Atherogenesis: hemodynamics, vascular geometry, and the endothelium

The evidence for a hemodynamic involvement and possible mechanisms by which hemodynamic-related events could influence the arterial wall, and in particular the vascular endothelium, are reviewed and used to speculate on the role of fluid mechanics in atherogenesis and specifically in lesion localization. The evidence presented suggests that it is vascular geometry, and the way it influences the local detailed flow properties, which is the primary determinant of a hemodynamic effect on the arterial wall and in the initiation of atherosclerosis.     

The accumulation of specific types of proteoglycans in eroded plaques: a role in coronary thrombosis in the absence of rupture

PURPOSE OF REVIEW: Although fibrous cap rupture is the primary cause of coronary thrombosis, plaque erosion is responsible for 30%-40% of acute thrombotic events. The interface of the eroded surface involves a denuded endothelium allowing direct contact of the platelet/fibrin thrombus with the underlying lesion. This review discusses the putative role of extracellular matrix molecules, in particular proteoglycans/hyaluronan, in the development of acute coronary thrombosis associated with erosion. RECENT FINDINGS: The plaque/thrombus interface in erosion presents a unique surface since it consists of predominantly SMCs and proteoglycans with minimal or no inflammation. The lack of significant inflammation raises the possibility that erosion represents chronic wounding rather than true atherogenesis. The abundance of proteoglycan and hyaluronan matrix suggests their potential role in the development of thrombosis. Matrix changes may contribute to endothelial loss, the magnitude of the thrombotic event, or both. Versican facilitates platelet adhesion at low shear and cooperates with collagen to promote platelet aggregation. Further, versican may, in part, regulate water content and in turn support coagulation because water-dependent functionality of anticoagulation molecules. Finally, experimental models of plaque erosion are currently being developed guided by the premise that the loss of surface endothelium together with other procoagulant factors may underlie the development of platelet-rich thrombi. SUMMARY: The loss of endothelium and exposure of a potentially procoagulant versican-hyaluronan matrix may be largely responsible for plaque erosion. The development of relevant animal models should allow further insight into the pathophysiology of coronary thrombosis in the absence of rupture.     

Vascular fluid mechanics, the arterial wall, and atherosclerosis.

Atherosclerosis, a disease of large- and medium-size arteries, is the chief cause of death in the United States and in most of the western world. Severe atherosclerosis interferes with blood flow; however, even in the early stages of the disease, i.e. during atherogenesis, there is believed to be an important relationship between the disease processes and the characteristics of the blood flow in the arteries. Atherogenesis involves complex cascades of interactions among many factors. Included in this are fluid mechanical factors which are believed to be a cause of the highly focal nature of the disease. From in vivo studies, there is evidence of hemodynamic influences on the endothelium, on intimal thickening, and on monocyte recruitment. In addition, cell culture studies have demonstrated the important effect of a cell's mechanical environment on structure and function. Most of this evidence is for the endothelial cell, which is believed to be a key mediator of any hemodynamic effect, and it is now well documented that cultured endothelial monolayers, in response to a fluid flow-imposed laminar shear stress, undergo a variety of changes in structure and function. In spite of the progress in recent years, there are many areas in which further work will provide important new information. One of these is in the engineering of the cell culture environment so as to make it more physiologic. Animal studies also are essential in our efforts to understand atherogenesis, and it is clear that we need better information on the pattern of the disease and its temporal development in humans and animal models, as well as the specific underlying biologic events.(ABSTRACT TRUNCATED AT 250 WORDS)     

Coronary angiography via femoral and radial accesses in patients with extensive atherosclerosis

The incidence of complications and the comparative results of endovascular interventions made via femoral and radial accesses are analyzed. The study included 142 patients with coronary atherosclerosis and coronary heart disease showing a hemodynamically significant atherosclerotic lesion of at least three vascular beds. Angiography was made via femoral and radial accesses in 86 and 56 patients, respectively. In patients with multifocal atherosclerosis, the number of cardiac events (myocardial infarction, death) did not differ significantly when coronarography was made by applying different accesses. There were a significantly larger number of peripheral thrombotic events in the femoral access group (p < 0.05). Aneurysm of the abdominal aorta with its thrombosis was found to be a risk factor of the occurrence of thrombotic complications when coronary angiography was made via the femoral access. Coronary angiography performed through the radial artery allows the risk of thrombotic complications to be substantially reduced in patients with multifocal atherosclerosis: such complications were not observed in the radial access group, they were in 5 (5.8%) cases in the femoral access group.     

