This Article Abstract Full Text (PDF) All Versions of this Article: 43/5/924    most recent 01.HYP.0000123070.31763.55v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Granger, D. N. Articles by Petnehazy, T. Search for Related Content PubMed PubMed Citation Articles by Granger, D. N. Articles by Petnehazy, T. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Related Collections ACE/Angiotension receptors Pathophysiology Cell signalling/signal transduction Signal transduction Acute coronary syndromes Acute myocardial infarction Endothelium/vascular type/nitric oxide

(Hypertension. 2004;43:924.)
© 2004 American Heart Association, Inc.

Brief Reviews

Modulation of the Inflammatory Response in Cardiovascular Disease

From the Department of Molecular and Cellular Physiology (D.N.G.), Louisiana State University Health Sciences Center, Shreveport; the Department of General Surgery (T.V.), University of Münster, Germany; and the University Clinic for Pediatric Surgery (T.P.), University of Graz, Austria.

Correspondence to D. Neil Granger, PhD, Department of Molecular and Cellular Physiology, LSU Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130-3932. E-mail dgrang{at}lsuhsc.edu

	Abstract

Top Abstract Introduction Adhesion Molecules Platelets Oxidative Stress Renin-Angiotensin System CD40/CD40L Interactions Conclusions References

 
There is a growing body of evidence that inflammation might play an important role in the initiation and progression of cardiovascular diseases (CVDs). The designation of CVD as a chronic inflammatory process is further supported by evidence that the risk factors for CVD cause endothelial cells throughout the vascular tree to assume an inflammatory phenotype. These activated endothelial cells characteristically exhibit oxidative stress and increased adhesiveness for circulating leukocytes. Although initial efforts to define the mechanisms underlying the inflammatory phenotype in diseased endothelial cells have focused on the linkage between oxidative stress and adhesion molecule activation/expression, recent work has implicated a variety of additional factors that can modulate the magnitude and/or nature of the inflammatory responses in CVD. Platelets, angiotensin II, and the CD40/CD40 ligand signaling system are gaining recognition as contributors to the pathogenesis of CVD. These factors appear to converge with known pathways that link oxidative stress with adhesion molecule expression and help to explain the apparent integration of coagulation with inflammation in CVD. These factors also hold the promise of offering multiple sites for therapeutic intervention in CVD.

Key Words: oxidative stress • integrins • angiotensin II • adhesion molecules

	Introduction

Top Abstract Introduction Adhesion Molecules Platelets Oxidative Stress Renin-Angiotensin System CD40/CD40L Interactions Conclusions References

 
Inflammation is gaining widespread attention for its role in the initiation and progression of cardiovascular disease (CVD). Epidemiological studies have revealed strong associations between biochemical markers of systemic inflammation and both the presence of and future risk for symptomatic CVD. Animal experimentation as well as clinical studies has provided convincing evidence that the known risk factors for CVD (hypertension, diabetes, hypercholesterolemia, and smoking) can elicit both an inflammatory and a prothrombogenic phenotype in the vascular system. The phenotypic changes are more pronounced in endothelial cells and can include oxidative stress, increased expression of endothelial cell adhesion molecules (CAMs), activation of cell signaling pathways (eg, the CD40/CD40 ligand [CD40L] dyad), and the consequent adhesion and activation of leukocytes and platelets. In the microcirculation, the inflammatory manifestations of CVD are more readily visible in postcapillary venules. There is growing evidence, however, that the endothelium-dependent arteriolar dysfunction often associated with CVD is also linked to the systemic inflammatory response.^1–4

Because the expression of adhesion glycoproteins by activated endothelial cells is a rate-determining step in the recruitment of inflammatory cells, much attention has been devoted to the role of endothelial CAMs in CVD. This attention has produced considerable evidence for the: (1) altered endothelial CAM expression in animal models of CVD^2,5; (2) use of circulating levels of soluble endothelial CAMs (eg, soluble intercellular adhesion molecule-1 [sICAM-1]) as a marker for the severity of inflammation in clinical CVD⁶; (3) endothelial CAM expression as a critical determinant of the end-organ damage and vascular dysfunction associated with experimental CVD^2,4,5; and (4) linkage between endothelial CAM expression and several other factors (eg, oxidative stress) that have also been implicated in the development of CVD.^7,8 Oxidative stress, platelets, the CD40/CD40L signaling system, and angiotensin II (Ang II) are some of the factors that influence endothelial CAM expression, and there is evidence for their involvement in the initiation and/or perpetuation of inflammation in CVD.^8,9

	Adhesion Molecules

Top Abstract Introduction Adhesion Molecules Platelets Oxidative Stress Renin-Angiotensin System CD40/CD40L Interactions Conclusions References

 
Leukocytes are recruited to sites of inflammation by a highly coordinated and well-regulated process that involves the expression and/or activation of adhesion molecules on endothelial cells and circulating inflammatory cells.^2,4 These CAMs ensure an orderly sequence of cell-cell interactions that initially involve slowing the leukocyte with a weak adhesive interaction that is manifested as rolling. As the adhesive forces between leukocytes and endothelial cells strengthen, the leukocytes become firmly attached and remain stationary on the vessel wall (adherence), where the process of transendothelial migration can occur. Each stage of leukocyte recruitment is mediated by different families of adhesion molecules that are expressed on leukocytes or endothelial cells (Table 1).

The selectins, which mediate leukocyte rolling, are expressed by leukocytes (L-selectin), platelets (P-selectin), and endothelial cells (E- and P-selectin).^2,4 L-selectin is constitutively expressed on leukocytes, yet it is shed after leukocyte activation. P-selectin is normally stored in granules within endothelial cells (Weibel-Palade bodies) and platelets (-granules), where it can be rapidly mobilized to the surface of activated cells. E-selectin is not normally expressed on endothelial cells; however, cytokines, reactive oxygen species (ROS), and bacterial endotoxin can elicit E-selectin expression through transcription-dependent mechanisms.^2,4

ß₂-Integrins are present on different leukocyte populations, where they exhibit unique binding specificity and signaling properties that depend on the combination of - and ß-subunits. The ß₂-integrins share a common ß₂-chain (CD18) that is linked to 1 of 4 -chains designated CD11a, CD11b, CD11c, and CD11d. In the nonactivated leukocyte, CD11a/CD18 (lymphocyte function–associated antigen-1 [LFA-1]) is in a nonadhesive state. Receptor-mediated leukocyte activation leads to conformational changes in LFA-1 structure; increased adhesiveness of the glycoprotein; and the subsequent adhesion, activation, and transendothelial migration of leukocytes. Although CD11b/CD18 (Mac-1) is constitutively expressed on circulating leukocytes, it is also stored in secretory granules from which the glycoprotein can be mobilized when leukocytes are activated. The leukocyte adhesion mediated by both Mac-1 and LFA-1 most likely involves an interaction with ICAM-1 or ICAM-2 expressed on endothelial cells.^2,4

Five members of the immunoglobulin supergene family have been implicated as mediators of leukocyte–endothelial cell adhesion: ICAM-1, ICAM-2, vascular cell adhesion molecule-1 (VCAM-1), platelet and endothelial cell adhesion molecule-1 (PECAM-1), and mucosal addressin CAM (MAdCAM-1). ICAM-1 is constitutively expressed on endothelial cells in most regional vascular beds, and its expression can be significantly increased on endothelial cell activation with cytokines or bacterial endotoxins. ICAM-2 is expressed on resting endothelial cells, and its expression is not influenced by endothelial cell activation.^2,4

VCAM-1, which mediates the adhesion of lymphocytes and monocytes, exhibits a lower level of constitutive expression on endothelial cells than does ICAM-1. However, its cell surface expression can increase dramatically by way of transcription-dependent (nuclear factor [NF]-B) mechanisms. PECAM-1 is constitutively expressed on endothelial cells, leukocytes, and platelets, where it can mediate heterotypic and homotypic cell interactions. This adhesion molecule, which does not respond to cytokine challenge, plays an important role in regulating the transendothelial migration of leukocytes. MAdCAM-1 is mainly expressed on high endothelial venules, where it mediates the trafficking of lymphocytes in lymphoid tissues.^2,4

Soluble isoforms of the different endothelial CAMs can be detected in normal serum, and elevated levels of these soluble CAMs have been noted in a variety of inflammatory diseases and CVDs.^6,10 The soluble CAMs are widely used as a surrogate marker of disease activity in different inflammatory conditions, including CVD. Soluble CAMs contain most of the extracellular domain of its endothelial counterpart, suggesting that the circulating isoform is shed from endothelial cells. However, the existence of endothelial cell mRNAs that specifically encodes sICAM-1,¹¹ as well as the different kinetics of sICAM-1 appearance and disappearance in blood compared with ICAM-1 expression on endothelial cells in cytokine-challenged mice,¹² suggests that soluble CAMs are unlikely to reflect corresponding changes in CAM expression on endothelial cells. Soluble P-selectin originates from both endothelial cells and platelets,¹³ thereby limiting its utility as a marker of endothelial cell activation.

There is a large body of evidence that implicates inflammation and adhesion molecules in the pathogenesis of CVD, including atherosclerosis, stroke, and myocardial infarction.^2,5 Hypertension, diabetes, hypercholesterolemia, hyperhomocysteinemia, and smoking are all associated with increased CAM expression on endothelial cells and/or increased levels of circulating soluble CAMs.^2,3,6,10,14 More direct evidence for the involvement of adhesion molecules has been generated from animals models of CVD. Monoclonal antibodies that block the function of specific CAMs and mutant mice that are genetically deficient in 1 or more CAMs have been used to demonstrate a critical role for inflammation and adhesion molecules in animal models of myocardial infarction and stroke.^2,4 The comparable protective actions of P-selectin and ICAM-1 (or CD11/CD18) directed interventions in many of these models suggest that interference with either the rolling or firm adherence of leukocytes effectively blunts leukocyte accumulation and the resulting tissue necrosis. Similarly dramatic results with antiadhesion strategies have been reported in animal models of atherosclerosis. For example, the complete absence of P-selectin, E-selectin, or ICAM-1 or the partial absence of VCAM-1 in mice that are genetically predisposed to atherosclerosis results in a significant delay in the development of atherosclerotic lesions.^5,13

Despite the immense success seen with antiadhesion strategies in animal models of CVD, the efficacy of antiadhesion therapy has not been as encouraging in the clinical setting. The limited numbers of phase II and III clinical trials based on antiadhesion therapy for CVD have not shown significant protection against either myocardial infarction or stroke.¹⁵ Nonetheless, comparable reagents have shown efficacy in clinical trials for chronic inflammatory diseases, such as psoriasis, rheumatoid arthritis, and inflammatory bowel disease,¹⁵ suggesting that either leukocyte–endothelial cell adhesion is not a critical component of human CVD or that better drugs or improved drug delivery strategies are needed to realize the potential of antiadhesion therapy in CVD. Opportunities to address the latter possibility are likely to result from ongoing industry efforts to develop improved humanized antibodies and small-molecule CAM inhibitors.

	Platelets

Top Abstract Introduction Adhesion Molecules Platelets Oxidative Stress Renin-Angiotensin System CD40/CD40L Interactions Conclusions References

 
An important function of the vasculature is to prevent the adhesion of platelets and subsequent formation of microthrombi, which can lead to impaired tissue perfusion. Endothelial cells help create this antithrombogenic surface. Accordingly, endothelial denudation or injury will lead to immediate platelet adhesion and aggregation at the site of injury. The binding of platelets to exposed regions of the subendothelial matrix is mediated by specific adhesion glycoproteins expressed on platelets that bind to ligands embedded in the matrix, such as von Willebrand factor, collagen, and fibronectin. There is evidence that platelets can also bind to the surface of activated endothelial cells and to leukocytes that are already adherent to the vessel wall.^7,16–19 These adhesive interactions between platelets and endothelial cells can be mediated by a variety of glycoproteins that are expressed on activated platelets, including P-selectin, PECAM-1, von Willebrand factor, and ß₃-integrins (glycoprotein IIb/IIIa).

There is growing recognition that platelets not only are involved in hemostasis and thrombosis but also can modulate acute and chronic inflammatory responses. The binding of activated platelets to endothelial cells and/or leukocytes can influence the intensity of an inflammatory response through the release of different bioactive compounds. Platelets release factors that might either inhibit (soluble P-selectin, nitric oxide [NO]) or activate (oxygen radicals, leukotrienes, thromboxane A₂) neutrophils.^20,21 Activated platelets can release and/or activate a variety of inflammatory molecules (Table 2) that can elicit endothelial activation.²² Platelets can also enhance the recruitment of leukocytes into inflamed tissue by serving as a P-selectin–rich platform on the endothelium for leukocyte adhesion²³ and by reducing shear rates in venules through the release of potent vasoconstrictors (eg, thromboxane A). Thrombin is another link between coagulation and inflammation. When thrombin binds to its receptor, protease-activated receptor-1, on endothelial cells, it induces the expression of P-selectin, E-selectin, VCAM-1, and ICAM-1 through activation of NF-B.²⁴

There are several lines of evidence that support an intimate connection between the hemostatic and inflammatory systems in CVD. Hypercholesterolemia appears to exert a profound influence on platelet reactivity to aggregating stimuli. Platelet activation in human subjects with elevated serum cholesterol levels is evident from the increased expression of P-selectin on platelets²⁵ and the corresponding increase in plasma levels of soluble P-selectin.²⁶ Mice maintained on a cholesterol-enriched diet exhibit P-selectin–dependent rolling and adhesion of platelets in postcapillary venules.²⁷ Platelet accumulation in atherosclerotic lesions is also well documented.^28–30 Recent studies in hypercholesterolemic apolipoprotein E^–/– mice indicate that platelets adhere to the carotid artery endothelium long before the development of atherosclerotic lesions and that prolonged blockade of platelet adhesion reduces leukocyte recruitment into the arterial wall and attenuates atherosclerotic lesion formation.^29,30

Although the link between hemostasis and inflammation is less clear in hypertension, this disease is associated with altered platelet function. Platelets from hypertensive subjects have an increased tendency to aggregate,³¹ an increased expression of P-selectin,^32,33 and increased intraplatelet calcium (a measure of cell activation).³⁴ Antiplatelet agents have also been shown to confer a degree of benefit to "high-risk" hypertensive patients.³⁵

	Oxidative Stress

Top Abstract Introduction Adhesion Molecules Platelets Oxidative Stress Renin-Angiotensin System CD40/CD40L Interactions Conclusions References

 
Oxidative stress is a characteristic feature of the inflammatory response. There are several enzymes that can generate ROS and result in oxidative stress, including the mitochondrial oxidases, xanthine oxidase, NAD(P)H oxidase, nitric oxide synthase (NOS), cytochrome P450, lipoxygenase, and cyclooxygenase.^7,36 The dominant ROS-producing enzyme in leukocytes is NAD(P)H oxidase, whereas endothelial cells have the capacity to generate ROS from several of the aforementioned enzymes. In normal tissues, ROS are detoxified by antioxidant enzymes like superoxide dismutase (SOD) and catalase and by the free radical scavengers normally present in extracellular fluid (eg, bilirubin, uric acid). The consumption of superoxide by basally generated NO appears to be of equal or greater quantitative importance (relative to SOD) in preventing oxidative stress.³⁶

During inflammation, ROS can promote the adhesion of blood cells to vascular endothelium by (1) eliciting the production of inflammatory mediators, (2) activating nuclear transcription factors that bind to genes encoding endothelial CAMs or cytokines, or (3) mobilizing preformed adhesion molecules to the endothelial cell surface.^7,36 Hydrogen peroxide can generate platelet-activating factor and leukotriene B₄, both of which will upregulate/activate ß₂-integrins on leukocytes. The ROS-sensitive nuclear transcription factors NF-B and activation protein-1 (AP-1) are present in the promoter regions of the genes for endothelial CAMs, such as E-selectin, ICAM-1, and VCAM-1. Oxidative stress has been linked to the activation of both NF-B and AP-1. ROS can also mobilize preformed pools of adhesion molecules in leukocytes (CD11b/CD18) and endothelial cells (P-selectin), which might explain the rapid recruitment of rolling and adherent leukocytes in inflamed tissue.

The importance of ROS in the initiation of leukocyte– and platelet–endothelial cell adhesion has been demonstrated in studies of reagents that either scavenge (eg, SOD or catalase) or inhibit (eg, allopurinol) the production of ROS.^37,38 Similarly, mice that are genetically deficient in critical protein subunits (eg, p47^phox) of NAD(P)H oxidase or transgenic mice that overexpress SOD exhibit attenuated leukocyte adhesion responses in models of oxidative stress.³⁹ Studies demonstrating that treatment of otherwise normal animals with inhibitors of NOS ⁴⁰ and endothelial NOS–knockout mice⁴¹ exhibit increased leukocyte adhesion support the view that a critical determinant of whether the vasculature assumes a proinflammatory or an anti-inflammatory (and therefore, a prothrombogenic or an antithrombogenic) phenotype is the balance between ROS and NO. Although NO and superoxide per se are often ascribed anti-inflammatory and proinflammatory (and antithrombogenic and prothrombogenic) roles, respectively, the products of their chemical interaction (RNOS) can yield either phenotype, depending on whether there is net oxidation or nitrosation of specific molecular targets that regulate the inflammatory response (Figure 1).^3,36

View larger version (90K): [in this window] [in a new window]   Figure 1. Role of superoxide-NO balance in determining the anti/proinflammatory phenotype assumed by the vasculature. Under normal conditions (left), the flux of NO generated by the vascular wall greatly exceeds the production of superoxide. Antioxidant enzymes (SOD, catalase) prevent oxidative stress. NO acts through transcription-dependent and -independent (eg, cGMP) mechanisms to prevent the adhesion of leukocytes and platelets. The risk factors for CVD can result in the activation of enzymes (xanthine oxidase, XO; NAD(P)H oxidase) that produce large quantities of superoxide (right). The resulting superoxide-NO imbalance promotes the formation of mediators (eg, leukotriene [LT] B4, platelet-activating factor [PAF], interleukin [IL]-8) that activate and induce the homo- and heterotypic adhesion of leukocytes and platelets. The activation of oxidant-sensitive transcription factors (NF-B, activator protein [AP]-1) leads to increased synthesis and surface expression of endothelial CAMs, which further enhance leukocyte recruitment. Statins and drugs targeting the RAS appear to limit the transition from an anti-inflammatory to a proinflammatory phenotype. GSH indicates reduced glutathione; Tx, thromboxane; ACE, angiotensin-converting enzyme; e, endothelial; and GC, guanylyl cyclase. Other abbreviations are as defined in text.

There is evidence implicating oxidative stress in the pathogenesis of stroke,⁴² myocardial infarction,⁴³ myocardial stunning,⁴⁴ atherosclerosis,^8,45 and congestive heart failure.⁴⁶ Similarly, there is evidence that implicates ROS in the deleterious effects of hypercholesterolemia,^3,7 hypertension,⁴⁷ diabetes mellitus,⁴⁸ cigarette smoke,⁴⁹ and hyperhomocysteinemia.⁵⁰ How much of the protective effect afforded by antioxidant therapy can be attributed to an attenuated inflammatory response remains unclear for many models of experimental CVD. However, large-scale clinical trials of antioxidant vitamin supplementation have failed to confirm the benefits predicted from animal studies.⁵¹

	Renin-Angiotensin System

Top Abstract Introduction Adhesion Molecules Platelets Oxidative Stress Renin-Angiotensin System CD40/CD40L Interactions Conclusions References

 
Whereas Ang II has long been appreciated for its role in the regulation of blood pressure and salt balance, there is evidence that implicates the renin-angiotensin system (RAS) in the inflammation associated with CVD. A key response of endothelial cells and inflammatory cells to Ang II is increased production of ROS and the consequent imbalance between ROS and NO.^47,52 This pro-oxidative effect of Ang II results from its engagement to the high-affinity angiotensin II type 1 (AT₁) receptor, which leads to the activation of NAD(P)H.⁵³ The proinflammatory AT₁ receptor is found on endothelial cells and circulating blood cells, including neutrophils, monocytes, T lymphocytes, and platelets. AT₁ receptor antagonists block the oxidative stress induced in these cells by Ang II.^54,55

The redox-sensitive nuclear transcription factor NF-B appears to be an important link between AT₁ receptor activation, oxidative stress, and the inflammatory phenotype that is assumed by Ang II–responsive cells.⁵⁶ Activation of NF-B by the AT₁ receptor induces redox-sensitive genes for certain endothelial CAMs (eg, VCAM-1), cytokines (eg, tumor necrosis factor [TNF]-), and chemokines (monocyte chemoattractant protein-1).⁵⁷ Ang II can also engage the AT₁ receptors on leukocytes to promote ß₂-integrin upregulation.⁴⁷ Superfusion of the rat mesentery with subvasoconstrictor doses of Ang II induces an AT₁ receptor–dependent rolling, firm adhesion and emigration of leukocytes, and an enhanced production of ROS in postcapillary venules.⁵⁸ These effects of Ang II appear to result from an ROS-dependent mobilization of preformed P-selectin to the endothelial cell surface.⁵⁸

Losartan decreases P-selectin expression on platelets,⁵⁹ suggesting that Ang II might also exert some of its proinflammatory actions in vivo by activating platelets. Platelets normally express AT₁ receptors, and AT₁ receptor antagonists have been shown to attenuate platelet adhesion⁶⁰ and aggregation⁵⁹ in vitro and to mediate an antithrombotic effect in vivo.⁵⁹ This action might be linked to NO production, because losartan is known to enhance NO release from platelets.⁶¹

Although there is limited evidence for the involvement of inflammation-dependent processes in the protective effects of AT₁ receptor antagonists in myocardial infarction⁶² and stroke,⁶³ a more compelling case can be made for the involvement of Ang II and AT₁ receptors in the inflammatory responses associated with hypercholesterolemia and atherosclerosis.⁶⁴ Hypercholesterolemia is associated with an increased density of AT₁ receptors on endothelial cells, circulating leukocytes, and platelets.^45,54,55 This response is prevented by statin treatment through a mechanism that is independent of the drugs’ lipid-lowering effect.^54,55 The possibility that Ang II and AT₁ receptors are involved in eliciting the oxidative stress and leukocyte–endothelial cell adhesion of hypercholesterolemia is supported by studies of both large and microscopic blood vessels.^52,65 Furthermore, surrogate markers for endothelial activation and inflammation (eg, sVCAM-1) indicate that RAS-directed drugs might exert some of their beneficial effects by controlling the inflammatory response that accompanies CVD.

	CD40/CD40L Interactions

Top Abstract Introduction Adhesion Molecules Platelets Oxidative Stress Renin-Angiotensin System CD40/CD40L Interactions Conclusions References

 
CD40/CD40L signaling might represent an important communication system that enables blood cells to amplify the endothelial cell responses to inflammation and contribute to the regulation of hemostasis.⁶⁶ CD40, a member of the TNF receptor family of proteins, is constitutively expressed on platelets and endothelial cells. CD154 (or CD40L), the ligand for CD40, is found on cells of the immune system (eg, T lymphocytes) and on activated platelets.⁶⁷ CD40L also exists in a soluble form (sCD40L), which is shed from lymphocytes and platelets within minutes to hours after cell activation.⁶⁸ Engagement of CD40L with CD40 on endothelial cells results in phenotypic changes in the endothelial cell that are similar to those induced by TNF-, ie, increased expression of E-selectin, ICAM-1, and VCAM-1; increased secretion of the chemokines interleukin-8, interleukin-6, and monocyte chemoattractant protein-1^66,68; and enhanced production of ROS.⁶⁹

There are several lines of evidence that implicate CD40/CD40L signaling in the vascular pathology associated with hypercholesterolemia. Patients with moderate hypercholesterolemia exhibit significantly increased expression of CD40L and P-selectin on platelets and elevated CD40 expression on monocytes.²⁵ Statin treatment significantly reduces CD40 and CD40L expression and lowers sCD40L in patients with familial hypercholesterolemia.⁷⁰ Blockade of CD40L by neutralizing antibodies or genetic disruption of CD40L in mice appears to prevent the initiation and progression of atherosclerosis and induces a more stable plaque with fewer inflammatory cells, less lipids, and more smooth muscle cells and collagen.^71,72 Elevated levels of soluble and membrane-bound forms of CD40L have been reported for patients with angina,⁷³ after cardiopulmonary bypass surgery,⁷⁴ and with congestive heart failure.⁷⁵ Elevated blood levels of sCD40L even appear to be associated with the risk of future cardiovascular events in otherwise healthy women and predict patients with high-risk atherosclerotic lesions.^76,77

	Conclusions

Top Abstract Introduction Adhesion Molecules Platelets Oxidative Stress Renin-Angiotensin System CD40/CD40L Interactions Conclusions References

 
Preclinical and clinical research has provided considerable evidence for the involvement of inflammation in CVD. Parallel efforts to better understand the processes of hemostasis and coagulation have revealed an intimate link between platelet function and the inflammatory response. These revelations have fueled an intense interest in defining the nature and consequences of the interactions of blood cells with the vessel wall in CVD. Although the adhesion molecules that mediate these interactions are now well defined, the mechanisms that underlie the activation and/or increased expression of these adhesion molecules in CVD remain incompletely understood. Four distinct lines of investigation dealing with platelets, oxidative stress, Ang II receptor activation, and the CD40/CD40L signaling system are now merging (Figure 2) as a result of the effort to understand the events that initiate adhesion molecule involvement in CVD. These relative newcomers to the field of cardiovascular research have led to novel predictors for cardiovascular risk and hold the promise of offering multiple sites for therapeutic intervention in CVD, which should be considered in the design of future clinical trials.

View larger version (72K): [in this window] [in a new window]   Figure 2. The coordinated interactions of Ang II, oxidative stress, adhesion molecules, CD40/CD40L, platelets, and leukocytes with activated endothelial cells of diseased blood vessels. Ang II is able to induce the expression of adhesion molecules on endothelial cells, leukocytes, and platelets through oxidative stress (NADPH)-dependent and -independent mechanisms. Activated endothelial cells can sustain the adhesion of platelets through direct and indirect (via adherent leukocytes) mechanisms. ESL indicates E-selectin ligand; VLA, very late antigen; and PSGL, P-selectin glycoprotein ligand.

	Acknowledgments

 
Supported by grants from the National Institutes of Health (R01 HL26441 and P01 DK43785).

Received October 29, 2003; first decision December 17, 2003; accepted February 9, 2004.

