation can be demonstrated in the absence of gross endothelial cell damage.

Endothelial dysfunction and endothelial cell activation lead to increased platelet aggregation and enhanced leukocyte adhesiveness to the vessel wall (71,72). In response to lipids, especially in the oxidized form (i.e., oxidized LDL), vascular endothelial and smooth muscle cells secrete monocyte chemotactic protein-1 and macrophage colony-stimulating factor (M-CSF or CSF-1), which promote monocyte chemotaxis, adhesion, and differentiation into macrophages (16,17). Macrophages in the vessel wall avidly accumulate oxidized lipids. Lipid accumulation in macrophage-derived foam cells and vascular smooth muscle cells form the fatty streak that is characteristic of Type II lesions. The endothelium in Type II lesions is morphologically intact although its function is impaired.

[FIGURE 2 OMITTED]

In Type III or intermediate lesions, lipid accumulation begins to overwhelm the uptake by macrophage-derived foam cells, and small extracellular lipid pools appear within the vessel wall. In addition, macrophage-derived cytokines, platelet-derived growth factors such as platelet-derived growth factor and transforming growth factor-[beta]1, and lipid pools stimulate the proliferation and migration of adjacent smooth muscle cells, forming the intimal layer of atherosclerotic lesions. Although Type III lesions possess lipid-laden macrophages and exhibit intimal smooth muscle proliferation, these lesions rarely encroach substantially on the vascular lumen because of compensatory dilatation of the vessel wall.

When the small extracellular lipid pools in the intima of a Type III lesion coalesce into a more organized dense lipid collection or lipid core, the lesion is sufficiently advanced to be classified as a Type IV lesion, or atheroma. Between the lipid core and endothelium of the atheroma is the proteoglycan-rich intimal layer containing mostly smooth muscle cells and macrophages and, to a lesser extent, T lymphocytes and mast cells. These inflammatory cells are concentrated particularly in the lateral or "shoulder" region of the atheroma. Fibrosis is not a predominant feature of Type IV lesions, and therefore, the atheroma is structurally weak and may be susceptible to fissuring from mechanical or tensile forces. Again, the endothelium covering the atheroma is functionally impaired with respect to NO release, allowing continued monocyte adhesion and influx into the vessel wall.

If the atheroma does not fissure, the smooth muscle cells within the intima will lay down collagen, forming a dense fibrous cap characteristic of a Type V lesion or fibroatheroma. Often the proliferation of intimal smooth muscle cells and the formation of connective fibrous tissue exceed the thickness of the underlying lipid core and cause substantial diminution of the vascular lumen. These fibrous plaques may sometimes become calcified, where mineralization may replace the entire lipid core. The stability of Type V lesions depends on the strength and thickness of the fibrous cap relative to the size of the lipid core. If the fibroatheroma is weakened by increased tensile forces or by enzymatic degradation of the fibrous cap by metalloproteinases such as collagenase, gelatinase, and elastase, then the plaque may rupture and expose highly thrombogenic material from its lipid core. This results in the complicated Type VI lesions, where hemorrhage-hematoma and thrombus formation may eventually occlude the vascular lumen, giving rise to acute coronary syndromes.

The morbidity and mortality associated with atherosclerosis are predominantly because of the rupture of Types IV and V lesions, with ensuing hematoma and thrombus formation, which occludes the vessel lumen (73). In most cases, the vessel repairs itself without major sequelae to the individual, although the atherosclerotic lesion develops surface defects, hematoma, and ulcerations, which can further compromise blood flow. In most myocardial infarctions, plaque rupture with thrombus formation is observed in the culprit vessel. It should be noted again that Types I-IV lesions are usually clinically silent because the lesions do not encroach substantially on the vessel lumen. Types V and VI lesions, however, are usually obstructive and are commonly the pathological basis of acute coronary syndromes (11,12,71,73).

Inflammation and Atherosclerosis

Accumulating evidence indicates that atherosclerosis is an immunologic process involving a network of vascular wall cells, mononuclear cells, T lymphocytes, cytokines, and growth factors (18). Macrophages, T lymphocytes, and vascular wall cells, particularly smooth muscle cells, elaborate cytokines and growth factors that regulate the cellular and matrix composition of the vascular wall. For example, cytokines stimulate collagen synthesis in smooth muscle cells and promote endothelial and vascular smooth muscle cell activation through the induction of cellular adhesion molecules. Chemokines and growth factors such as monocyte chemoattractant protein-1 and M-CSF promote monocyte chemotaxis and attachment to the endothelium and support their survival and differentiation into macrophage-derived foam cells. Thus, it appears likely that any effective strategy designed to counter the atherogenic process will have to take into account modulation of the immune system with the vessel wall.

The presence of cytokines and inflammatory mediators within the vascular wall has invoked speculation that atherogenesis may be the result of chronic infectious processes similar to that of duodenal ulcers caused by Helicobacter pylori (74). Indeed, serum markers of chronic inflammation, such as C-reactive protein and serum amyloid A protein, are increased in patients with atherosclerotic heart disease (75,76). Several infectious agents have been implicated in the atherogenic process including the herpes viruses, cytomegalovirus, and C. pneumoniae. For example, the immunohistochemical localization and antibody titer for C. pneumoniae correlate with increased incidence of coronary heart disease (77,78).

