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Endocrinology Vol. 144, No. 6 2195-2200
Copyright © 2003 by The Endocrine Society

Minireview: Adiposity, Inflammation, and Atherogenesis

Christopher J. Lyon, Ronald E. Law and Willa A. Hsueh

Division of Endocrinology, Diabetes, and Hypertension, University of California at Los Angeles, Los Angeles, California 90095-7073

Address all correspondence and requests for reprints to: Willa A. Hsueh, M.D., Chief, Division of Endocrinology, Diabetes and Hypertension, University of California at Los Angeles, 900 Veteran Avenue, Suite 24-130, Los Angeles, California 90095-7073. E-mail: whsueh{at}mednet.ucla.edu.


   Abstract
Top
 Abstract
Adipose Is a Proinflammatory...
 The Monocyte and Inflammation...
 Is Decreasing Adipokine...
 References
 
Adipose tissue is a dynamic endocrine organ that secretes a number of factors that are increasingly recognized to contribute to systemic and vascular inflammation. Several of these factors, collectively referred to as adipokines, have now been shown regulate, directly or indirectly, a number of the processes that contribute to the development of atherosclerosis, including hypertension, endothelial dysfunction, insulin resistance, and vascular remodeling. Several adipokines are preferentially expressed in visceral adipose tissue, and the secretion of proinflammatory adipokines is elevated with increasing adiposity. Not surprisingly, approaches that reduce adipose tissue depots, including surgical fat removal, exercise, and reduced caloric intake, improve proinflammatory adipokine levels and reduce the severity of their resultant pathologies. Systemic adipokine levels can also be favorably altered by treatment with several of the existing drug classes used to treat insulin resistance, hypertension, and hypercholesterolemia. Greater understanding of adipokine regulation, however, should result in the design of improved treatment strategies to control disease states associated with increase adiposity, an important outcome in view of the growing worldwide epidemic of obesity.


   Adipose Is a Proinflammatory Tissue
Top
 Abstract
 Adipose Is a Proinflammatory...
The Monocyte and Inflammation...
 Is Decreasing Adipokine...
 References
 
INCREASING EVIDENCE INDICATES that adipose tissue is an important source of cytokines (1) and that adiposity contributes to a proinflammatory milieu (2). Fat is both a dynamic endocrine organ, as well a highly active metabolic tissue. Fat produces and secretes inflammatory factors, which are well known to play important roles in the atherosclerotic process (Fig. 1Go). Collectively, these factors are called adipocytokines or adipokines. These include TNF{alpha}, leptin, plasminogen activator inhibitor-1 (PAI-1), IL-6, resistin, and angiotensinogen (1). Serum adipokine levels are elevated in humans and animals with excess adiposity (2, 3, 4, 5), and visceral fat appears to produce several of these adipokines more actively than sc adipose tissue (6, 7, 8, 9). Reduction in fat mass correlates with decrease in the serum levels of many of these adipokines (10, 11, 12, 13, 14), implying that approaches designed to promote fat loss should be useful in attenuating the proinflammatory milieu associated with obesity. Some of these adipokines, in addition to their proinflammatory actions, also affect insulin action. For example, TNF{alpha} inhibits tyrosine kinase phosphorylation of the insulin receptor, resulting in defects in insulin signaling and ultimately leading to insulin resistance and impaired glucose transport (15). Leptin has recently been shown to enhance cellular immune responses (16), as well as to increase blood pressure (17, 18). Leptin also tends to decrease insulin sensitivity when given to obese rats (19), although it markedly improves insulin sensitivity in patients with lipodystrophy, who tend to have low circulating levels of leptin (20). Resistin administration also markedly decreases insulin-mediated glucose uptake (21). Adiponectin (Acrp30), a recently described adipokine of emerging importance, is distinct from other known adipokines in that it alone among them appears to improve insulin sensitivity and inhibits vascular inflammation (22, 23, 24). Serum adiponectin levels are low in obese subjects but increase upon weight loss (25, 26).



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  		Figure 1. Many of the adipokines whose expressions are altered during obesity promote inflammation and can promote insulin resistance, endothelial dysfunction, and, ultimately, atherosclerosis.

 
Undoubtedly, other adipokines produced by fat are yet to be discovered. A potentially important therapeutic strategy for the treatment of obesity and the metabolic syndrome will be to alter the ratio of proinflammatory, insulin-desensitizing adipokines to antiinflammatory, insulin-sensitizing adipokines, to both attenuate the inflammatory milieu and improve the metabolic state.


   The Monocyte and Inflammation Are Integral Components of the Atherosclerotic Process
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 Abstract
 Adipose Is a Proinflammatory...
 The Monocyte and Inflammation...
Is Decreasing Adipokine...
 References
 
Monocyte migration is integral to the development of atherosclerosis. Early in the process of atherosclerosis, circulating monocytes adhere to the endothelial layer of the vessel wall, migrate into the vascular interstitium, and phagocytize oxidized low-density lipoprotein cholesterol (LDLC; Ref. 27). This process results in the formation of lipid-laden foam cells, which accumulate within the arterial wall to form fatty streaks. Ultimately, these early lesions evolve into advanced atherosclerotic plaques that contain necrotic lipid cores surrounded by proteoglycan matrix and covered by a fibrous cap and thickened intima. This structure defines an organized atherosclerotic plaque.

A number of approaches have been used to cripple macrophage activity in genetically prone mouse models of atherosclerosis, all of which attenuated the atherosclerotic process. These include mouse models deficient for expression of 1) macrophage chemoattractive protein-1 (MCP-1; Ref. 28), which stimulates macrophage movement into the vessel wall; 2) chemokine receptor-2 (29), a macrophage receptor that binds MCP-1; 3) macrophage colony stimulating factor (M-CSF; Ref. 30), which enhances conversion of monocytes to macrophages; 4) macrophage osteopontin, which may prevent macrophage apoptosis, similar to its effects on endothelial cell survival (31). These observations underscore the prominent role of the macrophage in the pathogenesis of atherosclerosis.