The immune response in atherosclerosis: a double-edged sword

Immune responses participate in every phase of atherosclerosis. There is increasing evidence that both adaptive and innate immunity tightly regulate atherogenesis. Although improved treatment of hyperlipidaemia reduces the risk for cardiac and cerebral complications of atherosclerosis, these remain among the most prevalent of diseases and will probably become the most common cause of death globally within 15 years. This Review focuses on the role of immune mechanisms in the formation and activation of atherosclerotic plaques, and also includes a discussion of the use of inflammatory markers for predicting cardiovascular events. We also outline possible future targets for prevention, diagnosis and treatment of atherosclerosis.     

Mechanisms of anti-atherosclerotic functions of soy-based diets

Soy-based diets have been reported to protect against the development of atherosclerosis. However, the underlying mechanism(s) for this protection remains unknown. Although atherosclerosis was traditionally considered a disease associated with impaired lipid metabolism, in recent years the inflammatory components of atherosclerosis have been explored. Recent studies have convincingly delineated that uncontrolled chronic inflammation is the principal contributing factor for the initiation and progression of atherosclerosis. Interaction between activated monocytes and vascular endothelial cells is an early event in atherogenesis. The adhesion of leukocytes, including monocytes, to the inflamed-vascular endothelium and their transmigration into intima initiate the inflammatory processes. Following transmigration, monocytes in the intima are transformed to macrophages, which take up oxidized-LDL (oxLDL) to generate lipid-laden macrophages, also known as foam cells. Hence, in this review article the inflammatory processes associated with atherosclerosis and possible anti-inflammatory functions of soy-based diets contributing to the prevention of atherosclerosis are presented.     

Nitric oxide and atherosclerosis.

Endothelial dysfunction has been shown in a wide range of vascular disorders including atherosclerosis and related diseases. Here, we examine and address the complex relationship among nitric oxide (NO)-mediated pathways and atherogenesis. In view of the numerous pathophysiological actions of NO, abnormalities could potentially occur at many sites: (a) impairment of membrane receptors in the arterial wall that interact with agonists or physiological stimuli capable of generating NO; (b) reduced concentrations or impaired utilization of l-arginine; (c) reduction in concentration or activity both of inducible and endothelial NO synthase; (d) impaired release of NO from the atherosclerotic damaged endothelium; (e) impaired NO diffusion from endothelium to vascular smooth muscle cells followed by decreased sensitivity to its vasodilator action; (f) local enhanced degradation of NO by increased generation of free radicals and/or oxidation-sensitive mechanisms; and (g) impaired interaction of NO with guanylate cyclase and consequent limitation of cyclic GMP production. Therefore, one target for new drugs should be the preservation or restoration of NO-mediated signaling pathways in arteries. Such novel therapeutic strategies may include administration of l-arginine/antioxidants and gene-transfer approaches.     

Role of extracellular retention of low density lipoproteins in atherosclerosis

The pathogenesis for atherosclerosis is still unclear, and several hypotheses have been articulated to explain the initiating events in atherogenesis. Although these hypotheses are by no means mutually exclusive, there is a growing body of recent evidence that has led to the concept that subendothelial retention of apolipoprotein B100-containing lipoproteins is the initiating event in atherogenesis. Subsequently, a series of biological responses to this retained material leads to specific molecular and cellular processes that promote lesion formation. The present review assesses some of the studies that support this concept.     

Pathophysiological significance of cylindromatosis in the vascular endothelium and macrophages for the initiation of age-related atherogenesis

Cardiovascular disease is one of the leading causes of death in the elderly, and novel therapeutic targets against atherogenesis are urgent. The initiation of atherosclerotic changes of monocyte adhesion on the vascular endothelium and subsequent foam cell formation are noteworthy pathophysiologies when searching for strategies to prevent the progression of age-related atherosclerosis. We report the significance of the deubiquitinating enzyme cylindromatosis (CYLD) in vascular remodeling by interference with inflammatory responses regulated by NF-κB signaling. The purpose of this study was to elucidate the pathological functions of CYLD in the early phase of atherogenesis associated with aging.Treatment with inflammatory cytokines induced endogenous CYLD in aortic endothelial cells (HAECs) and THP-1?cells. siRNA-mediated CYLD silencing led to enhanced monocyte adhesion along with increased adhesion molecules in HAECs treated with TNFα. In siRNA-mediated CYLD silenced RAW 264.7 macrophages treated with oxidized LDL (oxLDL), augmented lipid accumulation was observed, along with increased expression of the class A macrophage scavenger receptor (SR-A), lectin-like oxidized LDL receptor-1 (LOX-1), CD36, fatty acid binding protein 4 (FABP4), the cholesterol ester synthase acyl-CoA cholesterol acyltransferase (ACAT1), MCP-1, and IL-1β and decreased expression of scavenger receptor class B type I (SR-BI). Intriguingly, CYLD gene expression was significantly reduced in bone marrow-derived macrophages of aged mice compared that of young mice, as well as in senescent HAECs compared with young cells.These findings suggest that age-related attenuation of CYLD expression in endothelial cells (ECs) and macrophages triggers the initiation of age-related atherogenesis by exacerbating monocyte adhesion on the endothelium and foam cell formation. CYLD in the vasculature may be a novel therapeutic target, especially in the early preventive intervention against the initiation of age-related atherogenesis.     

Social behavior and gender in biomedical investigations using monkeys: studies in atherogenesis.

We review the use of socially housed cynomolgus monkeys (Macaca fascicularis) in biomedical research with emphasis on studies of atherosclerosis, particularly in the two specific domains of atherosclerosis investigation for which nonhuman primates are especially well-suited as animal models: gender differences and psychosocial influences. We found that the presence of normal ovarian function prevented exacerbation of diet-induced coronary artery atherosclerosis in female monkeys. However, any manipulation or condition which impaired ovarian function tended to diminish or abolish this "female" protection. Among group-housed female monkeys, low social status was accompanied by ovarian dysfunction and, not surprisingly, by exacerbated coronary artery atherosclerosis as well. Surgical menopause (ovariectomy) also induced exacerbation of coronary atherosclerosis in monkeys, a situation which was prevented by estrogen replacement therapy. Conversely, pregnancy (a hyperestrogenic state) resulted in markedly diminished atherosclerosis. A somewhat different pattern of atherogenesis emerged among socially-housed males. Here, socially dominant animals developed exacerbated coronary artery atherosclerosis, but only under conditions of social stress (viz., disruption caused by periodic reorganization of social group membership). We hypothesized that exposure to repeated group reorganizations provoked activation of the sympathetic nervous system among dominant animals; in turn, the hemodynamic and metabolic concomitants of sympathetic activation may have damaged the coronary arteries of these monkeys, potentiating atherogenesis. To test this hypothesis, males were housed in unstable social groupings, with half of the monkeys administered a beta-adrenergic blocking agent (to attenuate heart rate and blood pressure responses to stress). The beta-blocker inhibited atherosclerosis, but only among those animals behaviorally predisposed to develop exacerbated lesions (i.e. dominant monkeys). These results support the view that monkeys are suitable research models of atherosclerosis, a disease that affects millions of humans.     

c-Myc Oncoprotein: Cell Cycle-Related Events and New Therapeutic Challenges in Cancer and Cardiovascular Diseases

Advanced stages of both cancer and atherosclerosis are characterized by a local increase in tissue mass that may be hard to control. This increase in tissue mass can be attributed to oxidation-sensitive modification of cell cycle-related events, including cellular proliferation, differentiation, and apoptosis, which could be secondary to alteration in the activity of tumor suppressor gene and oncogene products. The oncogene c-Myc has classically been considered to be involved in carcinogenesis and has more recently been implicated in both endothelial dysfunction and atherogenesis as well. Consequently, inhibition of c-Myc-dependent signaling has become a novel therapeutic opportunity and challenge in atherosclerosis and other cardiovascular diseases.