With most of these infectious agents, however, rarely is the causative organism ever recovered from tissue specimen. Thus, controversy exists regarding whether microbial infections cause atherosclerosis because one of Koch's postulates has not been demonstrated. However, Koch's original postulates may be more applicable to acute rather than chronic infections. Because atherosclerotic lesions take three to four decades to develop, the causative organism that may have initiated the inflammatory process may no longer be present. Herein lies the "hit and run' hypothesis of atherosclerosis, where infectious agents may initially cause endothelial dysfunction and vascular inflammation without being present in the later stages of plaque development.

[FIGURE 3 OMITTED]

Oxidant Stress and Atherosclerosis

Some recent clinical trials have demonstrated beneficial effects of antioxidant therapy in individuals with atherosclerotic heart disease (79). These findings suggest that the development of atherosclerosis and acute coronary syndromes may be mediated, in part, by an oxidative process (Fig. 3). Oxidant stress leads to LDL oxidation, which inhibits EDRF release more than native or unoxidized LDL. Furthermore, LDL that is oxidized is more readily taken up by macrophages through the scavenger receptor than native LDL. The major sources of oxidants and reactive oxygen species in the atherosclerotic vessel are the macrophages and smooth muscle cells. Indeed, hypercholesterolemia stimulates the generation of superoxide anions from vascular smooth muscle cells, which can further oxidize LDL (59). In addition, superoxide anions may cause endothelial dysfunction by scavenging endothelium-derived NO (42). Recent studies have shown that antioxidants such as probucol, vitamin C, and vitamin E improve endothelial function, attenuate endothelial cell activation, and reduce cardiovascular events in individuals with atherosclerosis (79). However, the use of antioxidant therapy in acute coronary syndromes is still controversial because other studies using antioxidants do not show definite beneficial effects on endothelial function and cardiovascular morbidity (80).

One mechanism by which oxidant stress may contribute to the atherogenic process is via the induction of pro-inflammatory mediators. For example, the activation of pro-inflammatory transcription factors such as nuclear factor-kappa B (NF-[kappa]B), activator protein (AP)-1, and early growth response factor (egr)-1 occur through oxidant-sensitive mechanisms involving hydrogen peroxide ([H.sub.2][O.sub.2]) (81-83). Because cellular adhesion molecules such as VCAM-1, intercellular adhesion molecule-1, and E-selectin and many cytokines and growth factors such as M-CSF contain functional DNA-binding sequences for NF-[kappa]B, AP-1, and egr-1, their expression is induced by the activation of these transcription factors (84). Indeed, the NF-[kappa]B activation is found in intimal smooth muscle cells of atherosclerotic lesions (85).

Interestingly, NF-[sub.[kappa]]B activation is inhibited by antioxidants and antiinflammatory agents such as salicylates and glucocorticoids (86-88). These findings suggest that atherosclerosis is an inflammatory process initiated and propagated by oxidative stress. Thus, antioxidants may protect against the development of atherosclerotis by inhibiting the activation of pro-inflammatory transcription factors that are required for the induction of cellular adhesion molecules, cytokines, and growth factors in the vessel wall.

Mechanisms of Plaque Rupture

As previously mentioned, Types IV and V lesions are particularly susceptible to disruption by mechanical forces. The rupture of atherosclerotic plaques and exposure of procoagulant materials (i.e., tissue factor) within the lipid core cause acute thrombus formation. Indeed, findings from thrombolytic trials demonstrate that the majority of acute myocardial infarctions are precipitated by plaque rupture with ensuing thrombus formation and luminal obstruction (89). Angiographic studies, however, performed after successful thrombolytic therapy revealed that, in most cases, the culprit lesion producing the occluding thrombus did not exhibit high-grade stenosis (90-92). The premise that plaque stability and not luminal stenosis is of primary importance is supported by numerous clinical trials with lipid-lowering agents, showing improved cardiac morbidity and mortality in the absence of substantial changes in angiographic stenosis (93). Thus, plaque stability rather than its abluminal encroachment determines the propensity of the lesion to develop into an acute coronary syndrome.

Many Types N and VI lesions, however, do not rupture, and of the plaques that do rupture, the majority probably occur without symptoms. Asymptomatic plaque rupture may occur with nonoccluding thrombi or in vessels with sufficient collateral circulation to maintain perfusion. Indeed, plaque rupture is observed at autopsy in 9% of individuals with noncardiac deaths and 22% of individuals with diabetes and hypertension (94). Thus, subclinical plaque rupture with subsequent healing and reorganization may actually represent a natural progression of many atherosclerotic lesions.

