Plasma plasminogen activator inhibitor 1, insulin resistance and android obesity

Plasma plasminogen activator inhibitor 1, insulin resistance and android obesity

Biomed $L Pharmacother 1999 ; 53 : 455-61 0 1999 Editions scientifiques et medicales Elsevier SAS. All rights reserved Dossier: Diabetes and obesity...

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Biomed $L Pharmacother 1999 ; 53 : 455-61 0 1999 Editions scientifiques et medicales Elsevier

SAS. All rights reserved

Dossier: Diabetes and obesity

Plasma plasminogen activator inhibitor 1, insulin resistance and android obesity J.P. Bastard’, L. PiCroni* 2 Laboratoire

’ Laboratoire de biochimie

de biochimie, Hdpital Tenon, 4, rue de la Chine, 75020 Paris; B, Hdpital de Ia Salp&tri&-e, 47, boulevard de l’Hbpita1, 75671 Paris, France

Summary - Plasma plasminogen activator inhibitor 1 (PAL1) levels are elevated in insulin-resistant subjects and are associated with increased cardiovascular risk of atherothrombosis. Strong association between PAI- and the metabolic components of the insulin resistance syndrome is found in clinical studies, suggesting that insulin resistance may regulate circulating PAI-1. However, the mechanisms underlying increased PAI- 1 levels in such conditions are still poorly understood. Several studies have been carried out specifically in patients with central or android obesity, a major characteristic of the insulin resistance syndrome, and have suggested that visceral adipose tissue may be the major component of the relationship between android obesity and PAI-1. Accordingly, adipose tissue PAI- production was found to be elevated in obese human subjects, particularly in visceral adipose tissue. The genetic background for having high PAL1 levels in several populations have been looked for and its role appeared to be weaker than that of the metabolic condition, High plasma PAIlevels are then clearly related to android obesity and insulin resistance, but the mechanisms whereby PAI-I increases in plasma in these diseases remain to be determined. 0 1999 Editions scientifiques et mtdicales Elsevier SAS adipose

tissue / insulin

resistance

/ obesity

/ plasminogen

activator

Insulin resistance includes a cluster of risk factors for cardiovascular disease, such as android obesity (adipose tissue predominant in the upper part of the body), hypertension, a high level of very low-density lipoprotein (VLDL) triglycerides, low high-density lipoprotein (HDL) cholesterol levels and a dense low-density lipoprotein (LDL) particle pattern. All these metabolic components constitute the insulin resistance syndrome described previously by Reaven [72]. More recently, impaired fibrinolysis due to elevated circulating plasma plasminogen activator inhibitor 1 (PAI-1) was also included in the insulin resistance syndrome [40, 731. This abnormality increases the risk of atherothrombotic complications commonly observed in obesity and noninsulin-dependent diabetes mellitus (NIDDM) [41]. Although hepatocytes [ 1,471 and endothelial cells [80] have been suggested to contribute to elevated plasma PAI- levels in insulin-resistant states, the mechanisms which enhance circulating PAI- in obesity are not yet well understood. In the last few years, several studies suggested that visceral fat would be a major determinant in elevated circulating PAI- levels in android obesity. More recently, the expression of PAI- 1 has been

inhibitor

1

demonstrated in adipose tissue from animal models and humans [54], and the recent demonstration that visceral adipose tissue PAI- 1 expression is increased in obesity appeared to be of particular interest [3]. The genetic approach was also recently performed to explain elevated PAI- in several populations, but the results obtained are controversial [43]. After a brief survey on PAI- characteristics, the recent literature linking insulin resistance, obesity and adipose tissue to PAIwill be discussed. PHYSIOLOGY

OF PAI-

Biochemistry PAI- is a crucial element of the fibrinolytic system, as the main inhibitor of tissue-plasminogen activator (t-PA). Physiologic fibrinolysis is involved in the modulation of haemostasis and thrombosis by dissolving clots. Plasmin, a protease which catalyses the destruction of fibrin, is generated from inactive plasminogen, in the presence of activators, mainly urokinase and t-PA [2,53]. t-PA is the most important activator in humans.