Antioxidant strategies, RNA synthesis inhibitors such as mithramycin, and gene therapeutic approaches with antisense oligonucleotides against c-Myc are some of the promising strategies. In general, the increased biologic understanding of the participation of cell cycle events and targeting these events may enable to attenuate or prevent some of the complications of vascular and neoplastic diseases.     

c-Myc oncoprotein: cell cycle-related events and new therapeutic challenges in cancer and cardiovascular diseases

Advanced stages of both cancer and atherosclerosis are characterized by a local increase in tissue mass that may be hard to control. This increase in tissue mass can be attributed to oxidation-sensitive modification of cell cycle-related events, including cellular proliferation, differentiation, and apoptosis, which could be secondary to alteration in the activity of tumor suppressor gene and oncogene products. The oncogene c-Myc has classically been considered to be involved in carcinogenesis and has more recently been implicated in both endothelial dysfunction and atherogenesis as well. Consequently, inhibition of c-Myc-dependent signaling has become a novel therapeutic opportunity and challenge in atherosclerosis and other cardiovascular diseases. Antioxidant strategies, RNA synthesis inhibitors such as mithramycin, and gene therapeutic approaches with antisense oligonucleotides against c-Myc are some of the promising strategies. In general, the increased biologic understanding of the participation of cell cycle events and targeting these events may enable to attenuate or prevent some of the complications of vascular and neoplastic diseases.     

Oxidative stress in diabetes: a mechanistic overview of its effects on atherogenesis and myocardial dysfunction

Diabetes is a major risk factor for atherosclerosis. Atherogenesis involves endothelial dysfunction, activation and injury, inflammation, and smooth muscle cell migration and proliferation. Platelet activation in the narrowed arteries is the most proximate event in the culmination of an acute event such as acute myocardial infraction and stroke. Hyperglycemia is associated with all these adverse events in the process of genesis of atherosclerosis. The effect of diabetes (hyperglycemia) is mediated in large part by the state of enhanced oxidative stress, which is not counter-balanced by endogenous antioxidants. This paper reviews the ignition of oxidative stress in diabetes and the mediation of events leading to atherogenesis.     

Intracellular generation of MDA-LYS epitope in foam cells.

Oxidative stress plays a central role in atherogenesis. Antioxidants, such as probucol, inhibit oxidation of LDL, retard secretion of interleukin-1, growth factors and chemoattractants, and thus inhibit progression of atherosclerosis. Other antioxidants with an ability to inhibit LDL oxidation, however, could not prevent progression of atherosclerosis. The inconsistency between antioxidant potencies indicated oxidative events might have occurred at locations other than LDL. MDA-lysine epitope (MDA-lys) is closely associated with atherogenesis and was recognized as marker for oxidation. We traced formation of MDA-lys during oxidation of LDL and formation of foam cells. The results indicated that thiobarbituric acid reactive substance (TBARS) was primarily present in lipid fraction of ox-LDL not associated with protein fraction after Cu2+ oxidation in vitro. Oxidized LDL did not increase significant immunoreactivity of MDA-lys epitope under our experimental conditions. Foam cells, however, showed the presence of MDA-lys epitope suggesting that intracellular oxidation events occurred to internalized lipids. The uptake of non-oxidatively modified LDL (acetylated LDL) was sufficient to generate MDA-lys epitope in foam cells, consistent with the hypothesis that atherosclerosis is associated with oxidative events in addition to LDL oxidation. We hypothesized that MDA-lys may be generated through intracellular lipid metabolism during the formation of foam cells.     

Atherosclerosis: from lesion formation to plaque activation and endothelial dysfunction

Atherosclerosis is an important source of morbidity and mortality in the developed world. Despite the fact that the association between LDL cholesterol and atherosclerosis has been evident for at least three decades, our understanding of exactly how LDL precipitates atherosclerosis is still in its infancy. At least three working hypotheses of atherosclerosis are now nearing the stage where their critical evaluation is possible through a combination of basic science investigation and murine models of atherosclerosis. As we move forward in our understanding of this disease, efforts will be increasingly focused on the molecular mechanisms of disease activation that precipitate the clinical manifestations of atherosclerosis such as heart attack and stroke. Two candidates for such investigation involve the events surrounding plaque activation and endothelial dysfunction. Further investigation in these fields should provide the necessary insight to develop the next generation of interventions that will reduce the clinical manifestations of this devastating disease. The purpose of this work is to review the major theories of atherogenesis, examine the aspects of atherosclerosis that lead to disease activation and discuss aspects of disease activation that are amenable to treatment.     

HDL-associated PAF-AH reduces endothelial adhesiveness in apoE-/- mice.

Macrophage infiltration into the subendothelial space at lesion prone sites is the primary event in atherogenesis. Inhibition of macrophage homing might therefore prevent atherosclerosis. Since HDL levels are inversely correlated with cardiovascular risk, their effect on macrophage homing was assessed in apoE-deficient (apoE-/-) mice. Overexpression of human apolipoprotein AI in apoE-/- mice increased HDL levels 3-fold and reduced macrophage accumulation in an established assay of leukocyte homing to aortic root endothelium 3.2-fold (P<0.005). This was due to reduced in vivo betaVLDL oxidation, reduced betaVLDL triggered endothelial cytosolic Ca2+ signaling through PAF-like bioactivity, lower ICAM-1 and VCAM-1 expression, and diminished ex vivo leukocyte adhesion. Adenoviral gene transfer of human PAF-acetylhydrolase (PAF-AH) in apoE-/- mice increased PAF-AH activity 1.5-fold (P<0.001), reduced betaVLDL-induced ex vivo macrophage adhesion 3.5-fold (P<0.01), and reduced in vivo macrophage homing 2.6-fold (P<0.02). These inhibitory effects were observed in the absence of increased HDL cholesterol levels. In conclusion, HDL reduces macrophage homing to endothelium by reducing oxidative stress via its associated PAF-AH activity. This protective mechanism is independent of the function of HDL as cholesterol acceptor. Modulation of lipoprotein oxidation by PAF-AH may prevent leukocyte recruitment to the vessel wall, a key feature in atherogenesis.     

Value or desirability of hemorheological-hemostatic parameter changes as endpoints in blood lipid-regulating trials.

High levels of plasma lipids have been recognized as a major risk factor in the development and progression of atherosclerosis, and to influence hemorheological factors that may predispose to thrombotic complications. Lipid-lowering interventions have been associated with a significant reduction of morbidity and mortality. Several mechanisms have been postulated for the observed clinical effect. Serum lipid-regulating therapies may reduce cardiovascular risk not only by altering the arterial wall, improving disturbed endothelial function, atherogenesis and plaque stability, but also through their antithrombogenic effects and influence on blood flow properties associated with hyperlipidemia. In this article, we will review the recent literature and discuss the value of hemorheological-hemostatic findings as surrogate endpoints for clinical trials in dyslipidemic patients.     

Chlamydia pneumoniae-infected monocytes exhibit increased adherence to human aortic endothelial cells

Interactions between monocytes and endothelial cells play an important role in the pathogenesis of atherosclerosis, and monocyte adhesion to arterial endothelium is one of the earliest events in atherogenesis. Work presented in this study examined human monocyte adherence to primary human aortic endothelial cells following monocyte infection with Chlamydia pneumoniae, an intracellular pathogen associated with atherosclerosis by a variety of sero-epidemiological, pathological and functional studies. Infected monocytes exhibited enhanced adhesion to aortic endothelial cells in a time- and dose-dependent manner. Pre-treatment of C. pneumoniae with heat did not effect the organism's capacity to enhance monocyte adhesion, suggesting that heat-stable chlamydial antigens such as chlamydial lipopolysaccharide (cLPS) mediated monocyte adherence. Indeed, treatment of monocytes with cLPS was sufficient to increase monocyte adherence to endothelial cells, and increased adherence of infected or cLPS-treated monocytes could be inhibited by the LPS antagonist lipid X. Moreover, C. pneumoniae-induced adherence could be inhibited by incubating monocytes with a mAb specific to the human beta 2-integrin chain, suggesting that enhanced adherence resulted from increased expression of these adhesion molecules. These data show that C. pneumoniae can enhance the capacity of monocytes to adhere to primary human aortic endothelial cells. The enhanced adherence exhibited by infected monocytes may increase monocyte residence time in vascular sites with reduced wall shear stress and promote entry of infected cells into lesion-prone locations.