The fibrous cap of the atherosclerotic plaque separates the luminal clotting cascade from its procoagulant lipid core. Thus, factors that enhance the tensile strength of the fibrous cap relative to the its lipid core will ultimately make the plaque less vulnerable to rupture (Table 4). For example, less mechanical force is required to disrupt the plaque if the fibrous cap is relatively thin and devoid of intimal smooth muscle cells and collagen (i.e., thin fibrous cap). Recent studies demonstrate the presence of T lymphocytes and the expression of major histocompatibility class II in intimal smooth muscle cells within the fibrous cap (95,96). The expression of major histocompatibility class II antigens indicates the presence of the lymphokine, interferon-[gamma], which inhibits collagen synthesis, and which, in combination with other cytokines, induces vascular smooth muscle cell death by apoptosis (97). Both of these effects of interferon-y weaken the fibrous cap and make the plaque much more vulnerable to rupture.

Another determinant of plaque stability is the size of the lipid core relative to the thickness of its fibrous cap. Less tensile force is required to disrupt the plaque if a large lipid core containing liquified cholesterol ester is surrounded by a very thin, acellular, collagen-deficient fibrous cap. By mathematical modeling, the greatest mechanical force on the atherosclerotic lesion is exerted toward the shoulder region of the plaque, where the point of rupture frequently occurs (98). Ironically, the greater the luminal stenosis, the lesser is the circumferential force exerted on the atherosclerotic lesion. This may explain why lesions with the greatest lumenal stenoses, which cause chronic ischemia, are usually the more stable lesions with respect to plaque rupture. Conversely, the nonobstructive atheroma or Type N lesion, which has a nonfibrous, thin cap and does not cause lumenal obstruction, is often more susceptible to rupture compared with a more advanced, highly stenotic, fibrocalcific lesion.

The fibrous cap can be substantially weakened by matrix degrading enzymes known as matrix metalloproteinases (MMPs) (99,100). The MMPs are a family of extracellular enzymes that include interstitial collagenases and gelatinases. Exposure of macrophages and smooth muscle cells to certain cytokines such as interleukin-1 and tumor necrosis factor-a induce the expression and activity of interstitial collagenases within the fibrous cap (101,102). Because the strength of the fibrous cap is due to matrix proteins such as proteoglycans and collagen, the induction and activation of MMPs result in the thinning and weakening of the fibrous cap and would therefore make the plaque more susceptible to mechanical disruption.

Role of Endothelium in Atherosclerosis and Plaque Rupture

In addition to increasing blood flow through local vasodilation, the endothelium prevents platelet aggregation (7), smooth muscle cell proliferation (8), and monocyte adhesion (9,10). As previously mentioned, platelet aggregation leads to the release of mitogens such as platelet=derived growth factor and transforming growth factor-(31 and thrombosis of the vascular lumen. The growth factors released by platelets stimulate the vascular smooth muscle cells to proliferate, thus generating the intima of atherosclerotic lesions.

Endothelium-derived NO inhibits the expression of cellular adhesion molecules on the endothelial surface and thereby prevents leukocyte attachment to the vessel wall (31,103). Furthermore, inhibition of endogenous endothelial NO production by [N.sup.G]-monomethyl-L-arginine mildly induces VCAM-1 expression in cultured saphenous vein endothelial cells (Fig. 3) (104). Similarly, higher concentrations of NO are required to inhibit cytokine-induced endothelial adhesion molecule expression (31,103). The mechanism by which NO inhibits the expression of cellular adhesion molecule is via inhibiting the activation of the pro-inflammatory transcription factor, NF-[kappa]B (31,103-105).

Because many cytokines, growth factors, and adhesion molecules depend on NF-[sub.[kappa]]B for their transcriptional induction (84), the regulation of NF-[kappa]B by NO is an important mechanism by which the endothelium and other NO-producing cells can modulate the expression of pro-inflammmatory mediators during atherogenesis. The mechanism by which NO inhibits NF-[kappa]B occurs, in part, via the up-regulation of the NF-[kappa]B inhibitor, I[kappa]B-[alpha] (104,105). Decreased NO production in endothelial dysfunction, therefore, would foster the activation of endothelial cells and the production of many cellular adhesion molecules and pro-inflammatory cytokines during atherogenesis (Fig. 4).

[FIGURE 4 OMITTED]

In addition, monocyte adhesion to the activated and dysfunctional endothelium allows the formation of macrophage-derived foam cells, which subsequently produce MMPs that degrade and weaken the fibrous cap and make the lesion more susceptible to plaque rupture. Thus, the loss of endothelial function in atherosclerotic lesions initiates a cascade of events that permit atherogenesis to proceed unchecked, ultimately culminating in lesions that are more likely to result in acute coronary syndromes.

Future Directions

Recent insights from vascular biology concerning the developmental stages of atherosclerosis have shed light on the importance of the endothelium as a modulator of vascular reactivity, atherogenesis, and plaque stability. Because endothelial dysfunction is an early marker of atherosclerosis and is precipitated by atherosclerotic risk factors, strategies designed to prevent acute coronary syndromes should focus on preserving endothelial function through risk factor modification. Lowering serum cholesterol concentrations would have the added benefits of increasing plaque stability by decreasing and solidifying the lipid core without necessarily affecting lumenal stenosis. In addition, any future strategies to combat acute coronary syndromes should target therapeutic modalities that improve endothelial function and strengthen the fibrous cap of atherosclerotic lesions.

This work is supported in part by grants from the National Institutes of Health (HL-52233) and the American Heart Association (Established Investigigator Award).

References

(1.) Gimbrone MA Jr. Vascular endothelium: an integrator of pathophysiologic stimuli in atherosclerosis. Am J Cardiol 1995;75: 67B-70B.

(2.) Vane JR, Anggard EE, Bottin RM. Regulatory functions of the vascular endothelium. N Engl J Med 1990;323:27-36.

(3.) Cayatte AJ, Palacino JJ, Horten K, Cohen RA. Chronic inhibition of nitric oxide production accelerates neointimal formation and impairs endothelial function in hypercholesterolemic rabbits. Arterioscler Thromb 1994;14:753-9.

(4.) Hamon M, Vallet B, Bauters C, Wernert N, McFadden EP, Lablanche J-M, et al. Long-term oral administration of L-arginine reduces intimal thickening and enhances neoendothelium-dependent acetylcholine-induced relaxation after arterial injury. Circulation 1994;90:1357-62.

(5.) Ludmer PL, Selwyn AA, Shook TL, Wayne RR, Mudge GH, Alexander RW, Ganz P. Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic coronary arteries. N Engl J Med 1986;315:1046-51.

(6.) Tanner FC, Noll G, Boulanger CM, Luscher TF. Oxidized low density lipoproteins inhibit relaxations of porcine coronary arteries: role of scavenger receptor and endothelium-derived nitric oxide. Circulation 1991;83:2012-20.

(7.) Radomski MW, Palmer RM, Moncada S. An L-arginine/nitric oxide pathway present in human platelets regulates aggregation. Proc Natl Acad Sci U S A 1990;87:5193-7.

(8.) Garg UC, Hassid A. Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Investig 1989;83:1774-7.

(9.) Gauthier TW, Davenpeck KL, Lefer AM. Nitric oxide attenuates leukocyte-endothelial interaction via P-selectin in splanchnic ischemia-reperfusion. Am J Physiol 1994;267:6562-8.

(10.) Kubes P, Suzuki M, Granger DN. Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci USA 1991;88:4651-5.

(11.) Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes (Part 1). N Engl J Med 1992;326:242-50.

(12.) Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of coronary artery disease and the acute coronary syndromes (Part 2). N Engl J Med 1992;326:310-8.

(13.) Pober JS, Collins T, Gimbrone MA Jr, Cotran RS, Gitlin JD, Fiers W, et al. Lymphocytes recognize human vascular endothelial and dermal fibroblast la antigens induced by recombinant immune interferon. Nature 1983;305:726-9.

(14.) Cybulsky MI, Gimbrone MA Jr. Endothelial expression of a mononuclear leukocyte adhesion molecule during atherogenesis. Science 1991;251:788-91.

(15.) Bevilacqua MP. Endothelial-leukocyte adhesion molecules. Annu Rev Immunol 1993;11:767-804.

(16.) Libby P, Clinton SK. The role of macrophages in atherogenesis. Curr Opin Lipidol 1993;4:355-63.

(17.) Ross R, Harker L. Hyperlipidemia and atherosclerosis and chronic hyperlipidemia initiates and maintains lesions by endothelial cell desquamation and lipid accumulation. Science 1976; 193:1094-100.

(18.) Libby P. Inflammatory and immune mechanisms in atherogenesis. In: Leaf A, Weber P, eds. Atherosclerosis reviews. New York: Raven Press, 1990:79-89.

(19.) Berliner JA, Navab M, Fogelman AM, Frank JS, Demer LL, Edwards PA, et al. Atherosclerosis: basic mechanisms. Oxidation, inflammation, and genetics. Circulation 1995;91:2488-96.

(20.) Speir E, Modali R, Huang ES, Leon MB, Shawl F, Finkel T, Epstein SE. Potential role of human cytomegalovirus and p53 interaction in coronary restenosis. Science 1994;265:391-4.

(21.) Leinonen M, Linnanmaki E, Mattila K, Nieminan MS, Valtonen V, Seirisalo-Repo M, Saikku P. Circulating immune complexes containing chlamydial lipopolysaccharide in acute myocardial infarction. Microb Pathog 1990;9:67-73.

(22.) Cooke JP, Rossitch E Jr, Andon NA, Loscalzo J, Dzau VJ. Flow activates an endothelial potassium channel to release an endogenous nitrovasodilator. J Clin Investig 1991;88:1663-71.

(23.) Perrella MA, Edell ES, Krowka MJ, Cortese DA, Burnett JC Jr. Endothelium-derived relaxing factor in pulmonary and renal circulations during hypoxia. Am J Physiol 1992;263:845-50.

(24.) Ignarro LJ, Buga GM, Wood KS, Byrns RE, Chaudhuri G. Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide. Proc Natl Acad Sci USA 1987;84: 9265-9.

(25.) Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 1980;288:373-6.

(26.) Myers RP, Minor RL Jr, Fuerra R Jr, Bates JN, Harrison DG. Vasorelaxant properties of the endothelium-derived relaxing factor more closely resemble S-nitrosocysteine than nitric oxide. Nature 1990;345:161-3.

(27.) Palmer RMJ, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 1987;327:524-6.

(28.) Panza JA, Quyyumi AA, Brush JE Jr, Epstein SE. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med 1990;323:22-7.

(29.) Liao JK, Bettmann MA, Tucker JI, Sandor T, Coleman S, Meek M, Creager MA. Differential impairment of vasodilator responsiveness of peripheral resistance and conduit vessels in humans with atherosclerosis. Circ Res 1991;68:1027-34.

(30.) Kubo SH, Rector TS, Bank AJ, Williams RE, Heifez SM. Endothelium dependent vasodilation is attenuated in patients with congestive heart failure. Circulation 1991;84:1589-96.

(31.) De Caterina R, Libby P, Peng HB, Thannickal VJ, Rajavashisth TB, Gimbrone MA Jr, et al. Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J Clin Investig 1995;96:60-8.

(32.) Stamler JS. Redox signaling: nitrosylation and related target interactions of nitric oxide. Cell 1994;78:931-6.

(33.) Moncada S, Palmer RMJ, Higgs EA. Nitric oxide: physiology, pathophysiology and pharmacology. Pharmacol Rev 1991;43: 109-40.

(34.) Bredt DS, Hwang PH, Glatt C, Lowenstein C, Reed RR, Snyder SH. Cloned and expressed nitric oxide synthase structurally resembles cytochrome P-450 reductase. Nature 1991;351: 714-8.

(35.) Lyons CR, Orloff GJ, Cunningham JM. Molecular cloning and functional expression of an inducible nitric oxide synthase from a murine macrophage cell line. J Biol Chem 1992;267:6370-4.

(36.) Janssens SP, Shimouchi A, Quertermous T, Bloch DB, Bloch KD. Cloning and expression of a cDNA encoding human endotheliumderived relaxing factor/nitric oxide synthase. J Biol Chem 1992; 267:14519-22.

(37.) Tanner FC, Noll G, Boulanger CM, Luscher TF. Oxidized low density lipoproteins inhibit relaxations of porcine coronary arteries: role of scavenger receptor and endothelium-derived nitric oxide. Circulation 1991;83:2012-20.

(38.) Wolf A, Zalpour C, Theilmeier G, Wang BY, Ma A, Anderson B, et al. Dietary L-arginine supplementation normalizes platelet aggregation in hypercholesterolemic humans. J Am Coll Cardiol 1997; 29:479-85.

(39.) Kurose I, Kubes P, Wolf R, Anderson DC, Paulson J, Miyasaka M, Granger DN. Inhibition of nitric oxide production. Mechanisms of vascular albumin leakage. Circ Res 1993;73:164-71.

(40.) Huang PL, Huang Z, Mashimo H, Bloch KD, Moskowitz MA, Bevan JA, Fishman MC. Hypertension in mice lacking the gene for endothelial nitric oxide synthase. Nature 1995;377:239-42.

(41.) Moroi M, Zhang L, Yasuda T, Virmani R, Fishman MC, Huang PL. Interaction of genetic deficiency of endothelial nitric oxide, gender, and pregnancy in vascular response to injury in mice. J Clin Investig 1998;101:1225-32.

(42.) Munzel T, Sayegh H, Freeman BA, Tarpey MM, Harrison DG. Evidence for enhance vascular superoxide anion production in nitrate tolerance. A novel mechanism underlying tolerance and cross-tolerance. J Clin Investig 1995;95:187-94.

(43.) Rajagopaian S, Kurz S, Munzel T, Tarpey M, Freeman BA, Griendling KK, Harrison DG. Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation: contribution to alterations of vasomotor tone. J Clin Investig 1996;97:1916-23.

(44.) von der Leyen HE, Gibbons GH, Morishita R, Lewis NP, Zhang L, Nakajima M, et al. Gene therapy inhibiting neointimal vascular lesion: in vivo transfer of endothelial cell nitric oxide synthase gene. Proc Natl Acad Sci USA 1995;92:1137-41.

(45.) Cooke JP, Singer AH, Tsao P, Zera P, Rowan RA, Billingham ME. Antiatherogenic effects of L-arginine in the hypercholesterolemic rabbit. J Clin Investig 1992;90:1168-72.

(46.) Tsao PS, McEvoy LM, Drexler H, Butcher EC, Cooke JP. Enhanced endothelial adhesiveness in hypercholesterolemia is attenuated by L-arginine. Circulation 1994;89:2176-82.

(47.) Marks DS, Vita JA, Folts JD, Keaney JF Jr, Welch GN, Loscalzo J. Inhibition of neointimal proliferation in rabbits after vascular injury by a single treatment with a protein adduct of nitric oxide. J Clin Investig 1995;96:2630-8.

(48.) Lerman A, Holmes DR Jr, Bell MR, Garratt KN, Nishimura RA, Burnett JC Jr. Endothelin in coronary endothelial dysfunction and early atherosclerosis in humans. Circulation 1995;92:2426-31.

(49.) Lerman A, Edwards BS, Hallett, JW, Heublein DM, Sandberg SM, Burnett JC Jr. Circulating and tissue endothelin immunoreactivity in advanced atherosclerosis. N Engl J Med 1991;325:997-1001.

(50.) Zeiher AM, Goebel H, Schachinger V, Ihling C. Tissue endothelin-1 immunoreactivity in the active coronary atherosclerotic plaque: a clue to the mechanism of increased vasoreactivity of the culprit lesion in unstable angina. Circulation 1995;91: 941-7.

(51.) Martin-Nizard F, Houssaini HS, Lestavel-Delattre S, Duriez P, Fruchart JC. Modified low density lipoproteins activate human macrophages to secrete immunoreactive endothelin. FEBS Lett 1991; 293:127-30.

(52.) Weissberg PL, Witchell C, Davenport AP, Hesketh TR, Metcalfe JC. The endothelin peptides ET-1, ET-2, ET-3, and sarafotoxin S6b are co-mitogenic with platelet-derived growth factor for vascular smooth muscle cells. Atherosclerosis 1990;85:257-62.

(53.) Werns SW, Walton JA, Hsia HH, Nabel EG, Sanz ML, Pitt B. Evidence of endothelial dysfunction in angiographically normal coronary arteries of patients with coronary artery disease. Circulation 1989;79:287-91.

(54.) McLenachan JM, Williams JK, Fish RD, Ganz P, Selwyn AP. Loss of flow-mediated endothelium-dependent dilation occurs early in the development of atherosclerosis. Circulation 1991;84:1273-8.

(55.) Reddy KG, Nair RN, Sheehan HM, Hodgson JMcB. Evidence that selective endothelial dysfunction may occur in the absence of angiographic or ultrasound atherosclerosis in patients with risk factors for atherosclerosis. J Am Coll Cardiol 1994;23:833-43.

(56.) Creager MA, Cooke JP, Mendelsohn ME, Gallagher SJ, Coleman SM, Loscalzo J, Dzau VJ. Impaired vasodilation of forearm resistance vessels in hypercholesterolemic humans. J Clin Investig 1990;86:228-34.

(57.) Liao JK, Shin WS, Lee WY, Clark SL. Oxidized low-density lipoprotein decreases the expression of endothelial nitric oxide synthase. J Biol Chem 1995;270:319-24.

(58.) Liao JK. Inhibition of G; proteins by low-density lipoprotein attenuates bradykinin-stimulated release of endothelial-derived nitric oxide. J Biol Chem 1994;269:19528-33.

(59.) Ohara Y, Peterson TE, Harrison DG. Hypercholesterolemia increases endothelial superoxide anion production. J Clin Investig 1993;91:2546-51.

(60.) Anderson TJ, Meredith IT, Yeung AC, Frei B, Selwyn AP, Ganz P. The effect of cholesterol-lowering and antioxidant therapy on endothelium-dependent coronary vasomotion. N Engl J Med 1995;332:488-93.

(61.) Treasure CB, Klein JL, Weintraub WS, Talley JD, Stillabower ME, Kosinski AS, et al. Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease. N Engl J Med 1995;332:481-7.

(62.) Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the scandinavian simvastatin survival study (4S). Lancet 1994;344:1383-9.

(63.) Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, et al. Prevention of coronary heart disease with Pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med 1995;333:1301-7.

(64.) Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Ruthertord JD, Cole TG, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001-9.

(65.) Zeiher AM, Drexler H, Saurbier B, Just H. Endothelium-mediated coronary blood flow modulation in humans: effects of age, atherosclerosis, hypercholesterolemia, and hypertension. J Clin Investig 1993;92:652-62.

(66.) Celermajer DS, Adams MR, Clarkson P, Robinson J, McCredie R, Donald A, Deanfield JE. Passive smoking and impaired endothelium-dependent arterial dilation in healthy young adults. N Engl J Med 1996;334:150-4.

(67.) Johnstone MT, Creager SJ, Scales KM, Cusco JA, Lee BK, Creager MA. Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus. Circulation 1993;88:2510-6.

(68.) Panza JA, Quyyumi AA, Callahan TS, Epstein SE. Effect of anti-hypertensive treatment on endothelium-dependent vascular relaxation in patients with essential hypertension. J Am Coll Cardiol 1993;21:1145-51.

(69.) Collins P, Rosano GMC, Sarrel PM, Ulrich L, Adamopoulos S, Beale CM, et al. 17R-estradiol attenuates acetylcholine-induced coronary arterial constriction in women but not in men with coronary heart disease. Circulation 1995;92:24-30.

(70.) Ross R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1993;362:801-9.

(71.) Fuster V. Mechanisms leading to myocardial infarction: insights from studies of vascular biology. Circulation 1994;90:2126-46.

(72.) Libby P, Sukhova G, Lee RT, Liao JK. Molecular biology of atherosclerosis. Int J Cardiol 1998;(in press).

(73.) Stary HC, Chandler AB, Dinsmore RE, Fuster V, Glagov S, Insull W Jr, et al. A definition of advanced types of atherosclerotic lesions and a histological classification of atherosclerosis. Circulation 1995;92:1355-74.

(74.) Mendall MA, Goggin P, Molineaux N, Levy J, Toosy T, Strachan DP, Northfield TC. Association between childhood living conditions and Helicobacter seropositivity in adult life. Lancet 1992; 1:896-7.

(75.) Ridker PM, Cushman M, Stampfer M, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997;336:973-9.

(76.) Liuzzo G, Biasucci LM, Gallimore JR, Grillo RL, Rebuzzi AG, Pepys MB, Maseri A. The prognostic value of C-reactive protein and serum amyloid A protein in severe unstable angina. N Engl J Med 1994;331:417-24.

(77.) Saikku P, Leinonen M, Mattila K, Elkman MR, Nieminan MS, Makela PH, et al. Serological evidence of an association of a novel Chlamydia, TWAR, with chronic coronary heart disease and acute myocardial infarction. Lancet 1988;2:983-6.

(78.) Campbell LA, O'Brien ER, Cappuccio AL, Kuo CC, Wang SP, Stewart D, et al. Detection of Chlamydia pneumoniae TWAR in human coronary atherectomy tissues. J Infect Dis 1995;172: 585-8.

(79.) Stephens NG, Parsons A, Schofield P, Kelly F, Cheeseman K, Mitchinson JM, Brown MJ. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet 1996;347:781-6.

(80.) Omenn GS, Goodman GE, Thornquist MD, Balmes J, Cullen MR, Glass A, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med 1996;334:1150-5.

(81.) Schreck R, Albermann K, Baeuerle PA. Nuclear Factor-[kappa]B: an oxidative stress-responsive transcription factor of eukaryotic cells. Free Rad Res Commun 1992;17:221-37.

(82.) Abate C, Patel L, Rauscher FJ III, Curran T. Redox regulation of Fos and Jun DNA-binding activity in vitro. Science 1990;249: 1157-60.

(83.) Ohba M, Shibanuma M, Kuroki T, Nose K. Production of hydrogen peroxide by transforming growth factor-[beta]1 and its involvement in induction of egr-1 in mouse osteoblastic cells. J Cell Biol 2994;126:1079-88.

(84.) Collins T. Endothelial nuclear factor-[kappa]B and the initiation of the atherosclerotic lesion. Lab Investig 1993;68:499-508.

(85.) Bourcier T, Sukhova G, Libby P. The nuclear factor-[kappa]B signaling pathway participates in deregulation of vascular smooth muscle cells in vitro and in human atherosclerosis. J Biol Chem 1997; 272:15817-24.

(86.) Kopp E, Ghosh S. Inhibition of NF-[kappa]B by sodium salicylate and aspirin. Science 1994;265:956-8.

(87.) Scheinman RI, Cogswell PC, Lofquist AK, Baldwin AS Jr. Role of transcriptional activation of I[kappa]B-[alpha] in mediation of immunosuppression by glucocorticoids. Science 1995;270:283-6.

(88.) Auphan N, DiDonato JA, Rosette C, Helmberg A, Karin M. Immunosuppression by glucocorticoids: inhibition of NF-KB activity through induction of I.[kappa]B synthesis. Science 1995;270:286-90.

(89.) Davies MJ, Thomas AC. Plaque fissuring: the cause of acute myocardial infarction, sudden ischemic death, and crescendo angina. Br Heart J 1985;53:363-73.

(90.) Hackett D, Davies G, Maseri A. Pre-existing coronary stenoses in patients with first myocardial infarction are not necessarily severe. Eur Heart J 1988;9:1317-23.

(91.) Ambrose JA, Tannenbaum MA, Alexopoulos D, Hjemdahl-Monsen CE, Leavy J, Weiss M, et al. Angiographic progression of coronary artery disease and the development of myocardial infarction. J Am Coll Cardiol 1988;12:56-62.

(92.) Giroud D, Li JMM, Urban P, Meier B, Rutishauer W. Relation of the site of acute myocardial infarction to the most severe coronary arterial stenosis at prior angiography. Am J Cardiol 1992;69:729-32.

(93.) Brown BG, Zhao XQ, Sacco DE, Albers JJ. Lipid lowering and plaque regression: new insights into prevention of plaque disruption and clinical events in coronary disease. Circulation 1993; 87:1781-91.

(94.) Davies MJ, Bland JM, Hangartner JRW, Angelini A, Thomas AC. Factors influencing the presence or absence of acute coronary artery thrombi in sudden ischaemic death. Eur Heart J 1989;10: 203-8.

(95.) Libby P, Hansson GK. Involvement of the immune system in human atherogenesis: current knowledge and unanswered questions. Lab Investig 1991;64:5-15.

(96.) Hansson GK, Holm J, Jonasson L. Detection of activated T lymphocytes in the human atherosclerotic plaque. Am J Pathol 1989;135:169-75.

(97.) Geng Y, Wu Q, Muszynski M, Hansson GK, Libby P. Apoptosis of vascular smooth muscle cells induced by in vitro stimulation with interferon-g, tumor necrosis factor-a, and interleukin-1R. Arterioscler Thromb Vasc Biol 1996;16:19-27.

(98.) Cheng GC, Loree Hm, Kamm RD, Fishbein MC, Lee RT. Distribution of circumferential stress in ruptured and stable atherosclerotic lesions: a structural analysis with histopathologic correlation. Circulation 1993;87:1179-87.

(99.) Woessner JJ. Matrix metalloproteinases and their inhibitors in connective tissue remodeling. FASEB J 1991;5:2145-54.

(100.) Galis Z, Sukhova G, Kranzhofer R, Clark S, Libby P. Macrophage foam cells from experimental atheroma constitutively produce matrix-degrading proteinases. Proc Natl Acad Sci USA 1995; 92:402-6.

(101.) Galis Z, Sukhova G, Lark M, Libby P. Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques. J Clin Investig 1994;94:2493-503.

(102.) Libby P. Molecular bases of the acute coronary syndromes. Circulation 1995;91:2844-50.

(103.) Khan BV, Harrison DG, Olbrych MT, Alexander RW, Medford RM. Nitric oxide regulates vascular cell adhesion molecule 1 gene expression and redox-sensitive transcriptional events in human vascular endothelial cells. Proc Natl Acad Sci USA 1996;93: 9114-9.

(104.) Spiecker M, Peng HB, Liao JK. Inhibition of endothelial vascular cell adhesion molecule-1 expression by nitric oxide involves the induction and nuclear translocation of I[kappa]B-[alpha]. J Biol Chem 1997; 272:30969-74.

(105.) Peng HB, Libby P, Liao JK. Induction and stabilization of I[kappa]B-[alpha] by nitric oxide mediate inhibition of NF-KB. J Biol Chem 1995;270: 14214-9.

Cardiovascular Division, Department of Medicine, 221 Longwood Avenue, LMRC-316, Boston, MA 02115. Fax 617-264-6336; e-mail jliao@bustoii.bwh.harvard.edu.

[1] Nonstandard abbreviations: NO, nitric oxide; VCAM, vascular cell adhesion molecule; ET, endothelin; EDRF, endothelium-derived relaxing factor; NOS, nitric oxide synthase; M-CSF, macrophage-colony stimulating factor; NF-KB, nuclear factor-kappa B; AP, activator protein; egr, early growth response factor; and MMP, matrix metalloproteinase.

Received February 5, 1998; revision accepted March 9, 1998.
Table 1. Endothelium-derived substances.

Vasodilators
 Nitric oxide (EDRF)
 Hyperpolarizing factors)
 Prostacyclin
Vasoconstrictors
 ET
 Angiotensin II
 Thromboxane A2
Cellular adhesion molecules
 VCAM-1
 Intercellular cell adhesion molecule
 E-selectin
Growth factors
 Vascular endothelial growth factor
 Platelet-derived growth factor
 Transforming growth factor
 Heparin-binding epidermal growth factor
 M-CSF
Coagulants/fibrinolytics
 von Willebrand factor
 Tissue type plasminogen activator
 Plasminogen activator inhibitor
Chemokines
 Monocyte chemotactic protein
 ?Interleukin-8

Table 2. Nitric oxide synthases.

 Basal NO Stimulated NO
Isoforms Cell types concentrations concentrations

Type I Neurons, skeletal muscle, Low Transient, low
 (nNOS) ? smooth muscle
Type II Macrophages, myocytes, None Sustained,
 (iNOS) smooth muscle, high
 hepatocytes
Type III Endothelial cells, Low Transient, high
(eNOS) platelets

Table 3. Factors that cause endothelial dysfunction.

Atherosclerotic risk factors
 Hypertension
 Cigarette smoking
 Hypercholesterolemia
 Diabetes mellitus
 Male gender
 Increased age
 Family history of atherosclerosis
Chronic infections
 Herpes viruses
 Cytomegalovirus
 Respiratory syncytial virus
 Helicobacter pylori
 C. pneumoniae
Environmental factors
 Hypoxia
 Turbulent flow
 Oxidants
Genetic factors
 Homocysteine
 Lipoprotein (a)
 Familial hypercholesterolemia
 Hypertriglyceridemia

Table 4. Factors that increase plaque rupture.

Mechanical factors
 Increased circumferential stress
 Vasospasm
 High turbulent flow
 Increased liquidity of lipid core
 Thin fibrous cap
Plaque constituents
 Increased esterified cholesterol
 Decreased extracellular matrix
 Increased metalloproteinases
 Presence of T cells and macrophages
Fibrous cap
 Decreased synthesis of collagen
 Degradation of collagen
 Loss of smooth muscle cells
 Increased presence of cytokines
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Title Annotation:Beckman Conference
Author:Liao, James K.
Publication:Clinical Chemistry
Date:Aug 1, 1998
Words:7195
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