Adipokines enhance the attachment and migration of monocytes into the vessel wall and their conversion into macrophages. In particular, TNF{alpha} activates the transcription factor nuclear factor-{kappa}ß, which orchestrates a series of inflammatory changes in vascular tissue, including expression of adhesion molecules on the surface of the endothelial cells and vascular smooth muscle cells (VSMC). This includes elevated expression of intracellular adhesion molecule-1 and vascular cell adhesion molecule-1 (32, 33, 34, 35), which enhance monocyte adhesion to the vessel wall (36, 37, 38, 39, 40); endothelial cells and VSMC production of MCP-1 and M-CSF (32, 41, 42, 43); and activation of a proinflammatory macrophage state resulting in increased macrophage expression of inducible nitric oxide (NO) synthase, interleukins, superoxide dismutase, etc. (44, 45, 46, 47). T lymphocytes are also activated and enhance macrophage atherosclerotic activity (48). Leptin is also reported to stimulate cholesterol accumulation by the macrophage, particularly in the presence of high glucose (49). The cytokine, IL-6, also has proinflammatory activity by itself and through increasing the levels of IL-1 and TNF{alpha}; all of these have been implicated in atherogenesis (CRP; Ref. 50). Importantly, IL-6 stimulates liver production of CRP (51). Serum CRP measured by a highly sensitive assay (hsCRP) has become an important marker of vascular inflammation and predictor of atherosclerosis (52, 53, 54, 55, 56). Recent data suggest that hsCRP is as important a predictor of atherosclerosis as circulating LDLC (57). Thus, inflammation may be potentially as important as cholesterol in contributing to atherosclerosis. High levels of hsCRP in obesity also predict later development of diabetes (58).

Angiotensinogen is a precursor to a major vasconstrictive, proatherogenic peptide, angiotensin II (AngII). This product of the renin-angiotensin system enhances multiple steps leading to foam cell formation. AngII directly stimulates intracellular adhesion molecule-1, vascular cell adhesion molecule-1, MCP-1, and M-CSF expression in the cells of the vessel wall (59). When infused into animal models, an early increase in arterial macrophage accumulation occurs in the vessel wall (60). In addition, another important affect of AngII is to enhance the metabolism of NO into oxygen free radicals, which damage the vascular tissue. AngII accomplishes this effect by stimulating nicotinamide adenine dinucleotide phosphate (reduced) oxidase, resulting in decreased bioavailability of NO (61). Importantly, NO is not only a vasodilator, but protects the vessel wall from macrophage adhesion and accumulation (62), decreases VSMC growth (63), and decreases platelet adherence to the endothelium (64). An imbalance between AngII and NO leads to endothelial dysfunction with not only a loss of vasodilator capacity, but also increased monocytes/macrophage platelet activity in the vessel wall.

PAI-1 has two important actions in the vessel wall. First, it inhibits the breakdown of fibrin clots and, therefore, plays a key role in promoting thrombus formation upon rupture of unstable atherosclerotic plaques (65). In addition, elevated PAI-1 activity, by altering the fibrinolytic balance, also contributes to remodeling of the vascular architecture (66, 67, 68, 69). In human population studies, circulating PAI-1 levels correlate with atherosclerotic events and mortality, and some studies suggest that PAI-1 may be an independent risk factor for coronary artery disease (CAD; Ref. 70, 71, 72). Hyperglycemia (73, 74), AngII (75, 76), and very LDLC (77), in addition to obesity (78), contribute to elevated serum PAI-1 levels. All of these factors increase PAI-1 gene expression (79, 80, 81, 82, 83). High levels of PAI-1 in patients with diabetes are a major contributor to the prothrombotic state in diabetes, which leads to enhanced atherosclerotic mortality (84). Use of aspirin to attenuate this prothrombotic state is associated with attenuation of CAD (85).

Diabetes is an atherosclerotic risk equivalent. Both are the end result of two important parallel pathways (Fig. 2Go): 1) the progression of insulin resistance to the metabolic syndrome, prediabetes, and, ultimately, diabetes and 2) the progression of endothelial dysfunction with progressive inflammation, thrombosis, and oxidation at the vessel wall to fatty streak formation and, ultimately, to development of advanced atherosclerotic plaques. Indeed, in the prediabetic state (impaired glucose tolerance), there is a 2-fold increased atherosclerosis risk, and, in frank diabetes, the risk is increased 3- to 4-fold (86). The metabolic syndrome, itself, is also associated with increased CAD risk (87). Early in the insulin resistant, hyperinsulinemic state, there is also evidence of brachial artery endothelial dysfunction, as well as abnormal coronary artery vasomotion, which appears to result from the endothelial dysfunction (88). Thus, insulin resistance, itself, appears to be an endothelial dysfunction risk equivalent. The pathways are clearly interdigitated and sparked in obesity, in large part by excess adipokine production.



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  		Figure 2. Obesity promotes the parallel progression of insulin resistance to type 2 diabetes and endothelial dysfunction to atherosclerosis.

 

   Is Decreasing Adipokine Production Useful?
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 Abstract
 Adipose Is a Proinflammatory...
 The Monocyte and Inflammation...
 Is Decreasing Adipokine...
References
 
Reducing adipocyte mass is associated with a reduction in proinflammatory, insulin-desensitizing adipokines and a rise in circulating adiponectin. Exercise and weight loss improve endothelial function and prevent diabetes (89, 90, 91). Thus, there is a strong association between changes in adipokines, endothelial function, and prevention of diabetes through lifestyle modifications.

Treatment with insulin-sensitizing ligands that activate the nuclear receptor, peroxisome proliferator activated receptor {gamma} (PPAR{gamma}), is reported to decrease serum hsCRP (92), leptin (5), PAI-1 (93), and TNF{alpha} (94) levels and to increase circulating adiponectin (95, 96). These agents also improve endothelial function (97, 98, 99). The TRIPOD study suggested that an early PPAR{gamma} ligand, troglitazone, prevented type 2 diabetes in a high-risk cohort (100). The PPAR{gamma} ligands currently in clinical use, rosiglitazone and pioglitazone, are being tested in clinical trials for their ability to prevent diabetes and decrease CAD events. In mice that are genetically prone to develop atherosclerosis, PPAR{gamma} ligands consistently attenuate vascular lesions (101, 102).

Statins decrease hsCRP by 30–40%, which is not correlated with their cholesterol-lowering capability (103); they consistently improve endothelial function, decrease cardiovascular events and mortality, and in the West of Scotland study decreased new onset type 2 diabetes (104, 105). Statins are reported to have additive and possibly synergistic effects with PPAR{gamma} ligands on vascular inflammation (106). Statins have also been reported to decrease plasma TNF{alpha} (107) and may also lower plasma PAI-1 (108).

Angiotensin converting enzyme inhibitors and AngII AT1 receptor blockers (ARBs) lower hsCRP, although inconsistently, and angiotensin converting enzyme inhibitors are reportedly better at lowering serum PAI-1 than ARBs, although ARBs have been reported to have this effect (109, 110, 111, 112). Both classes of agents improve endothelial function and reduce atherosclerosis-associated events. In the HOPE trial, Ramipril administration was associated with 32% less new-onset diabetes than placebo (113), and, in the LIFE trial, Losartan administration was associated with less new-onset diabetes than its comparator, Atenolol (114, 115). These agents tend to decrease circulating TNF{alpha}, but their effects on leptin and adiponectin are unknown (116, 117, 118). AngII is reported to increase leptin secretion from cultured adipocytes through a prostaglandin-independent mechanism but has no effect on adiponectin expression in these cells.

Clearly, much more investigation is needed, but insight into mechanisms by which the adipocyte communicates with both insulin target tissues and the vasculature allows us to better understand the relationships between obesity and cardiovascular disease. Furthermore, study of the regulation of these mechanisms will help us to develop treatment strategies to prevent diabetes and heart disease in the growing epidemic of obesity.


   Footnotes
 
This work was supported by NIH/National Heart, Lung and Blood Institute Grant 1P01 HIG0030-01A1 (to W.A.H.).

Abbreviations: AngII, Angiotensin II; ARBs, AngII AT1 receptor blockers; CAD, coronary artery disease; CRP, C-reactive protein; hsCRP, CRP measured by a highly sensitive assay; LDLC, low-density lipoprotein cholesterol; MCP-1, macrophage chemoattractive protein-1; M-CSF, macrophage colony stimulating factor; NO, nitric oxide; PAI-1, plasminogen activator inhibitor-1; PPAR{gamma}, peroxisome proliferator activated receptor {gamma}; VSMC, vascular smooth muscle cells.

Received March 4, 2003.

Accepted for publication March 10, 2003.


   References
Top
 Abstract
 Adipose Is a Proinflammatory...
 The Monocyte and Inflammation...
 Is Decreasing Adipokine...
 References
 

  1. Ahima RS, Flier JS 2000 Adipose tissue as an endocrine organ. Trends Endocrinol Metab 11:327–332[CrossRef][Medline]
  2. Yudkin JS, Stehouwer CD, Emeis JJ, Coppack SW 1999 C-reactive protein in healthy subjects: associations with obesity, insulin resistance, and endothelial dysfunction: a potential role for cytokines originating from adipose tissue? Arterioscler Thromb Vasc Biol 19:972–978[Abstract/Free Full Text]
  3. Samad F, Loskutoff DJ 1996 Tissue distribution and regulation of plasminogen activator inhibitor-1 in obese mice. Mol Med 2:568–582[Medline]
  4. Samad F, Yamamoto K, Pandey M, Loskutoff DJ 1997 Elevated expression of transforming growth factor-ß in adipose tissue from obese mice. Mol Med 3:37–48[Medline]
  5. Zhang B, Graziano MP, Doebber TW, Leibowitz MD, White-Carrington S, Szalkowski DM, Hey PJ, Wu M, Cullinan CA, Bailey P, Lollmann B, Frederich R, Flier JS, Strader CD, Smith RG 1996 Down-regulation of the expression of the obese gene by an antidiabetic thiazolidinedione in Zucker diabetic fatty rats and db/db mice. J Biol Chem 271:9455–9459[Abstract/Free Full Text]
  6. Dusserre E, Moulin P, Vidal H 2000 Differences in mRNA expression of the proteins secreted by the adipocytes in human subcutaneous and visceral adipose tissues. Biochim Biophys Acta 1500:88–96[Medline]
  7. Fried SK, Bunkin DA, Greenberg AS 1998 Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid. J Clin Endocrinol Metab 83:847–850[Abstract/Free Full Text]
  8. Eriksson P, Van Harmelen V, Hoffstedt J, Lundquist P, Vidal H, Stemme V, Hamsten A, Arner P, Reynisdottir S 2000 Regional variation in plasminogen activator inhibitor-1 expression in adipose tissue from obese individuals. Thromb Haemost 83:545–548[Medline]
  9. Giacchetti G, Faloia E, Mariniello B, Sardu C, Gatti C, Camilloni MA, Guerrieri M, Mantero F 2002 Overexpression of the renin-angiotensin system in human visceral adipose tissue in normal and overweight subjects. Am J Hypertens 15:381–388[CrossRef][Medline]
  10. Dandona P, Weinstock R, Thusu K, Abdel-Rahman E, Aljada A, Wadden T 1998 Tumor necrosis factor-{alpha} in sera of obese patients: fall with weight loss. J Clin Endocrinol Metab 83:2907–2910[Abstract/Free Full Text]
  11. Ziccardi P, Nappo F, Giugliano G, Esposito K, Marfella R, Cioffi M, D’Andrea F, Molinari AM, Giugliano D 2002 Reduction of inflammatory cytokine concentrations and improvement of endothelial functions in obese women after weight loss over one year. Circulation 105:804–809[Abstract/Free Full Text]
  12. Primrose JN, Davies JA, Prentice CR, Hughes R, Johnston D 1992 Reduction in factor VII, fibrinogen and plasminogen activator inhibitor-1 activity after surgical treatment of morbid obesity. Thromb Haemost 68:396–399[Medline]
  13. Folsom AR, Qamhieh HT, Wing RR, Jeffery RW, Stinson VL, Kuller LH, Wu KK 1993 Impact of weight loss on plasminogen activator inhibitor (PAI-1), factor VII, and other hemostatic factors in moderately overweight adults. Arterioscler Thromb 13:162–169[Abstract/Free Full Text]
  14. Itoh K, Imai K, Masuda T, Abe S, Tanaka M, Koga R, Itoh H, Matsuyama T, Nakamura M 2002 Relationship between changes in serum leptin levels and blood pressure after weight loss. Hypertens Res 25:881–886[CrossRef][Medline]
  15. Feinstein R, Kanety H, Papa MZ, Lunenfeld B, Karasik A 1993 Tumor necrosis factor-{alpha} suppresses insulin-induced tyrosine phosphorylation of insulin receptor and its substrates. J Biol Chem 268:26055–26058[Abstract/Free Full Text]
  16. Lord GM, Matarese G, Howard JK, Baker RJ, Bloom SR, Lechler RI 1998 Leptin modulates the T-cell immune response and reverses starvation-induced immunosuppression. Nature 394:897–901[CrossRef][Medline]
  17. Shek EW, Brands MW, Hall JE 1998 Chronic leptin infusion increases arterial pressure. Hypertension 31:409–414[Abstract/Free Full Text]
  18. Correia ML, Morgan DA, Sivitz WI, Mark AL, Haynes WG 2001 Leptin acts in the central nervous system to produce dose-dependent changes in arterial pressure. Hypertension 37:936–942[Abstract/Free Full Text]
  19. Buettner R, Newgard CB, Rhodes CJ, O’Doherty RM 2000 Correction of diet-induced hyperglycemia, hyperinsulinemia, and skeletal muscle insulin resistance by moderate hyperleptinemia. Am J Physiol Endocrinol Metab 278:E563–E569
  20. Oral EA, Simha V, Ruiz E, Andewelt A, Premkumar A, Snell P, Wagner AJ, DePaoli AM, Reitman ML, Taylor SI, Gorden P, Garg A 2002 Leptin-replacement therapy for lipodystrophy. N Engl J Med 346:570–578[Abstract/Free Full Text]
  21. Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, Patel HR, Ahima RS, Lazar MA 2001 The hormone resistin links obesity to diabetes. Nature 409:307–312[CrossRef][Medline]
  22. Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Reitman ML, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T 2001 The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 7:941–946[CrossRef][Medline]
  23. Ouchi N, Kihara S, Arita Y, Okamoto Y, Maeda K, Kuriyama H, Hotta K, Nishida M, Takahashi M, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Funahashi T, Matsuzawa Y 2000 Adiponectin, an adipocyte-derived plasma protein, inhibits endothelial NF-{kappa}B signaling through a cAMP-dependent pathway. Circulation 102:1296–1301[Abstract/Free Full Text]
  24. Okamoto Y, Kihara S, Ouchi N, Nishida M, Arita Y, Kumada M, Ohashi K, Sakai N, Shimomura I, Kobayashi H, Terasaka N, Inaba T, Funahashi T, Matsuzawa Y 2002 Adiponectin reduces atherosclerosis in apolipoprotein E-deficient mice. Circulation 106:2767–2770[Abstract/Free Full Text]
  25. Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K, Kuriyama H, Nishida M, Yamashita S, Okubo K, Matsubara K, Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y 1999 Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 257:79–83[CrossRef][Medline]
  26. Yang WS, Lee WJ, Funahashi T, Tanaka S, Matsuzawa Y, Chao CL, Chen CL, Tai TY, Chuang LM 2001 Weight reduction increases plasma levels of an adipose-derived anti-inflammatory protein, adiponectin. J Clin Endocrinol Metab 86:3815–3819[Abstract/Free Full Text]
  27. Libby P 2000 Changing concepts of atherogenesis. J Intern Med 247:349–358[CrossRef][Medline]
  28. Gu L, Okada Y, Clinton SK, Gerard C, Sukhova GK, Libby P, Rollins BJ 1998 Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. Mol Cell 2:275–281[CrossRef][Medline]
  29. Dawson TC, Kuziel WA, Osahar TA, Maeda N 1999 Absence of CC chemokine receptor-2 reduces atherosclerosis in apolipoprotein E-deficient mice. Atherosclerosis 143:205–211[CrossRef][Medline]
  30. Qiao JH, Tripathi J, Mishra NK, Cai Y, Tripathi S, Wang XP, Imes S, Fishbein MC, Clinton SK, Libby P, Lusis AJ, Rajavashisth TB 1997 Role of macrophage colony-stimulating factor in atherosclerosis: studies of osteopetrotic mice. Am J Pathol 150:1687–1699[Abstract]
  31. Ophascharoensuk V, Giachelli CM, Gordon K, Hughes J, Pichler R, Brown P, Liaw L, Schmidt R, Shankland SJ, Alpers CE, Couser WG, Johnson RJ 1999 Obstructive uropathy in the mouse: role of osteopontin in interstitial fibrosis and apoptosis. Kidney Int 56:571–580[CrossRef][Medline]
  32. Landry DB, Couper LL, Bryant SR, Lindner V 1997 Activation of the NF-{kappa}B and I{kappa}B system in smooth muscle cells after rat arterial injury. Induction of vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1. Am J Pathol 151:1085–1095[Abstract]
  33. Iademarco MF, McQuillan JJ, Dean DC 1993 Vascular cell adhesion molecule 1: contrasting transcriptional control mechanisms in muscle and endothelium. Proc Natl Acad Sci USA 90:3943–3947[Abstract/Free Full Text]
  34. Eck SL, Perkins ND, Carr DP, Nabel GJ 1993 Inhibition of phorbol ester-induced cellular adhesion by competitive binding of NF-{kappa}B in vivo. Mol Cell Biol 13:6530–6536[Abstract/Free Full Text]
  35. Clesham GJ, Adam PJ, Proudfoot D, Flynn PD, Efstathiou S, Weissberg PL 1998 High adenoviral loads stimulate NF{kappa}B-dependent gene expression in human vascular smooth muscle cells. Gene Ther 5:174–180[CrossRef][Medline]
  36. Weber C, Springer TA 1998 Interaction of very late antigen-4 with VCAM-1 supports transendothelial chemotaxis of monocytes by facilitating lateral migration. J Immunol 161:6825–6834[Abstract/Free Full Text]
  37. Manduteanu I, Voinea M, Serban G, Simionescu M 1999 High glucose induces enhanced monocyte adhesion to valvular endothelial cells via a mechanism involving ICAM-1, VCAM-1 and CD18. Endothelium 6:315–324[Medline]
  38. Ramos CL, Huo Y, Jung U, Ghosh S, Manka DR, Sarembock IJ, Ley K 1999 Direct demonstration of P-selectin- and VCAM-1-dependent mononuclear cell rolling in early atherosclerotic lesions of apolipoprotein E-deficient mice. Circ Res 84:1237–1244[Abstract/Free Full Text]
  39. Cybulsky MI, Iiyama K, Li H, Zhu S, Chen M, Iiyama M, Davis V, Gutierrez-Ramos JC, Connelly PW, Milstone DS 2001 A major role for VCAM-1, but not ICAM-1, in early atherosclerosis. J Clin Invest 107:1255–1262[Medline]
  40. Meerschaert J, Furie MB 1995 The adhesion molecules used by monocytes for migration across endothelium include CD11a/CD18, CD11b/CD18, and VLA-4 on monocytes and ICAM-1, VCAM-1, and other ligands on endothelium. J Immunol 154:4099–4112[Abstract]
  41. Martin T, Cardarelli PM, Parry GC, Felts KA, Cobb RR 1997 Cytokine induction of monocyte chemoattractant protein-1 gene expression in human endothelial cells depends on the cooperative action of NF-{kappa}B and AP-1. Eur J Immunol 27:1091–1097[Medline]
  42. Peng HB, Rajavashisth TB, Libby P, Liao JK 1995 Nitric oxide inhibits macrophage-colony stimulating factor gene transcription in vascular endothelial cells. J Biol Chem 270:17050–17055[Abstract/Free Full Text]
  43. Rajavashisth TB, Yamada H, Mishra NK 1995 Transcriptional activation of the macrophage-colony stimulating factor gene by minimally modified LDL. Involvement of nuclear factor-{kappa}B. Arterioscler Thromb Vasc Biol 15:1591–1598[Abstract/Free Full Text]
  44. Xie QW, Kashiwabara Y, Nathan C 1994 Role of transcription factor NF-{kappa}B/Rel in induction of nitric oxide synthase. J Biol Chem 269:4705–4708[Abstract/Free Full Text]
  45. Goto M, Katayama KI, Shirakawa F, Tanaka I 1999 Involvement of NF-{kappa}B p50/p65 heterodimer in activation of the human pro-interleukin-1ß gene at two subregions of the upstream enhancer element. Cytokine 11:16–28[CrossRef][Medline]
  46. Kawashima T, Murata K, Akira S, Tonozuka Y, Minoshima Y, Feng S, Kumagai H, Tsuruga H, Ikeda Y, Asano S, Nosaka T, Kitamura T 2001 STAT5 induces macrophage differentiation of M1 leukemia cells through activation of IL-6 production mediated by NF-{kappa}B p65. J Immunol 167:3652–3660[Abstract/Free Full Text]
  47. Kelly KA, Hill MR, Youkhana K, Wanker F, Gimble JM 1994 Dimethyl sulfoxide modulates NF-{kappa}B and cytokine activation in lipopolysaccharide-treated murine macrophages. Infect Immun 62:3122–3128[Abstract/Free Full Text]
  48. Frostegard J, Ulfgren AK, Nyberg P, Hedin U, Swedenborg J, Andersson U, Hansson GK 1999 Cytokine expression in advanced human atherosclerotic plaques: dominance of pro-inflammatory (Th1) and macrophage-stimulating cytokines. Atherosclerosis 145:33–43[CrossRef][Medline]
  49. O’Rourke L, Gronning LM, Yeaman SJ, Shepherd PR 2002 Glucose-dependent regulation of cholesterol ester metabolism in macrophages by insulin and leptin. J Biol Chem 277:42557–42562[Abstract/Free Full Text]
  50. Yudkin JS, Kumari M, Humphries SE, Mohamed-Ali V 2000 Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link? Atherosclerosis 148:209–214[CrossRef][Medline]
  51. Castell JV, Gomez-Lechon MJ, David M, Fabra R, Trullenque R, Heinrich PC 1990 Acute-phase response of human hepatocytes: regulation of acute-phase protein synthesis by interleukin-6. Hepatology 12:1179–1186[Medline]
  52. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH 1997 Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 336:973–979[Abstract/Free Full Text]
  53. Ridker PM, Stampfer MJ, Rifai N 2001 Novel risk factors for systemic atherosclerosis: a comparison of C-reactive protein, fibrinogen, homocysteine, lipoprotein(a), and standard cholesterol screening as predictors of peripheral arterial disease. JAMA 285:2481–2485[Abstract/Free Full Text]
  54. Ridker PM, Hennekens CH, Buring JE, Rifai N 2000 C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 342:836–843[Abstract/Free Full Text]
  55. Van Der Meer IM, De Maat MP, Hak AE, Hak AE, Kiliaan AJ, Del Sol AI, Van Der Kuip DA, Nijhuis RL, Hofman A, Witteman JC 2002 C-reactive protein predicts progression of atherosclerosis measured at various sites in the arterial tree: the Rotterdam Study. Stroke 33:2750–2755[Abstract/Free Full Text]
  56. Hashimoto H, Kitagawa K, Hougaku H, Shimizu Y, Sakaguchi M, Nagai Y, Iyama S, Yamanishi H, Matsumoto M, Hori M 2001 C-reactive protein is an independent predictor of the rate of increase in early carotid atherosclerosis. Circulation 104:63–67[Abstract/Free Full Text]
  57. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR 2002 Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med 347:1557–1565[Abstract/Free Full Text]
  58. Han TS, Sattar N, Williams K, Gonzalez-Villalpando C, Lean ME, Haffner SM 2002 Prospective study of C-reactive protein in relation to the development of diabetes and metabolic syndrome in the Mexico City Diabetes Study. Diabetes Care 25:2016–2021[Abstract/Free Full Text]
  59. Tham DM, Martin-McNulty B, Wang YX, Wilson DW, Vergona R, Sullivan ME, Dole W, Rutledge JC 2002 Angiotensin II is associated with activation of NF-{kappa}B-mediated genes and downregulation of PPARs. Physiol Genomics 11:21–30[Abstract/Free Full Text]
  60. Wang YX, Martin-McNulty B, Freay AD, Sukovich DA, Halks-Miller M, Li WW, Vergona R, Sullivan ME, Morser J, Dole WP, Deng GG 2001 Angiotensin II increases urokinase-type plasminogen activator expression and induces aneurysm in the abdominal aorta of apolipoprotein E-deficient mice. Am J Pathol 159:1455–1464[Abstract/Free Full Text]
  61. Cai H, Li Z, Dikalov S, Holland SM, Hwang J, Jo H, Dudley Jr SC, Harrison DG 2002 NAD(P)H oxidase-derived hydrogen peroxide mediates endothelial nitric oxide production in response to angiotensin II. J Biol Chem 277:48311–48317[Abstract/Free Full Text]
  62. Tsao PS, McEvoy LM, Drexler H, Butcher EC, Cooke JP 1994 Enhanced endothelial adhesiveness in hypercholesterolemia is attenuated by L-arginine. Circulation 89:2176–2182[Abstract/Free Full Text]
  63. De Meyer GR, Bult H, Ustunes L, Kockx MM, Feelisch M, Herman AG 1995 Effect of nitric oxide donors on neointima formation and vascular reactivity in the collared carotid artery of rabbits. J Cardiovasc Pharmacol 26:272–279[Medline]
  64. Radomski MW, Palmer RM, Moncada S 1987 Endogenous nitric oxide inhibits human platelet adhesion to vascular endothelium. Lancet 2:1057–1058[Medline]
  65. Sobel BE 1999 Increased plasminogen activator inhibitor-1 and vasculopathy. A reconcilable paradox. Circulation 99:2496–2498[Free Full Text]
  66. Eitzman DT, Westrick RJ, Xu Z, Tyson J, Ginsburg D 2000 Plasminogen activator inhibitor-1 deficiency protects against atherosclerosis progression in the mouse carotid artery. Blood 96:4212–4215[Abstract/Free Full Text]
  67. Hattori N, Degen JL, Sisson TH, Liu H, Moore BB, Pandrangi RG, Simon RH, Drew AF 2000 Bleomycin-induced pulmonary fibrosis in fibrinogen-null mice. J Clin Invest 106:1341–1350[Medline]
  68. Kaikita K, Fogo AB, Ma L, Schoenhard JA, Brown NJ, Vaughan DE 2001 Plasminogen activator inhibitor-1 deficiency prevents hypertension and vascular fibrosis in response to long-term nitric oxide synthase inhibition. Circulation 104:839–844[Abstract/Free Full Text]
  69. Oda T, Jung YO, Kim HS, Cai X, Lopez-Guisa JM, Ikeda Y, Eddy AA 2001 PAI-1 deficiency attenuates the fibrogenic response to ureteral obstruction. Kidney Int 60:587–596[CrossRef][Medline]
  70. Thogersen AM, Jansson JH, Boman K, Nilsson TK, Weinehall L, Huhtasaari F, Hallmans G 1998 High plasminogen activator inhibitor and tissue plasminogen activator levels in plasma precede a first acute myocardial infarction in both men and women: evidence for the fibrinolytic system as an independent primary risk factor. Circulation 98:2241–2247[Abstract/Free Full Text]
  71. Scarabin PY, Aillaud MF, Amouyel P, Evans A, Luc G, Ferrieres J, Arveiler D, Juhan-Vague I 1998 Associations of fibrinogen, factor VII and PAI-1 with baseline findings among 10,500 male participants in a prospective study of myocardial infarction—the PRIME Study. Prospective Epidemiological Study of Myocardial Infarction. Thromb Haemost 80:749–756[Medline]
  72. Bavenholm P, de Faire U, Landou C, Efendic S, Nilsson J, Wiman B, Hamsten A 1998 Progression of coronary artery disease in young male post-infarction patients is linked to disturbances of carbohydrate and lipoprotein metabolism and to impaired fibrinolytic function. Eur Heart J 19:402–410[Abstract/Free Full Text]
  73. Meigs JB, Mittleman MA, Nathan DM, Tofler GH, Singer DE, Murphy-Sheehy PM, Lipinska I, D’Agostino RB, Wilson PW 2000 Hyperinsulinemia, hyperglycemia, and impaired hemostasis: the Framingham Offspring Study. JAMA 283:221–228[Abstract/Free Full Text]
  74. Hanefeld M, Koehler C, Henkel E, Fuecker K, Schaper F, Temelkova-Kurktschiev T 2000 Post-challenge hyperglycaemia relates more strongly than fasting hyperglycaemia with carotid intima-media thickness: the RIAD Study. Risk Factors in Impaired Glucose Tolerance for Atherosclerosis and Diabetes. Diabet Med 17:835–840[CrossRef][Medline]
  75. Srikumar N, Brown NJ, Hopkins PN, Jeunemaitre X, Hunt SC, Vaughan DE, Williams GH 2002 PAI-1 in human hypertension: relation to hypertensive groups. Am J Hypertens 15:683–690[CrossRef][Medline]
  76. Brown NJ, Kumar S, Painter CA, Vaughan DE 2002 ACE inhibition versus angiotensin type 1 receptor antagonism: differential effects on PAI-1 over time. Hypertension 40:859–865[Abstract/Free Full Text]
  77. Mussoni L, Mannucci L, Sirtori M, Camera M, Maderna P, Sironi L, Tremoli E 1992 Hypertriglyceridemia and regulation of fibrinolytic activity. Arterioscler Thromb 12:19–27[Abstract/Free Full Text]
  78. Juhan-Vague I, Vague P, Alessi MC, Alessi MC, Badier C, Valadier J, Aillaud MF, Atlan C 1987 Relationships between plasma insulin triglyceride, body mass index, and plasminogen activator inhibitor 1. Diabetes Metab 13:331–336
  79. Gabriely I, Yang XM, Cases JA, Ma XH, Rossetti L, Barzilai N 2002 Hyperglycemia induces PAI-1 gene expression in adipose tissue by activation of the hexosamine biosynthetic pathway. Atherosclerosis 160:115–122[CrossRef][Medline]
  80. Feener EP, Northrup JM, Aiello LP, King GL 1995 Angiotensin II induces plasminogen activator inhibitor-1 and -2 expression in vascular endothelial and smooth muscle cells. J Clin Invest 95:1353–1362
  81. Skurk T, Lee YM, Hauner H 2001 Angiotensin II and its metabolites stimulate PAI-1 protein release from human adipocytes in primary culture. Hypertension 37:1336–1340[Abstract/Free Full Text]
  82. Sironi L, Mussoni L, Prati L, Baldassarre D, Camera M, Banfi C, Tremoli E 1996 Plasminogen activator inhibitor type-1 synthesis and mRNA expression in HepG2 cells are regulated by VLDL. Arterioscler Thromb Vasc Biol 16:89–96[Abstract/Free Full Text]
  83. Eriksson P, Reynisdottir S, Lonnqvist F, Stemme V, Hamsten A, Arner P 1998 Adipose tissue secretion of plasminogen activator inhibitor-1 in non-obese and obese individuals. Diabetologia 41:65–71[CrossRef][Medline]
  84. Juhan-Vague I, Alessi MC, Vague P 1996 Thrombogenic and fibrinolytic factors and cardiovascular risk in non-insulin-dependent diabetes mellitus. Ann Med 28:371–380[Medline]
  85. Mustard JF, Kinlough-Rathbone RL, Packham MA 1983 Aspirin in the treatment of cardiovascular disease: a review. Am J Med 74:43–49[CrossRef][Medline]
  86. Nesto R 2001 CHD: a major burden in type 2 diabetes. Acta Diabetol 38(Suppl 1):S3–S8
  87. Lakka HM, Laaksonen DE, Lakka TA, Niskanen LK, Kumpusalo E, Tuomilehto J, Salonen JT 2002 The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 288:2709–2716[Abstract/Free Full Text]
  88. Pinkney JH, Stehouwer CD, Coppack SW, Yudkin JS 1997 Endothelial dysfunction: cause of the insulin resistance syndrome. Diabetes 46(Suppl 2): S9–S13
  89. Clarkson P, Montgomery HE, Mullen MJ, Donald AE, Powe AJ, Bull T, Jubb M, World M, Deanfield JE 1999 Exercise training enhances endothelial function in young men. J Am Coll Cardiol 33:1379–1385[Abstract/Free Full Text]
  90. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM 2002 Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 346:393–403[Abstract/Free Full Text]
  91. Brendle DC, Joseph LJ, Corretti MC, Gardner AW, Katzel LI 2001 Effects of exercise rehabilitation on endothelial reactivity in older patients with peripheral arterial disease. Am J Cardiol 87:324–329[CrossRef][Medline]
  92. Haffner SM, Greenberg AS, Weston WM, Chen H, Williams K, Freed MI 2002 Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation 106:679–684[Abstract/Free Full Text]
  93. Kato K, Yamada D, Midorikawa S, Sato W, Watanabe T 2000 Improvement by the insulin-sensitizing agent, troglitazone, of abnormal fibrinolysis in type 2 diabetes mellitus. Metabolism 49:662–665[CrossRef][Medline]
  94. Katsuki A, Sumida Y, Murata K, Furuta M, Araki-Sasaki R, Tsuchihashi K, Hori Y, Yano Y, Gabazza EC, Adachi Y 2000 Troglitazone reduces plasma levels of tumour necrosis factor-{alpha} in obese patients with type 2 diabetes. Diabetes Obes Metab 2:189–191[CrossRef][Medline]
  95. Maeda N, Takahashi M, Funahashi T, Kihara S, Nishizawa H, Kishida K, Nagaretani H, Matsuda M, Komuro R, Ouchi N, Kuriyama H, Hotta K, Nakamura T, Shimomura I, Matsuzawa Y 2001 PPAR{gamma} ligands increase expression and plasma concentrations of adiponectin, an adipose-derived protein. Diabetes 50:2094–2099[Abstract/Free Full Text]
  96. Yu JG, Javorschi S, Hevener AL, Kruszynska YT, Norman RA, Sinha M, Olefsky JM 2002 The effect of thiazolidinediones on plasma adiponectin levels in normal, obese, and type 2 diabetic subjects. Diabetes 51:2968–2974[Abstract/Free Full Text]
  97. Walker AB, Chattington PD, Buckingham RE, Williams G 1999 The thiazolidinedione rosiglitazone (BRL-49653) lowers blood pressure and protects against impairment of endothelial function in Zucker fatty rats. Diabetes 48:1448–1453[Abstract]
  98. Watanabe Y, Sunayama S, Shimada K, Sawano M, Hoshi S, Iwama Y, Mokuno H, Daida H, Yamaguchi H 2000 Troglitazone improves endothelial dysfunction in patients with insulin resistance. J Atheroscler Thromb 7:159–163[Medline]
  99. Kotchen TA, Reddy S, Zhang HY 1997 Increasing insulin sensitivity lowers blood pressure in the fructose-fed rat. Am J Hypertens 10:1020–1026[CrossRef][Medline]
  100. Buchanan TA, Xiang AH, Peters RK, Kjos SL, Marroquin A, Goico J, Ochoa C, Tan S, Berkowitz K, Hodis HN, Azen SP 2002 Preservation of pancreatic ß-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk hispanic women. Diabetes 51:2796–2803[Abstract/Free Full Text]
  101. Collins AR, Meehan WP, Kintscher U, Jackson S, Wakino S, Noh G, Palinski W, Hsueh WA, Law RE 2001 Troglitazone inhibits formation of early atherosclerotic lesions in diabetic and nondiabetic low density lipoprotein receptor-deficient mice. Arterioscler Thromb Vasc Biol 21:365–371[Abstract/Free Full Text]
  102. Chen Z, Ishibashi S, Perrey S, Osuga Ji, Gotoda T, Kitamine T, Tamura Y, Okazaki H, Yahagi N, Iizuka Y, Shionoiri F, Ohashi K, Harada K, Shimano H, Nagai R, Yamada N 2001 Troglitazone inhibits atherosclerosis in apolipoprotein E-knockout mice: pleiotropic effects on CD36 expression and HDL. Arterioscler Thromb Vasc Biol 21:372–377[Abstract/Free Full Text]
  103. Ansell BJ, Watson KE, Weiss RE, Fonarow GC 2003 hsCRP and HDL Effects of Statins Trial (CHEST): rapid effect of statin therapy on C-reactive protein and high-density lipoprotein levels. A clinical investigation. Heart Dis 5:2–7[CrossRef][Medline]
  104. Freeman DJ, Norrie J, Sattar N, Neely RD, Cobbe SM, Ford I, Isles C, Lorimer AR, Macfarlane PW, McKillop JH, Packard CJ, Shepherd J, Gaw A 2001 Pravastatin and the development of diabetes mellitus: evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study. Circulation 103:357–362[Abstract/Free Full Text]
  105. Freeman DJ, Norrie J, Caslake MJ, Gaw A, Ford I, Lowe GD, O’Reilly DS, Packard CJ, Sattar N 2002 C-reactive protein is an independent predictor of risk for the development of diabetes in the West of Scotland Coronary Prevention Study. Diabetes 51:1596–1600[Abstract/Free Full Text]
  106. Inoue I, Itoh F, Aoyagi S, Tazawa S, Kusama H, Akahane M, Mastunaga T, Hayashi K, Awata T, Komoda T, Katayama S 2002 Fibrate and statin synergistically increase the transcriptional activities of PPAR{alpha}/RXR{alpha} and decrease the transactivation of NF{kappa}B. Biochem Biophys Res Commun 290:131–139[CrossRef][Medline]
  107. Holm T, Andreassen AK, Ueland T, Jekshus J, Froland SS, Kjekshus E, Simonsen S, Aukrust P, Gullestad L 2001 Effect of pravastatin on plasma markers of inflammation and peripheral endothelial function in male heart transplant recipients. Am J Cardiol 87:815–818, A9[CrossRef][Medline]
  108. Koh KK, Son JW, Ahn JY, Choi YM, Jin DK, Park GS, Choi IS, Sohn MS, Shin EK 2001 Non-lipid effects of statin on hypercholesterolemic patients established to have coronary artery disease who remained hypercholesterolemic while eating a step-II diet. Coron Artery Dis 12:305–311[CrossRef][Medline]
  109. Brown NJ, Agirbasli M, Vaughan DE 1999 Comparative effect of angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor antagonism on plasma fibrinolytic balance in humans. Hypertension 34:285–290[Abstract/Free Full Text]
  110. Fogari R, Zoppi A, Preti P, Fogari E, Malamani G, Mugellini A 2001 Differential effects of ACE-inhibition and angiotensin II antagonism on fibrinolysis and insulin sensitivity in hypertensive postmenopausal women. Am J Hypertens 14:921–926[CrossRef][Medline]
  111. Pahor M, Franse LV, Deitcher SR, Cushman WC, Johnson KC, Shorr RI, Kottke-Marchant K, Tracy RP, Somes GW, Applegate WB 2002 Fosinopril versus amlodipine comparative treatments study: a randomized trial to assess effects on plasminogen activator inhibitor-1. Circulation 105:457–461[Abstract/Free Full Text]
  112. Fogari R, Mugellini A, Zoppi A, Corradi L, Preti P, Lazzari P, Derosa G 2002 Losartan and perindopril effects on plasma plasminogen activator inhibitor-1 and fibrinogen in hypertensive type 2 diabetic patients. Am J Hypertens 15:316–320[CrossRef][Medline]
  113. Yusuf S, Gerstein H, Hoogwerf B, Pogue J, Bosch J, Wolffenbuttel BH, Zinman B 2001 Ramipril and the development of diabetes. JAMA 286:1882–1885[Abstract/Free Full Text]
  114. Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, Faire U, Fyhrquist F, Ibsen H, Kristiansson K, Lederballe-Pedersen O, Lindholm LH, Nieminen MS, Omvik P, Oparil S, Wedel H 2002 Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 359:995–1003[CrossRef][Medline]
  115. Lindholm LH, Ibsen H, Borch-Johnsen K, Olsen MH, Wachtell K, Dahlof B, Devereux RB, Beevers G, de Faire U, Fyhrquist F, Julius S, Kjeldsen SE, Kristianson K, Lederballe-Pedersen O, Nieminen MS, Omvik P, Oparil S, Wedel H, Aurup P, Edelman JM, Snapinn S 2002 Risk of new-onset diabetes in the Losartan Intervention For Endpoint reduction in hypertension study. J Hypertens 20:1879–1886[CrossRef][Medline]
  116. Fukuzawa M, Satoh J, Sagara M, Muto G, Muto Y, Nishimura S, Miyaguchi S, Qiang XL, Sakata Y, Nakazawa T, Ikehata F, Ohta S, Toyota T 1997 Angiotensin converting enzyme inhibitors suppress production of tumor necrosis factor-{alpha} in vitro and in vivo. Immunopharmacology 36:49–55[CrossRef][Medline]
  117. Stenvinkel P, Andersson P, Wang T, Lindholm B, Bergstrom J, Palmblad J, Heimburger O, Cederholm T 1999 Do ACE-inhibitors suppress tumour necrosis factor-{alpha} production in advanced chronic renal failure? J Intern Med 246:503–507[CrossRef][Medline]
  118. Wu L, Iwai M, Nakagami H, Li Z, Chen R, Suzuki J, Akishita M, de Gasparo M, Horiuchi M 2001 Roles of angiotensin II type 2 receptor stimulation associated with selective angiotensin II type 1 receptor blockade with valsartan in the improvement of inflammation-induced vascular injury. Circulation 104:2716–2721[Abstract/Free Full Text]



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