456

J.P.Bastard, L. PiCroni

Its inhibition by PAI- 1, in the absence of fibrin, occurs in a rapid and stochiometric manner, resulting in a covalent bond between the two molecules. PAI- is consumed in the process and is called ‘suicide inhibitor’. PAI- is a single-chain glycoprotein of molecular weight 50,000 and belongs to the serine protease inhibitors (serpins). It is synthesised in its active form in a number of cells, especially in endothelial cells, mononuclear cells, hepatocytes, fibroblasts and adipocytes [48, 761. PAI- is also present in platelets, where it is stored. The majority of blood PAI- 1 is active and circulates in a complex with the glycoprotein vitronectin, which stabilises the active conformation and increases its biological half-life [93]. Regulation

of PAI-

secretion

There is a circadian variation of PAI- 1 levels, the highest occurring between midnight and 6 a.m. [48]. The low plasma concentrations rapidly increase in response to a variety of agents and changes in physiological states, indicating that the regulation of PAI- levels is a complex process. In-vitro studies have shown an increase in PAIrelease by endothelial cells, in the presence of several inductors. These inductors are cytokines, such as TNFa [75, 771, insulin and growth factors such as IGF-1 [5, 67, 78, 801, TGFP [77], endotoxin [75, 771, lipoprotein a (Lpa) [26], VLDL triglycerides [61, 821, unsaturated fatty acids [65] or angiotensin II [29, 951 and IV [45]. Injection of TNF-a, TGF-P or insulin in animals induces an increase in PAT- 1 mRNA expression in adipose tissue [55, 75, 761. Furthermore, injection of angiotensin II in humans also induces an increase in plasma PAI- levels [74]. GENETIC

VARIATIONS

OF PAI-

Several polymorphisms of the PAI- gene have been described. They include two dinucleotide (CA) repeats in the promoter and in the intron 4 [22,56], a Hind III restriction fragment length polymorphism [46] and an insertion (SG)/deletion (4G) polymorphism at position 675 of the PAI- 1 promoter [23]. More recently, four other polymorphisms have been identified [36]. They are two G-to-A substitutions at position -844 and +9,785, a T-to-G substitution at position +11,053 and a deletion of nine nucleotides from a threefold repeated sequence between nucleotides +11,320 and 11,345. The most significant association between polymorphism of the PAI- gene and plasma PAI- levels concerns the polymorphism at position 675 in the promoter. Subjects

homozygous for the 4G allele present higher plasma PAI- levels, either in patients with previous myocardial infarction [22, 981, in non-insulin-dependent diabetics [68] or in healthy subjects [27, 981. In patients aged 3545 years, the prevalence of the 4G allele is significantly higher in subjects with myocardial infarction than in controls [27]. However, this relation was not confirmed in patients with myocardial infarction aged 25 to 64 years [98]. In diabetic patients, the correlation between PAI- activity and serum triglycerides is stronger in subjects homozygous for the 4G allele than in subjects heterozygous or homozygous for the 5G allele [68]. Studies on the Hind III RFLP demonstrate that the plasma PAI- 1 level is lower in patients with an additional Hind III site, in controls and in patients with myocardial infarction [22,57]. In healthy subjects, the genotypes A-844G, -675 4G/5G and G+12078A polymorphism are associated with elevated plasma PAIlevels, but insulin resistance has a larger contribution for PAI- variability than polymorphism [36]. Furthermore, no increased risk of myocardial infarction was observed in carriers of the 4G allele and no association was found between the 4G/5G polymorphism and PAI- antigen levels in control subjects, but other cardiovascular risk factors, such as obesity, smoking habits or hypertension are associated with higher PAI- 1 levels [25]. Thus, the contribution of genetic factors to phenotypic variation in PAI- levels has to be considered, though further studies are still required to determine the role of genetic and environmental factors on PAI- 1 levels. PAI- AS A RISK FACTOR FOR ATHEROSCLEROSIS Clinical manifestations of coronary heart disease result from the progressive development of atherosclerotic plaques. Disturbance of the haemostatic system favours vascular damage and thrombus formation at the site of a suddenly ruptured atherosclerotic plaque. Indeed, fibrin deposition induces occlusion of coronary arteries [2 I] and plays a role in the development of atherosclerotic lesions [2, 13, 871. Fibrin is a component of the atherosclerotic plaque. It may contribute to plaque growth by stimulating cell proliferation [64], and binding and accumulating LDL, especially Lpa [83]. Hypofibrinolysis, which increases fibrin deposition, could play a major role in the development of atherothrombosis [42]. In this context, experimental studies have shown that increased levels of PAI-1, which lead to impaired fibrinolysis, enhanced the progression of thrombosis [94], and that antibodies

PAI-

457

and obesity

directed against PAI- prevented this progression [52]. Clinical studies have demonstrated an association between high levels of PAI- and myocardial infarction [4, 341 or recurrence of myocardial infarction [35], coronary heart disease [66] and insulin resistance syndrome [43]. PAI-1, OBESITY

AND INSULIN

RESISTANCE

A high level of PAI- is associated with obesity, and both PAI- [41] and obesity [7, 371 represent independent risk factors for atherosclerosis and cardiovascular diseases. To date, the mechanisms underlying increased PAI- levels in obese subjects are unknown. At least three sources of increased PAI- 1 levels in plasma may be involved: adipocytes, liver cells and endothelial cells (figure 1). Previous studies have shown that hyperinsulinemia is associated with high PAI- 1 levels in obesity [90] and non-insulin dependent diabetes mellitus (NIDDM) [39], suggesting a possible link between insulin resistance and elevated PAI- levels. However, whether insulin acted directly or via insulin resistance to enhance circulating PAI- levels is not clear. PAI-

insulin resistance and hyperinsulinemia

Studies performed in vitro have shown that insulin enhances PAI- expression in arterial endothelial cells [79, 801, in human hepatocytes in primo culture [47] and in the Hep G2 hepatoma cell line [ 11, while it is not the case in the human umbilical vein [ 11.Although positive correlations between plasma PAI- 1 levels and fasting insulin were found in cross-sectional studies [89, 903, studies performed in vivo in humans showed that acute hyperinsulinemia did not modify plasma PAIconcentrations [33,5 1,69,96]. Several other studies have examined the relationship between PAI- levels and insulin resistance directly assessed in vivo, either by the hyperinsulinemic euglycemic clamp [49,50,70] or by the minimal model [6, 631, and reported conflicting data. With the hyperinsulinemic euglycemic clamp method [24], Potter Van Loon et al. found that, among the following parameters, insulin resistance, diastolic arterial blood pressure, body mass index (BMI) and waist-to-hip ratio, insulin resistance was the major determinant explaining PAIvariation in obese subjects, diabetic or not [70]. By using the minimal model [12], multivariate analysis showed that plasma triglycerides [6,63] and BMI [63] and not insulin resistance were the major determinants that could explain plasma PAI- variations in males. However, in females the major determinants that could

NEFA

c/ If

Liver

I

Steatosis

+

PAM

w

0 Platelets

c7 t VLDL

Endothelial

cells

Figure 1. Plasminogen activator inhibitor 1 (PAI-1) in patients with insulin resistance syndrome. Increased plasma PAI- levels might arise from adipocytes, liver cells (possibly liver with steatosis) and endothelial cells. NEFA: nonesterified fatty acids; VLDL: very low density lipoprotein.

explain plasma PAI- variations were different and more complex since they included triglycerides, HDLcholesterol, BMI and 2 h post-load insulin concentrations [63]. Nevertheless, all these metabolic components are included in the insulin resistance syndrome, particularly lipid abnormalities, which are frequently associated with elevated PAI- levels [40-43,911. PAI-

insulin resistance and lipid abnormalities

Several studies have shown an independent positive correlation between PAI- and VLDL triglycerides after adjusting for potential confounding components of the insulin resistance syndrome [ 18,57,68]. Accordingly, studies performed in vitro showed that VLDL from hypertriglyceridemic subjects increased PAI- 1 production in endothelial cells more importantly than did VLDL from controls [61, 821. These results were also found in liver cells [62]. However, Raccah et al. studied PAI- 1 activity in three highly selected groups of

458

J.P. Bastard.

hypertriglyceridemic subjects with different degrees of insulin resistance and found that hypertriglyceridemia was not always associated with elevated PAI- levels [7 11. Thus, as for hyperinsulinemia, studies performed in vivo in humans did not confirm results obtained in vitro in culture cells. The antilipolytic effect of insulin, which can be evaluated in viva by nonesterified fatty acids (NEFA) clearance during a hyperinsulinemic euglycemic clamp, is also impaired in insulin resistance [30]. Studies were performed to investigate the relationship between insulin resistance of antilipolysis and alteration of fibrinolysis in several insulin-resistant states [8, 16, 881. They showed that insulin suppression of NEFA during the hyperinsulinemic euglycemic clamp was inversely correlated with plasma PAI- levels [8, 16, 881, suggesting a possible relationship between increased PAI- levels and insulin resistance at the level of lipid rather than glucose metabolism. It was then hypothesized that insulin resistance of adipose tissue, resulting in increased plasma NEFA concentrations, could participate in elevated PAI- levels in obese subjects. Accordingly, unsaturated fatty acids were shown to increase PAI- transcription and secretion in endothelial cells [65]. Regarding the mechanism of the fatty acids on the regulation of PAIgene expression, two recent studies have pointed out the role of the peroxisome proliferator activated receptor-y(PPAR-y) [44,58]. Interestingly, PPAR-yis also the receptor of thiazolindindione, a new class of antidiabetic agent, and seems to be involved in insulin resistance [84]. PAI-

and liver dysfunction

Another mechanism emerged from several clinical studies showing a significant correlation between PAI- levels and gamma glutamyl transferase (GGT) [6, 10, 151. It was hypothesised that liver steatosis was related to elevated circulating PAI-I levels in humans [lo, 151. A strong correlation was also found between PAI- 1 and GGT in insulin-resistant obese subjects [9] in whom steatosis and liver abnormalities were also a common feature [14, 971. However, the mechanisms whereby insulin resistance induces such liver damage, and consequently an increase in PAI- levels, remain unclear. It was hypothesized that insulin resistance of the antilipolytic pathway, with increased NEFA in the portal circulation, was one explanation for the fat deposition observed in the liver in obese patients with or without NIDDM [92]. The relation between insulin resistance of the antilipolytic pathway and PAI- lev-

L. PiCroni

els in android obese subjects [8], NIDDM women [ 161 and more recently in hypertensive subjects [88] supports this hypothesis. Hence, the metabolic insulin resistance syndrome, consisting of an increased fatty acid influx into the liver, may overburden the ability of the liver to metabolize or resecrete the fatty acids into the circulation, and so may induce storage of triglycerides within hepatocytes, i.e., liver fat. Interestingly, Cigolini et al. recently found that liver steatosis, evaluated by ultrasonography, correlated specifically with PAI- and suggested that this relation was mediated by concomitant alterations in plasma insulin and triglyceride levels [ 191. Therefore, steatosis could be an additional characteristic component of the insulin resistance syndrome related to increase PAIlevels. PAI-

and adipose tissue

It has been recently proposed that adipose tissue itself may directly contribute to the elevated PAI- levels in obesity [54]. Indeed, several intervention studies have shown a significant reduction in PAI- levels after weight loss either by dieting [17, 31, 59, 851 or after jejuno-ileal bypass [86] in obese subjects. Moreover, it has been shown that the decrease in circulating PAI- levels after weight loss was only related to the degree of weight loss and not to changes in metabolic variables such as plasma insulin or triglycerides [3 1, 591. Therefore, the participation of adipose tissue in the PAI- increase in obesity was highly suggested. Thereafter, the expression of PAI- has been demonstrated in cultured adipose cell lines [55] and in adipose tissue from rodents [75] and humans [3, 281. In addition, it was demonstrated that adipose tissue PAI-I gene expression and release of PAI- were increased in obesity [28], and that visceral adipose tissue produced more PAI- than subcutaneous adipose tissue [3,60,81]. All these results are in line with several clinical studies suggesting visceral adipose tissue as a main determinant of elevated PAI- in humans [20, 32, 381. However, it was recently shown that PAI-I gene expression increased during very lowcalorie diets in subcutaneous abdominal adipose tissue from obese subjects, while plasma PAI- levels decreased [ 111. Therefore, the mechanisms responsible for the increase of PAI- 1 expression in adipose tissue in obesity is still unclear. Additional studies are thus required to elucidate the precise mechanisms involved in the regulation of circulating PAI- levels in obesity, particularly during diet therapy inducing weight loss.

PAI- 1 and obesity

REFERENCES 1 Alessi MC, Juhan-Vague I, Kooistra T, Declerck PJ, Collen D. Insulin stimulates the synthesis of plasminogen activator inhibitor 1 by the human hepatocellular cell line HepG2. Thromb Haemost 1988 ; 60 : 491-4. 2 Alessi MC, Juhan-Vague I. Endothelium, thrombosis and fibrinolysis. Rev Prat 1997 ; 47 : 2227-3 1. 3 Alessi MC, Peiretti F, Morange P, Henry M, Nalbone G, JuhanVague I. Production of plasminogen activator inhibitor 1 by human adipose tissue. Possible link between visceral fat accumulation and vascular disease. Diabetes 1997 ; 46 : 860-7. 4 Almer LO, Ohlin H. Elevated levels of the rapid inhibitor of plasminogen activator inhibitor (t-PAI) in acute myocardial infarction. Thomb Res 1987 ; 47 : 335-9. 5 Anfosso F, Chomiki N, Alessi MC, Vague P, Juhan-Vague I. Plasminogen activator inhibitor 1 synthesis in the human hepatoma cell line Hep G2. Metformin inhibits the stimulating effect of insulin. J Clin Invest 1993 ; 91 : 218593. 6 Asplund-Carlson A, Hamsten A, Wiman B, Carlson LA. Relationship between plasma plasminogen activator inhibitor 1 activity and VLDL triglyceride concentration, insulin levels and insulin sensitivity: studies in randomly selected normo- and hyper-triglyceridaemic men. Diabetologia 1993 ; 36 : 817-25. 7 Barret-Connor EL. Obesity, atherosclerosis, and coronary disease. Ann Intern Med 1985 ; 103 : 1010-9. E, Robert JJ, Ankri A, Grimaldi A, 8 Bastard JP, Bruckert Jardel C, et al. Are free fatty acids related to plasma plasminogen activator inhibitor 1 in android obesity? Int J Obesity 1995 ; 19 : 836-8. 9 Bastard JP, Bruckert E, Porquet D, Ankri A, Jardel C, Delattre J, et al. Evidence for a relationship between plasminogen activator inhibitor-l and gamma glutamyl transferase. Thromb Res 1996 ; 81 : 271-5. 10 Bastard JP, Bruckert E, Giral P, Beucler I, Ankri A, Hainque B, et al. Plasminogen activator inhibitor-l antigen levels are related to gamma glutamyl transferase in hyperlipidaemic women. Nutr Metab Cardiovasc Dis 1997 ; 7 : 371-5. 11 Bastard JP, Vidal H, Jardel C, Bruckert E, Robin D, Vallier P, et al. Subcutaneous adipose tissue expression of plasminogen activator inhibitor-l gene during very low calorie diet in obese subjects. Int J Obesity 1999 ; inpress. 12 Bergman RN, Finegood DT, Ader M. Assessment of insulin sen&ivity in vivo. Endocr Rev 1985 ; 6 : 45-86. 13 Bini A, Kudryk BJ. Fibrin and its derivatives in the normal and diseased vessel wall. Ann NY Acad Sci 1992 ; 667 : 112-26. 14 Bjomtorp P. Liver triglycerides and metabolism. Int J Obesity 1995 ; 19 : 839-40. 15 Bruckert E, Ankri A, Giral P, Turpin G. Relationship between plasma plasminogen activator inhibitor-l and hepatic enzyme concentrations in hyperlipidemic patients. Thromb Haemost 1994 ; 72 : 434-7. 16 Brussard HE, Gevers-Leuven JA, Krans HMJ, Meijer P, Buytenhek R, Kluft C. Non-esterified fatty acids are related to hypofibrinolysis in type 2 diabetes mellitus. Fibrinolysis 1994 ; 8-Suppl2 : 25-7. -17 Calles-Escandon J. Ballor D. Harvey-Berino J, Ades P, Tracy R, Sobel B. Amelioration of the inhibition of fibrinolysis in elderly, obese subjects by moderate energy intake restriction. Am J Clin Nutr 1996 ; 64 : 7- 11. 18 Cigolini M, Targher G, Seidell JC, Tonoli M, Schiavon R, Agostino G, et al. Relationships of blood pressure to fibrinolysis: influence of anthropometry, metabolic profile and behavioural variables. J Hypertens 1995 ; 13 : 659-66.

459

19 Cigolini M, Targher G, Agostino G, Tonoli M, Muggeo M, De Sandre G. Liver steatosis and its relation to plasma haemostatic factors in apparently healthy men: role of the metabolic syndrome. Thromb Haemost 1996 ; 76 : 69-73. 20 Cigolini M, Targher G, Bergamo Andreis IA, Tonoli M, Agostino G, De Sandre G. Visceral fat accumulation and its relation to plasma hemostatic factors in healthy men. Arterioscler Thromb Vast Biol 1996 ; 16 : 368-74. 21 Davies MJ, Thomas A. Thrombosis and acute coronary artery lesions in sudden cardiac ischemic death. N England J Med 1984; 310: 1137-40. 22 Dawson S, Hamsten A, Wiman B, Henney A, Humphries S. Genetic variation at the plasminoyen activator inhibitor 1 locus is associated with altered levels of plasma plasminogen activator inhibitor- 1 activity. Arterioscler Thromb Vast Biol199 1 ; 11 : 183-90. 23 Dawson S, Wiman B, Hamsten A, Green F, Humphries S, Henney AM. The two allele sequences of a common polymorphism in the promoter of the plasminogen activator inhibitor 1 (PAI-1) gene respond differently to Interleukin-1 in Hep G2 cells, J 601 Chem 1993 ; 268 : 10739-45. 24 De Fronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 1979 ; 237 : E214-23. 25 Doggen CJM, Bertina RM, Mager Cats V, Reistma PH, Rosendall FR. The 4G/5G polymorphism in the plasminogen activator inhibitor-l gene is not associated with myocardial infarction. Thromb Haemost 1999 ; 82 : 115-20. 26 Etingin OR, Hajjar DP, Hajjar KA, Harpel PC, Nachman RL. Lipoprotein (a) regulates plasminogen activator inhibitor 1 expression in endothelial cells. A potential mechanism in thrombogenesis. J Biol Chem 1991 ; 266 : 2459-65. 27 Eriksson P, Kallin B, Van’tHoof FM, Bavenholm P, Hamsten A. Allele-specific increase in basal transcription of the plasminogen activator inhibitor 1 gene is associated with myocardial infarction. Proc Nat1 Acad Sci USA 1995 ; 92 : 1852-5. 28 Eriksson P, Reynisdottir S, Lonnqvist F, Stemme V, Hamsten A, Amer P. Adipose tissue secretion of plasminogen activator inhibitor 1 in non-obese and obese individuals. Diabetologia 1998 ; 41 : 65-7 1. 29 Feener EP, Northrup JM, Aiello LP, King GL. Angiotensin II induces plasminogen activator inhibitor 1 and -2 expression in vascular endothelial and smooth muscle cells. J Clin Invest 1995 ; 95 : 1353-62. 30 Frayn KN. Insulin resistance and lipid metabolism. Curr Opin Lipidol 1993 ; 4 : 197-204. 31 Folsom AR, Qamhieh HK, Wing RR, Jeffrey RW, Stinson VL, Kuller LH, et al. Impact of weight loss on plasminogen activator inhibitor 1 (PAI-I), factor VII, and other hemostatic factors in moderately overweight adults. Arterioscler Thromb Vast Biol 1993 ; 13 : 161-9. 32 Giltay EJ, Elbers JMH, Gooren LJG, Emeis JJ, KooistraT, Asscheman H, et al. Visceral fat accumulation is an important determinant of PAIlevels in young, non obese men and women. Modulation by cross-sex hormone administration. Arterioscler Thromb Vast Biol 1998 ; 18 : 1716-22. 33 Grant PJ, Kmithof EKO, Felley CP, Felber JP, Bachmann I. Short-term infusions of insulin, triacylglycerol and glucose do not cause acute increases in plasminogen activator inhibitor 1 concentrations in man. Clin Sci 1990 ; 79 : 513-6. 34 Hamsten A, Wiman B, de Faire U, Blomback M. Increased plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction. N Eng J Med 1985 ; 31 : 1557-63. 35 Hamsten A, de Faire U, Walldius G, Dahlen G, Szamosi A, Landou C, et al. Plasminogen activator inhibitor in plasma: risk

460

36

37

38

39

40

41 42 43

44

45

46

47

48

49

50

51

52

J.P. Bastard,

factor for recurrent myocardial infarction. Lancet 1987 ; 2 : 3-9. Henry M, Chomiki N, Scarabin PY, Alessi MC, Peiretti F, Arveiler D, et al. Five frequent polymorphism of plasminogen activator inhibitor 1 gene: lack of association between genotypes, PAI activity and triglyceride levels in a healthy population. Arterioscler Thromb Vast Biol 1997 ; 17 : 851-8. Hubert HB, Feinlieb MD, McNamara PM, Castelli WP. Obesity as an independent risk factor for cardiovascular disease: a 26.year follow-up of participants in the Framingham study. Circulation 1983 ; 67 : 968-76. Janand-Delenne B, Chagnaud C, Raccah D, Alessi MC, JuhanVague I, Vague P. Visceral fat as a main determinant of plasminogen activator inhibitor 1 level in women. Int J Obesity 1998 ; 22 : 312-7. Juhan-Vague I, Roul C, Alessi MC, Ardissone JP, Heim M, Vague P. Increased plasminogen activator inhibitor activity in non-insulin-dependent diabetic patients. Relationship with plasma insulin. Thromb Haemost 1989 ; 61 : 370-3. Juhan-Vague I, Alessi MC, Vague P. Increased plasma plasminogen inhibitor 1 levels. A possible link between insulin resistance and atherothrombosis. Diabetologia 1991 ; 34 : 457-62. Juhan-Vague I, Alessi MC, Nalbone G. Fibrinolysis and atherothrombosis. Curr Opin Lipidol 1993 ; 4 : 477-83. Juhan-Vague I, Alessi MC. Plasminogen Activator Inhibitor 1 and atherothrombosis. Thromb Haemost 1993 ; 70 : 138.43. Juhan-Vague I, Alessi MC. PAI-1. obesitv. insulin resistance and risk of cardiovascular events. Thromb-Haemost 1997 ; 78 : 656-60. Kato K, Satoh H, Endo Y, Yamada D, Midorikawa S, Sato W, et al. Thiazolidindiones down-regulate plasminogen activator inhibitor type 1 expression in human vascular endothelial cells: a possible role for PPARr in endothelial function. Biochem Biophys Res Commun 1999 ; 258 : 431-5. Kerins DM, Hao Q, Vaughan DE. Angiotensin induction of PAIexpression in endothelial cells is mediated by the hexapeptide angiotensin IV. J Clin Invest 1995 ; 96 : 2515-20. Klinger KW, Winqvist R, Riccio A. Plasminogen activator inhibitor type 1 gene is located at region q21.3rq22 of chromosome 7 and genetically linked with cystic fibrosis. Proc Nat1 Acad Sci USA 1987 ; 84 : 8548-52. Kooistra T, Bosma PJ, Tons HAM, van den Berg AP, Meyer P, Princen HMG. Plasminogen activator inhibitor 1: biosynthesis and mRNA level are increased by insulin in cultured human hepatocytes. Thromb Haemost 1989 ; 62 : 723-8. Kruithof EKO. Plasminogen activator inhibitor type 1: biochemical, biological and clinical aspects. Fibrinolysis 1988 ; 2 : 59-70. Landin K, Stigendal L, Eriksson E, Krotkiewski M, Risberg B, Tengbom L, et al. Abdominal obesity is associated with an impaired fibrinolytic activity and elevated plasminogen activator inhibitor 1. Metabolism 1990 : 39 : 1044-g. Landin K, Tengbom L, Smith U. Elevated fibrinogen and plasminogen activator inhibitor (PAI-1) in hypertension are related to metabolic risk factors for cardiovascular disease. J Intern Med 1990 ; 227 : 273-8. Landin K, Tengborn L, Chmielewska J, von Schenk H, Smith U. The acute effect of insulin on tissue plasminogen activator and plasminogen activator inhibitor in man. Thromb Haemost 1991 : 65 ; 130-3. Levi M, Biemond BJ, Van Zonneveld AJ, Ten Cate JW, Pannekoek H. Inhibition of plasminogen activator inhibitor 1 activity results in promotion of endogenous thrombolysis and inhibition of thrombus extension in models of experimental thrombosis. Circulation 1992 ; 85 : 305-12.

L. Pieroni

53 Lijnen HR, Collen D. Mechanism of physiological fibrinolysis. Baillitres Clin Haematol 1995 ; 8 : 277-90. 54 Loskutoff DJ, Samad F. The adipocyte and hemostatic balance in obesity. Studies of PAI-1. Arterioscler Thromb Vast Biol 1998 ; 18 : l-6. 55 Lundgren CH, Brown SL, Nordt TD, Sobel BE, Fijii S. Elaboration of type 1 plasminogen activator inhibitor from adipocytes. A potential link between obesity and cardiovascular disease. Circulation 1996 ; 93 : 106- 10. 56 Mansfield MW, Strickland MH, Carter AM, Grant PJ. Polymorphisms of the plasminogen activator inhibitor 1 gene in type 1 and type 2 diabetes, and in patients with diabetic retinopathy. Thromb Haemost 1994 ; 7 1 : 73 l-6. 57 Mansfield MW, Stickland MH, Grant PJ. Environmental and genetic factors in relation to elevated circulating levels of plasminogen activator inhibitor 1 in Caucasian patients with noninsulin-dependent diabetes mellitus. Thromb Haemost 1995 ; 74 : 842-7. 58 Marx N, Bourcier T, Sukhova GK, Libby P, Plutzky J. PPARy activation in human endothelial cells increases plasminogen activator inhibitor type-l expression: PPARg as a potential mediator in vascular disease. Arterioscler Thromb Vast Biol 1999 ; 19 : 546-51. 59 Mavri A, Stegnar M, Krebs M, Sentocnick JT, Geiger M, Binder BR. Impact of adipose tissue on plasma plasminogen activator inhibitor 1 in dieting obese women. Arterioscler ThrombVasc Biol 1999 ; 19 : 1582-7. 60 Moranue PE. Alessi MC. Verdier D. Casanova G. Maualon G. Juhan-Hague I. PAI- 1 produced ex vivo by human adipose tissue is relevant to PAI- 1 blood level. Arterioscler Thromb Vast Biol 1999 ; 19 : 1361-5. 61 Mussoni L, Madema P, Camera M, Bemini F, Sironi L, Sirtori M, et al. Atherogenic lipoproteins and PAI- 1 releases by endothelial cells. Fibrinolysis 1990 ; 4 Suppl 2 : 79-8 1. 62 Mussoni L, Mannucci L, Sirtori M, Camera M, Madema P, Sironi L, et al. Hypertriglyceridemia and regulation of fibrinolytic activity. Arterioscler Thromb Vast Biol 1992 ; 12 : 19-27. L, Ronnemaa T, Mamiemi J, Haffner SM, Berg63 Mykkanen man R, Laasko M. Insulin sensitivity is not an independent determinant of plasma plasminogen activator inhibitor 1 activity. Arterioscler Thromb Vast Biol 1994 ; 14 : 126471. 64 Naito M, Funaki C, Hayashi T, Yamada K, Asai K, Yoshimine N, et al. Substrate-bound fibrinogen, fibrin and other cell attachment-promoting proteins as a scaffold for cultures vascular smooth muscle cells. Athersclerosis 1992 ; 96 : 227-34. 65 Nilsson L, Banfi C, Diczfalusy U, Tremoli E, Hamsten A, Eriksson P Unsaturated fatty acids increase plasminogen activator inhibitor 1 expression in endothelial cells. Arterioscler Thromb Vast Biol 1998 : 18 : 1679-85. 66 Olofsson BO, Dahlen G, Nilsson TK. Evidence for increased levels of plasminogen activator inhibitor and tissue plasminogen activator in plasma of patients with angiographitally verified coronary artery disease. Eur Heart J 1989 ; 10 : 77-82. 67 Padayatty SJ, Orme S, Zenobi PD, Stickland MH, Belchetz PE, Grant PJ. The effects of insulin-like growth factor-l on plasminogen activator inhibitor 1 synthesis and secretion: Results from in vitro and in vivo studies. Thromb Haemostas 1993 ; 70 : 1009-13. 68 Panahloo A, Mohamed-Ali V, Lane A, Green F, Humphries SE, Yudkin JS. Determinants of plasminogen activator inhibitor 1 activity in treated NIDDM and its relation to a polymorphism in the plasminogen activator inhibitor 1 gene. Diabetes 1995 ; 44 : 37-42.

PAI- 1 and obesity

69 Potter Van Loon BJ, de Bart ACW, Radder JK, Frouch M, Kluft C, Menders AE. Acute exogenous hyperinsulinaemia does not result in elevation of plasma plasminogen activator inhibitor 1 (PAI-1) in human. Fibrinolysis 1990 ; 4 : 93-4. 70 Potter Van Loon BJ, