Infection and inflammation as risk factors for thrombosis and atherosclerosis

Severe infection and inflammation almost invariably lead to hemostatic abnormalities, ranging from insignificant laboratory changes to gross activation of coagulation that may result in localized thrombotic complications or systemic intravascular fibrin deposition. Systemic inflammation results in activation of coagulation, due to tissue factor-mediated thrombin generation, downregulation of physiological anticoagulant mechanisms, and inhibition of fibrinolysis. Proinflammatory cytokines, immune cells, and the endothelium play a central role in the differential effects on the coagulation and fibrinolysis pathways. Vice-versa, activation of the coagulation system may importantly affect inflammatory responses by direct and indirect mechanisms. Similar mechanisms appear to play a role in the development of atherosclerosis and related arterial thrombosis. Apart from the general coagulation response to inflammation associated with severe infection, specific infections may cause distinct features, such as hemorrhagic fever or thrombotic microangiopathy.     

Coronary atherosclerosis, low-density lipoproteins and markers of thrombosis, inflammation and endothelial dysfunction

Available information regarding the relation among atherosclerosis, low-density lipoproteins, markers of thrombosis, inflammation and endothelial dysfunction has accumulated, but is still very limited, making only minimal contributions to clinical decision-making. Many more clinical trials are needed, but unless there is a relationship between atherosclerosis prevention, specific markers and a pharmaceutical product, financial support for such trials will be difficult to obtain. The anti-inflammatory effect of statins is well established. Angiotensin-converting enzyme inhibitors are generally not thought of as having anti-inflammatory effects, but the European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA) study observed extensive RR reduction with perindopril. It was explained not simply by control of hypertension, but by reduced activity of multiple factors, supported by specific substudies. The 'cardiovascular continuum' is an excellent unifying term to explain atherosclerosis mechanisms, relate mechanisms to clinical understanding, and assist the clinician in selecting the appropriate prevention and control therapies. This so-called continuum actually describes a relationship among different biochemical, enzymatic and hormonal factors that affect the cardiovascular system. It can be seen in the downregulation of the angiotensin II receptor type 1 by statins, which contributes to hypertension control while lowering low-density lipoproteins. Peroxisome proliferator activator receptor-gamma also demonstrates the cardiovascular continuum with activation of the receptor by glitazones. The glitazones increase insulin sensitivity for diabetes control. Activation of the peroxisome proliferator activator receptor-gamma inhibits inflammation, which is possibly related to atherosclerosis, normalization of endothelial function, suppression of metalloproteinases and a decrease in smooth muscle cell migration. All of these effects may decrease atherosclerosis production while improving control of diabetes mellitus, a key disease in the cardiovascular continuum for development of atherosclerosis. Consideration of such interrelationships is just scratching the surface. Nevertheless, it can be seen that the complicated process of atherosclerosis development has a multifaceted explanation that has been minimally defined, but holds the key to prevention and control of this major medical problem faced in modern society.     

Platelets in inflammation and thrombosis

For many years it has been known that platelets play an important role in thrombosis and hemostasis. In recent times, however, it has become evident that platelets also have relevant functions in inflammation. It was shown that thrombosis and inflammation share several key molecular mechanisms and in fact are 2 intrinsically linked processes. In this review, we intend to give a short overview with emphasis on work stemming from our laboratory.     

Arterial inflammation and atherosclerosis

Arterial inflammation is a significant component of atherosclerotic disease and it has been suggested that specific immune responses directed against autoantigens or pathogen-derived antigens presented in the vascular wall could initiate and/or maintain atherosclerotic processes. Atherogenic cofactors such as altered cholesterol metabolism may not only impact locally on inflammatory responses in atherosclerotic lesions, but may also alter general immune-responsiveness. The evidence to date suggests that the mutual chronic perpetuation of immune mediated vascular inflammation and cholesterol-induced atherosclerosis is a key step in atherogenesis.     

Potential role of viruses in thrombosis and atherosclerosis

Viruses have been implicated as triggers of endothelial injury initiating the process of atherosclerosis. Because patients with atherosclerosis suffer acute events associated with arterial thrombi obstructing a vital vessel, the role of viruses in promoting a procoagulant endothelium has been explored. This review targets the evidence that viruses contribute to atherogenesis, and discusses mechanisms by which specific herpes viruses promote inflammation and thrombosis.     

Novel markers of inflammation in atherosclerosis

Inflammation plays a key role in the pathogenesis of atherosclerosis. Understanding the process of inflammation as it pertains to atherosclerosis has provided researchers with multiple opportunities to identify novel markers for use in cardiovascular disease management. This article discusses the inflammatory cascade as it pertains to atherosclerosis and some of the well-studied markers of inflammation. It also discusses the limitations of current risk stratification models and characteristics of a good biomarker.     

Circulating markers of inflammation and atherosclerosis

Atherosclerosis is nowadays generally accepted as an inflammatory disease. It is known that local inflammation occurs in the formation the plaques, as macrophages and other immuno-competent cells are present in the lesions from an early stage, and it is also known that inflammation plays an important role in the weakening of the fibrous cap of the advanced plaque, eventually leading to plaque rupture and acute coronary syndromes. The present review focuses on two questions. First, if circulating markers of inflammation could differentiate between healthy subjects and those with atherosclerotic manifestations. Second, if those markers could differentiate between those with a stable atherosclerotic disease, such as stable angina pectoris, and those prone to unstable manifestations of atherosclerosis, such as acute coronary syndromes. Using data from both cross-sectional and prospective studies it could be shown that the majority of the studies which had investigated the role of markers for systemic inflammation, such as CRP, leukocyte count, serum fibrinogen and different cytokines, found elevated levels in patients with atherosclerosis and especially so in those with an unstable coronary disease. The same pattern was found when inflammatory markers with a vascular origin, such as the adhesion molecules, were investigated. Thus, based on the literature it is obvious that circulating markers of inflammation have a role as risk factors for unstable manifestations of atherosclerosis, but it is still unclear whether the different inflammatory markers merely are markers, or if they in an active way contribute to the development and progression of the atherosclerotic disease in their own.     

Liver x receptors in atherosclerosis and inflammation

Liver X receptors (LXRs) are cholesterol-sensing nuclear receptors that are not only key regulators of lipid metabolism and transport but also suppress inflammatory signaling in macrophages through a unique mechanism of transrepression. In this brief review, we focus on the regulatory actions of LXR primarily in macrophages responding to a proatherogenic environment. LXR potentially interferes with atherosclerosis by 2 different agonist-dependent signaling pathways. The first is through promoting reverse cholesterol transportby directly activating genes of cellular cholesterol export. The second is through a general inhibitory action on proinflammatory genes where sumo-modified and agonist-bound LXR recruits negative coregulatory proteins to nuclear factor κB at immune response gene promoters through protein-protein interactions. The antiinflammatory actions of LXR may be a direct response to the proinflammatory actions recently proposed for cholesterol on inflammasome activity in the vessel wall.     

Chronic infections and atherosclerosis/thrombosis

An emerging pathophysiologic paradigm implicates chronic inflammation in the initiation, progression, and destabilization of atherosclerotic vascular disease. Various potential contributors to the inflammatory response in the vessel wall include atherogenic lipids, mechanical stress and injury, hypertension and angiotensin II, cigarette smoking, immune response to neoantigens, and chronic infections with viruses and or bacteria (Table I). The potential link between chronic infection and atherosclerosis/thrombosis is under extensive investigation in several laboratories around the world. Although indirect evidence and experimental data tend to support this link, definitive proof is still lacking. If such a link is eventually proven to be causal in nature, it will provide a novel target for preventive and therapeutic strategies (anti-infective drugs, vaccines, etc.) against a common disease that is the leading killer of people in Western nations. Results of ongoing, large-scale clinical trials are eagerly awaited.     

Potential role of statins in inflammation and atherosclerosis

The mevalonate pathway plays a crucial role in regulation of cellular cholesterol synthesis and isoprenoid groups. The entire pathway is closely regulated by feedback from an enzyme in the cascade, 3-hydroxy-3-methyl-CoA (HMG-CoA) reductase, as well as LDL receptors. Clinically, inhibition of this pathway by statins, potent inhibitors of HMG-CoA reductase, has been shown to reduce plasma levels of LDL cholesterol and several clinical trials with this group of drugs have demonstrated a remarked improvement in cardiovascular risk reduction. Interestingly, the improvement in cardiovascular end points in those trials was superior to estimations calculated from the effect on LDL cholesterol lowering. These findings support the idea of non-lipid effects of statins in atherosclerosis. Further, recent observations using in vivo and in vitro models of atherosclerosis have shed light on their potential role for manipulation of various cellular functions via inhibition of the mevalonate pathway. Among them, recently identified inhibitory effects of statins on monocyte-endothelial interaction suggest their effect on inflammation. Herein, we discuss recent progress in this area of study, with special focus on the biological function of statins.     

同型半胱氨酸、炎症与动脉粥样硬化

高同型半胱氨酸血症是动脉粥样硬化形成的一种独立危险因素。动脉粥样硬化是一种慢性炎症过程,从炎症角度出发研究同型半胱氨酸与动脉粥样硬化的关系也得到了人们的关注。现就炎症在同型半胱氨酸致动脉粥样硬化的作用及其机制方面的研究进展作一综述。     

Macrophages, inflammation, and atherosclerosis

The macrophage plays a diverse array of roles in atherogenesis and lipoprotein metabolism. The macrophage functions as a scavenger cell, an immune mediator cell, and as a source of chemotactic molecules and cytokines. Chemokines have been implicated in promoting migration of monocytes into the arterial intima. Monocyte chemoattractant protein-1 (MCP-1) attracts monocytes bearing the chemokine receptor CCR-2. Macrophage expression of cyclooxygenase-2, a key enzyme in inflammation, promotes atherosclerotic lesion formation in low-density lipoprotein receptor (LDLR)-deficient mice. In the arterial intima, monocytes differentiate into macrophages, which accumulate cholesterol esters to form lipid-laden foam cells. Foam cell formation can be viewed as an imbalance in cholesterol homeostasis. The uptake of atherogenic lipoproteins is mediated by scavenger receptors, including SR-A and CD36. In the macrophage, ACAT-1 is responsible for esterifying free cholesterol with fatty acids to form cholesterol esters. Surprisingly, deficiency of macrophage ACAT-1 promotes atherosclerosis in LDLR-deficient mice. A number of proteins have been implicated in the process of promoting the efflux of free cholesterol from the macrophage, including apoE, ABCA1, and SRB-1. Macrophage-derived foam cells express the adipocyte fatty acid-binding protein (FABP), aP2, a cytoplasmic FABP that plays an important role in regulating systemic insulin resistance in the setting of obesity. ApoE-deficient mice null for macrophage aP2 expression develop significantly less atherosclerosis than controls wild type for macrophage aP2 expression. These results demonstrate a significant role for macrophage aP2 in the formation of atherosclerotic lesions independent of its role in systemic glucose and lipid metabolism. Furthermore, macrophages deficient in aP2 display alterations in inflammatory cytokine production. Through its distinct actions in adipocytes and macrophages, aP2 links features of the metabolic syndrome including insulin resistance, obesity, inflammation, and atherosclerosis.     

The role of adiponectin in atherosclerosis and thrombosis.

Obesity is a major risk factor for morbidity and mortality from cardiovascular causes. Adiponectin has been identified recently as one of the adipocytokines with important metabolic effects. It can suppress atherogenesis by inhibiting the adherence of monocytes, reducing their phagocytic activity, and suppressing the accumulation of modified lipoproteins in the vascular wall. In addition, as adiponectin decrease endothelial damage and stimulates production of NO from vascular endothelial cells, hypoadiponectinemia may be partially contribute to thrombus formation.     

New links between inflammation and thrombosis

This article is a summary of the Sol Sherry Lecture of the Council on Arteriosclerosis, Thrombosis, and Vascular Biology, which was presented at the Scientific Sessions of the American Heart Association in November 2004. It highlights work from our laboratory, focusing mainly on new aspects of P-selectin and CD40L (CD154) biology and on the interplay of platelets and leukocytes in thrombosis and inflammation.