	References

Top Abstract Introduction Adhesion Molecules Platelets Oxidative Stress Renin-Angiotensin System CD40/CD40L Interactions Conclusions References

 
1. Drexler H, Hornig B. Endothelial dysfunction in human disease. J Mol Cell Cardiol. 1999; 31: 51–60.[CrossRef][Medline] [Order article via Infotrieve]

2. Krieglstein CF, Granger DN. Adhesion molecules and their role in vascular disease. Am J Hypertens. 2001; 14: 44S–54S.[CrossRef][Medline] [Order article via Infotrieve]

3. Stokes KY, Cooper D, Tailor A, Granger DN. Hypercholesterolemia promotes inflammation and microvascular dysfunction: role of nitric oxide and superoxide. Free Radic Biol Med. 2002; 33: 1026–1036.[CrossRef][Medline] [Order article via Infotrieve]

4. Tailor A, Granger DN. Role of adhesion molecules in vascular regulation and damage. Curr Hypertens Rep. 2000; 2: 78–83.[Medline] [Order article via Infotrieve]

5. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation. 2002; 105: 1135–1143.[Abstract/Free Full Text]

6. Mulvihill NT, Foley JB, Crean P, Walsh M. Prediction of cardiovascular risk using soluble cell adhesion molecules. Eur Heart J. 2002; 23: 1569–1574.[Free Full Text]

7. Cooper D, Stokes KY, Tailor A, Granger DN. Oxidative stress promotes blood cell-endothelial cell interactions in the microcirculation. Cardiovasc Toxicol. 2002; 2: 165–180.[CrossRef][Medline] [Order article via Infotrieve]

8. Cai H, Harrison DG. Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ Res. 2000; 87: 840–844.[Abstract/Free Full Text]

9. Schönbeck U, Libby P. The CD40/CD154 receptor/ligand dyad. Cell Mol Life Sci. 2001; 58: 4–43.[CrossRef][Medline] [Order article via Infotrieve]

10. Meydani M. Soluble adhesion molecules: surrogate markers of cardiovascular disease? Nutr Rev. 2003; 61: 63–68.[CrossRef][Medline] [Order article via Infotrieve]

11. King PD, Sandberg ET, Selvakumar A, Fang P, Beaudet AL, Dupont B. Novel isoforms of murine intercellular adhesion molecule-1 generated by alternative RNA splicing. J Immunol. 1995; 154: 6080–6093.[Abstract]

12. Komatsu S, Flores S, Gerritsen ME, Anderson DC, Granger DN. Differential up-regulation of circulating soluble and endothelial cell intercellular adhesion molecule-1 in mice. Am J Pathol. 1997; 151: 205–214.[Abstract]

13. Burger PC, Wagner DD. Platelet P-selectin facilitates atherosclerotic lesion development. Blood. 2003; 101: 2661–2666.[Abstract/Free Full Text]

14. Lehr HA. Microcirculatory dysfunction induced by cigarette smoking. Microcirculation. 2000; 7: 367–384.[CrossRef][Medline] [Order article via Infotrieve]

15. Harlan JM, Winn RK. Leukocyte-endothelial interactions: clinical trials of anti-adhesion therapy. Crit Care Med. 2002; 30 (suppl): S214–S219.[CrossRef][Medline] [Order article via Infotrieve]

16. Massberg S, Enders G, Leiderer R, Eisenmenger S, Vestweber D, Krombach F, Messmer K. Platelet-endothelial cell interactions during ischemia/reperfusion: the role of P-selectin. Blood. 1998; 92: 507–512.[Abstract/Free Full Text]

17. Massberg S, Enders G, Matos FC, Tomic LI, Leiderer R, Eisenmenger S, Messmer K, Krombach F. Fibrinogen deposition at the postischemic vessel wall promotes platelet adhesion during ischemia-reperfusion in vivo. Blood. 1999; 94: 3829–3838.[Abstract/Free Full Text]

18. Kirton CM, Nash GB. Activated platelets adherent to an intact endothelial cell monolayer bind flowing neutrophils and enable them to transfer to the endothelial surface. J Lab Clin Med. 2000; 136: 303–313.[CrossRef][Medline] [Order article via Infotrieve]

19. Russell J, Cooper D, Tailor A, Stokes KY, Granger DN. Low venular shear rates promote leukocyte-dependent recruitment of adherent platelets. Am J Physiol Gastrointest Liver Physiol. 2003; 284: G123–G129.[Abstract/Free Full Text]

20. Mannaioni PF, DiBello MG, Masini E. Platelets and inflammation: role of platelet-derived growth factor, adhesion molecules and histamine. Inflammation Res. 1997; 46: 4–18.[CrossRef][Medline] [Order article via Infotrieve]

21. Bazzoni G, Dejana E, Del Maschio A. Platelet-neutrophil interactions, possible relevance in the pathogenesis of thrombosis and inflammation. Haematologica. 1991; 76: 491–499.[Medline] [Order article via Infotrieve]

22. Lindemann S, Tolley ND, Dixon DA, McIntyre TM, Prescott SM, Zimmermann GA, Weyrich AS. Activated platelets mediate inflammatory signaling by regulated interleukin 1â synthesis. J Cell Biol. 2001; 154: 485–490.[Abstract/Free Full Text]

23. Salter JW, Krieglstein CF, Issekutz AC, Granger DN. Platelets modulate ischemia/reperfusion-induced leukocyte recruitment in the mesenteric circulation. Am J Physiol Gastrointest Liver Physiol. 2001; 281: G1432–G1439.[Abstract/Free Full Text]

24. Strukova SM. Thrombin as a regulator of inflammation and reparative processes in tissues. Biochemistry (Mosc). 2001; 66: 8–18.[CrossRef][Medline] [Order article via Infotrieve]

25. Garlichs CD, John S, Schmeisser A, Eskafi S, Stumpf C, Karl M, Goppelt-Struebe M, Schmieder R, Daniel WG. Upregulation of CD40 and CD40 ligand (CD154) in patients with moderate hypercholesterolemia. Circulation. 2001; 104: 2395–2400.[Abstract/Free Full Text]

26. Ferroni P, Basili S, Vieri M, Martini F, Labbadia G, Bellomo A, Gazzaniga PP, Cordova C, Alessandri C. Soluble P-selectin and proinflammatory cytokines in patients with polygenic type IIa hypercholesterolemia. Haemostasis. 1999; 29: 277–285.[CrossRef][Medline] [Order article via Infotrieve]

27. Tailor A, Granger DN. Hypercholesterolemia promotes P-selectin-dependent platelet–endothelial cell adhesion in postcapillary venules. Arterioscler Thromb Vasc Biol. 2003; 23: 675–680.[Abstract/Free Full Text]

28. Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999; 340: 115–126.[Free Full Text]

29. Huo Y, Schober A, Forlow SB, Smith DF, Hyman MC, Jung S, Littman DR, Weber C, Ley K. Circulating activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein E. Nat Med. 2003; 9: 61–67.[CrossRef][Medline] [Order article via Infotrieve]

30. Massberg S, Brand K, Gruener S, Page S, Mueller E, Mueller I, Bergmeier W, Richter T, Lorenz M, Konrad I, Nieswandt B, Gawaz M. A critical role of platelet adhesion in the initiation of atherosclerotic lesion formation. J Exp Med. 2002; 196: 887–896.[Abstract/Free Full Text]

31. Tofler GH, Brezinski D, Schafer AI, Czeisler CA, Rutherford JD, Willich SN, Gleason RE, Williams GH, Miller JE. Concurrent morning increase in platelet aggregability and the risk of myocardial infarction and sudden cardiac death. N Engl J Med. 1987; 316: 1514–1518.[Abstract]

32. Goto S, Tamura N, Eto K, Ikeda Y, Handa S. Functional significance of adenosine 5'-diphosphonate receptor (P2Y₁₂) in platelet activation initiated by binding of von Willebrand factor to platelet GPIba induced by conditions of high shear rate. Circulation. 2002; 105: 2531–2536.[Abstract/Free Full Text]

33. Spencer CG, Gurney D, Blann AD, Beevers DG, Lip GY. Von Willebrand factor, soluble P-selectin, and target organ damage in hypertension: a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial. Hypertension. 2002; 40: 61–66.[Abstract/Free Full Text]

34. Quang-Sang KH, Levenson J, Simon A, Meyer P, Devynck MA. Platelet cytosolic free calcium concentration and plasma cholesterol in untreated hypertensives. J Hypertens. 1987; 5: S251–S254.

35. Nadar S, Lip GY. The prothrombotic state in hypertension and the effects of antihypertensive treatment. Curr Pharm Des. 2003; 9: 1715–1732.[Medline] [Order article via Infotrieve]

36. Grisham MB, Granger DN, Lefer DJ. Modulation of leukocyte-endothelial interactions by reactive metabolites of oxygen and nitrogen: relevance to ischemic heart disease. Free Radic Biol Med. 1998; 25: 404–433.[CrossRef][Medline] [Order article via Infotrieve]

37. Granger DN, Benoit JN, Suzuki M, Grisham MB. Leukocyte adherence to venular endothelium during ischemia-reperfusion. Am J Physiol. 1989; 257: G683–G688.[Medline] [Order article via Infotrieve]

38. Akgur FM, Brown MF, Zibari GB, McDonald JC, Epstein CJ, Ross CR, Granger DN. Role of superoxide in hemorrhagic shock-induced P-selectin expression. Am J Physiol Heart Circ Physiol. 2000; 279: H791–H797.[Abstract/Free Full Text]

39. Stokes KY, Clanton EC, Russell JM, Ross CR, Granger DN. NAD(P)H oxidase-derived superoxide mediates hypercholesterolemia-induced leukocyte-endothelial cell adhesion. Circ Res. 2001; 88: 499–505.[Abstract/Free Full Text]

40. Hickey MJ, Kubes P. Role of nitric oxide in regulation of leucocyte-endothelial cell interactions. Exp Physiol. 1997; 82: 339–348.[Medline] [Order article via Infotrieve]

41. Lefer DJ, Jones SP, Girod WG, Baines A, Grisham MB, Cockrell AS, Huang PL, Scalia R. Leukocyte-endothelial cell interactions in nitric oxide synthase-deficient mice. Am J Physiol. 1999; 276: H1943–H1950.[Medline] [Order article via Infotrieve]

42. Chan PH. Reactive oxygen radicals in signaling and damage in the ischemic brain. J Cereb Blood Flow Metab. 2001; 21: 2–14.[CrossRef][Medline] [Order article via Infotrieve]

43. Jones SP, Girod WG, Marotti KR, Aw TY, Lefer DJ. Acute exposure to a high cholesterol diet attenuates myocardial ischemia-reperfusion injury in cholesteryl ester transfer protein mice. Coron Artery Dis. 2001; 12: 37–44.[CrossRef][Medline] [Order article via Infotrieve]

44. Lefer DJ, Granger DN. Oxidative stress and cardiac disease. Am J Med. 2000; 109: 315–323.[CrossRef][Medline] [Order article via Infotrieve]

45. Warnholtz A, Nickenig G, Schulz E, Macharzina R, Brasen JH, Skatchkov M, Heitzer T, Stasch JP, Griendling KK, Harrison DG, Bohm M, Meinertz T, Munzel T. Increased NADH-oxidase-mediated superoxide production in the early stages of atherosclerosis: evidence for involvement of the renin-angiotensin system. Circulation. 1999; 99: 2027–2033.[Abstract/Free Full Text]

46. Byrne JA, Grieve DJ, Cave AC, Shah AM. Oxidative stress and heart failure. Arch Mal Coeur Vaiss. 2003; 96: 214–221.[Medline] [Order article via Infotrieve]

47. Nickenig G, Harrison DG. The AT₁-type angiotensin receptor in oxidative stress and atherogenesis, part I: oxidative stress and atherogenesis. Circulation. 2002; 105: 393–396.[Free Full Text]

48. Panes J, Kurose I, Rodriguez-Vaca D, Anderson DC, Miyasaka M, Tso P, Granger DN. Diabetes exacerbates inflammatory responses to ischemia-reperfusion. Circulation. 1996; 93: 161–167.[Abstract/Free Full Text]

49. Burke A, FitzGerald GA. Oxidative stress and smoking-induced vascular injury. Prog Cardiovasc Dis. 2003; 46: 79–90.[CrossRef][Medline] [Order article via Infotrieve]

50. Rodrigo R, Passalacqua W, Araya J, Orellana M, Rivera G. Implication of oxidative stress and homocysteine in the pathophysiology of essential hypertension. J Cardiovasc Pharmacol. 2003; 42: 453–461.[CrossRef][Medline] [Order article via Infotrieve]

51. Clarke R, Armitage J. Antioxidant vitamins and risk of cardiovascular disease: review of large-scale randomised trials. Cardiovasc Drugs Ther. 2002; 16: 411–415.[CrossRef][Medline] [Order article via Infotrieve]

52. Nickenig G, Harrison DG. The AT₁-type angiotensin receptor in oxidative stress and atherogenesis, part II: AT₁ receptor regulation. Circulation. 2002; 105: 530–536.[Free Full Text]

53. Cai H, Griendling KK, Harrison DG. The vascular NAD(P)H oxidases as therapeutic targets in cardiovascular diseases. Trends Pharmacol Sci. 2003; 24: 471–478.[CrossRef][Medline] [Order article via Infotrieve]

54. Strawn WB, Ferrario CM. Mechanisms linking angiotensin II and atherogenesis. Curr Opin Lipidol. 2002; 13: 505–512.[CrossRef][Medline] [Order article via Infotrieve]

55. Nickenig G. Central role of the AT₁-receptor in atherosclerosis. J Hum Hypertens. 2002; 16 (suppl 3): S26–S33.

56. Costanzo A, Moretti F, Burgio VL, Bravi C, Guido F, Levrero M, Puri PL. Endothelial activation by angiotensin II through NF-B and p38 pathways: involvement of NF-B-inducible kinase (NIK), free oxygen radicals, and selective inhibition by aspirin. J Cell Physiol. 2003; 195: 402–410.[CrossRef][Medline] [Order article via Infotrieve]

57. Phillips MI, Kagiyama S. Angiotensin II as a pro-inflammatory mediator. Curr Opin Invest Drugs. 2002; 3: 569–577.[Medline] [Order article via Infotrieve]

58. Alvarez A, Sanz MJ. Reactive oxygen species mediate angiotensin II-induced leukocyte-endothelial cell interactions in vivo. J Leukoc Biol. 2001; 70: 199–206.[Abstract/Free Full Text]

59. Lopez-Farre A, Sanchez de Miguel L, Monton M, Jimenez A, Lopez-Bloya A, Gomez J, Nunez A, Rico L, Casado S. Angiotensin II AT₁ receptor antagonists and platelet activation. Nephrol Dial Transplant. 2001; 16 (suppl 1): 45–49.[Abstract/Free Full Text]

60. Matys T, Chabielska E, Pawlak R, Kucharewicz I, Buczko W. Losartan inhibits the adhesion of rat platelets to fibrillar collagen: a potential role of nitric oxide and prostanoids. J Physiol Pharmacol. 2000; 51: 705–713.[Medline] [Order article via Infotrieve]

61. Kalinowski L, Matys T, Chabielska E, Buczko W, Malinski T. Angiotensin II AT₁ receptor antagonists inhibit platelet adhesion and aggregation by nitric oxide release. Hypertension. 2002; 40: 521–527.[Abstract/Free Full Text]

62. Liu YH, Xu J, Yang XP, Yang F, Shesely E, Carretero OA. Effect of ACE inhibitors and angiotensin II type 1 receptor antagonists on endothelial NO synthase knockout mice with heart failure. Hypertension. 2002; 39: 375–381.[Abstract/Free Full Text]

63. Dalmay F, Mazouz H, Allard J, Pesteil F, Achard JM, Fournier A. Non-AT₁-receptor-mediated protective effect of angiotensin against acute ischaemic stroke in the gerbil. J Renin Angiotensin Aldosterone Syst. 2001; 2: 103–106.[Abstract/Free Full Text]

64. Papademetriou V. The potential role of AT₁-receptor blockade in the prevention and reversal of atherosclerosis. J Hum Hypertens. 2002; 16 (suppl 3): S34–S41.

65. Petnehazy T, Stokes KY, Granger DN. Losartan attenuates the prothrombogenic and pro-inflammatory effects of acute hypercholesterolemia on the microvasculature. Circulation. 2003; 108: 164.

66. Henn V, Slupsky JR, Graefe M, Anagnostopoulos I, Foerster R, Mueller-Berghaus G, Kroczek RA. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature. 1998; 391: 591–594.[CrossRef][Medline] [Order article via Infotrieve]

67. Van Kooten C, Banchereau J. CD40-CD40 ligand. J Leukoc Biol. 2000; 67: 2–17.[Abstract]

68. Henn V, Steinbach S, Buchner K, Presek P, Kroczek RA. The inflammatory action of CD40 ligand (CD154) expressed on activated human platelets is temporally limited by co-expressed CD40. Blood. 2001; 98: 1047–1054.[Abstract/Free Full Text]

69. Urbich C, Dernbach E, Aicher A, Zeiher AM, Dimmeler S. CD40 ligand inhibits endothelial cell migration by increasing production of endothelial reactive oxygen species. Circulation. 2002; 106: 981–986.[Abstract/Free Full Text]

70. Semb AG, van Wissen S, Ueland T, Smilde T, Waehre T, Tripp MD, Froland SS, Kastelein JJ, Gullestad L, Pedersen TR, Aukrust P, Stalenhoef AF. Raised serum levels of soluble CD40 ligand in patients with familial hypercholesterolemia: downregulatory effect of statin therapy. J Am Coll Cardiol. 2003; 41: 275–279.[Abstract/Free Full Text]

71. Lutgens E, Gorelik L, Daemen MJ, de Muinck ED, Grewal IS, Koteliansky VE, Flavell RA. Requirement for CD154 in the progression of atherosclerosis. Nat Med. 1999; 5: 1313–1316.[CrossRef][Medline] [Order article via Infotrieve]

72. Lutgens E, Cleutjens KB, Heeneman S, Koteliansky VE, Burkly LC, Daemen MJ. Both early and delayed anti-CD40L antibody treatment induces a stable plaque phenotype. Proc Natl Acad Sci U S A. 2000; 97: 7464–7469.[Abstract/Free Full Text]

73. Aukrust P, Muller F, Ueland T, Berget T, Aaser E, Brunsvig A, Solum NO, Forfang K, Froland SS, Gullestad L. Enhanced levels of soluble and membrane-bound CD40 ligand in patients with unstable angina: possible reflection of T lymphocyte and platelet involvement in the pathogenesis of acute coronary syndromes. Circulation. 1999; 100: 614–620.[Abstract/Free Full Text]

74. Nannizzi-Alaimo L, Rubenstein MH, Alves VL, Leong GY, Phillips DR, Gold HK. Cardiopulmonary bypass induces release of soluble CD40 ligand. Circulation. 2002; 105: 2849–2854.[Abstract/Free Full Text]

75. Yndestad A, Kristian Damas J, Geir Eiken H, Holm T, Haug T, Simonsen S, Froland SS, Gullestad L, Aukrust P. Increased gene expression of tumor necrosis factor superfamily ligands in peripheral blood mononuclear cells during chronic heart failure. Cardiovasc Res. 2002; 54: 175–182.[Abstract/Free Full Text]

76. Schönbeck U, Varo N, Libby P, Buring J, Ridker PM. Soluble CD40L and cardiovascular risk in women. Circulation. 2001; 104: 2266–2268.[Abstract/Free Full Text]

77. Blake GJ, Ostfeld RJ, Yucel EK, Varo N, Schönbeck U, Blake MA, Gerhard M, Ridker PM, Libby P, Lee RT. Soluble CD40 ligand levels indicate lipid accumulation in carotid atheroma: an in vivo study with high-resolution MRI. Arterioscler Thromb Vasc Biol. 2003; 23: e11–e14.[Abstract/Free Full Text]

This article has been cited by other articles:

				B. T. Bikman, D. Zheng, W. J. Pories, W. Chapman, J. R. Pender, R. C. Bowden, M. A. Reed, R. N. Cortright, E. B. Tapscott, J. A. Houmard, et al. Mechanism for Improved Insulin Sensitivity after Gastric Bypass Surgery J. Clin. Endocrinol. Metab., December 1, 2008; 93(12): 4656 - 4663. [Abstract] [Full Text] [PDF]

				S.-Q. Xu, K. Mahadev, X. Wu, L. Fuchsel, S. Donnelly, R. G. Scalia, and B. J. Goldstein Adiponectin Protects Against Angiotensin II or Tumor Necrosis Factor {alpha}-Induced Endothelial Cell Monolayer Hyperpermeability: Role of cAMP/PKA Signaling Arterioscler Thromb Vasc Biol, May 1, 2008; 28(5): 899 - 905. [Abstract] [Full Text] [PDF]

				K. Mahadev, X. Wu, S. Donnelly, R. Ouedraogo, A. D. Eckhart, and B. J. Goldstein Adiponectin inhibits vascular endothelial growth factor-induced migration of human coronary artery endothelial cells Cardiovasc Res, May 1, 2008; 78(2): 376 - 384. [Abstract] [Full Text] [PDF]

				K. R. Pechman, D. P. Basile, H. Lund, and D. L. Mattson Immune suppression blocks sodium-sensitive hypertension following recovery from ischemic acute renal failure Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2008; 294(4): R1234 - R1239. [Abstract] [Full Text] [PDF]

				S. A. Crist, D. L. Sprague, and T. L. Ratliff Nuclear factor of activated T cells (NFAT) mediates CD154 expression in megakaryocytes Blood, April 1, 2008; 111(7): 3553 - 3561. [Abstract] [Full Text] [PDF]

				X. Wu, K. Mahadev, L. Fuchsel, R. Ouedraogo, S.-q. Xu, and B. J. Goldstein Adiponectin suppresses I{kappa}B kinase activation induced by tumor necrosis factor-{alpha} or high glucose in endothelial cells: role of cAMP and AMP kinase signaling Am J Physiol Endocrinol Metab, December 1, 2007; 293(6): E1836 - E1844. [Abstract] [Full Text] [PDF]

				B. Hocher, L. Liefeldt, T. Quaschning, P. Kalk, R. Ziebig, M. Godes, K. Relle, G. Asmus, and J.-P. Stasch Soluble CD154 Is a Unique Predictor of Nonfatal and Fatal Atherothrombotic Events in Patients Who Have End-Stage Renal Disease and Are on Hemodialysis J. Am. Soc. Nephrol., April 1, 2007; 18(4): 1323 - 1330. [Abstract] [Full Text] [PDF]

				J. Ruef, M. Browatzki, C. A. Pfeiffer, J. Schmidt, and R. Kranzhofer Angiotensin II promotes the inflammatory response to CD40 ligation via TRAF-2 Vascular Medicine, February 1, 2007; 12(1): 23 - 27. [Abstract] [PDF]

				M. Rodriguez-Yanez, M. Castellanos, M. Blanco, M. M. Garcia, F. Nombela, J. Serena, R. Leira, I. Lizasoain, A. Davalos, and J. Castillo New-onset hypertension and inflammatory response/poor outcome in acute ischemic stroke Neurology, December 12, 2006; 67(11): 1973 - 1978. [Abstract] [Full Text] [PDF]

				H.-Y. Huang, B. Caballero, S. Chang, A. J. Alberg, R. D. Semba, C. R. Schneyer, R. F. Wilson, T.-Y. Cheng, J. Vassy, G. Prokopowicz, et al. The Efficacy and Safety of Multivitamin and Mineral Supplement Use To Prevent Cancer and Chronic Disease in Adults: A Systematic Review for a National Institutes of Health State-of-the-Science Conference Ann Intern Med, September 5, 2006; 145(5): 372 - 385. [Abstract] [Full Text] [PDF]

				D. L. Mattson, L. James, E. A. Berdan, and C. J. Meister Immune Suppression Attenuates Hypertension and Renal Disease in the Dahl Salt-Sensitive Rat Hypertension, July 1, 2006; 48(1): 149 - 156. [Abstract] [Full Text] [PDF]

				T. Vowinkel, K. C. Wood, K. Y. Stokes, J. Russell, C. F. Krieglstein, and D. N. Granger Differential expression and regulation of murine CD40 in regional vascular beds Am J Physiol Heart Circ Physiol, February 1, 2006; 290(2): H631 - H639. [Abstract] [Full Text] [PDF]

				A. Benetos, J. P. Gardner, M. Kimura, C. Labat, R. Nzietchueng, B. Dousset, F. Zannad, P. Lacolley, and A. Aviv Aldosterone and Telomere Length in White Blood Cells J. Gerontol. A Biol. Sci. Med. Sci., December 1, 2005; 60(12): 1593 - 1596. [Abstract] [Full Text] [PDF]

				S. Chakrabarti, S. Varghese, O. Vitseva, K. Tanriverdi, and J. E. Freedman CD40 Ligand Influences Platelet Release of Reactive Oxygen Intermediates Arterioscler Thromb Vasc Biol, November 1, 2005; 25(11): 2428 - 2434. [Abstract] [Full Text] [PDF]

				A. P. V. Dantas and K. Sandberg Estrogen Regulation of Tumor Necrosis Factor-{alpha}: A Missing Link Between Menopause and Cardiovascular Risk in Women? Hypertension, July 1, 2005; 46(1): 21 - 22. [Full Text] [PDF]

				G. M. Kuster, E. Kotlyar, M. K. Rude, D. A. Siwik, R. Liao, W. S. Colucci, and F. Sam Mineralocorticoid Receptor Inhibition Ameliorates the Transition to Myocardial Failure and Decreases Oxidative Stress and Inflammation in Mice With Chronic Pressure Overload Circulation, February 1, 2005; 111(4): 420 - 427. [Abstract] [Full Text] [PDF]

				H. Morawietz Beyond Blood Pressure: Endothelial Protection Against Hypercholesterolemia by Angiotensin II Type-1 Receptor Blockade Hypertension, February 1, 2005; 45(2): 185 - 186. [Full Text] [PDF]

				T. Petnehazy, K. Y. Stokes, J. M. Russell, and D. N. Granger Angiotensin II Type-1 Receptor Antagonism Attenuates the Inflammatory and Thrombogenic Responses to Hypercholesterolemia in Venules Hypertension, February 1, 2005; 45(2): 209 - 215. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: 43/5/924    most recent 01.HYP.0000123070.31763.55v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Granger, D. N. Articles by Petnehazy, T. Search for Related Content PubMed PubMed Citation Articles by Granger, D. N. Articles by Petnehazy, T. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Related Collections ACE/Angiotension receptors Pathophysiology Cell signalling/signal transduction Signal transduction Acute coronary syndromes Acute myocardial infarction Endothelium/vascular type/nitric oxide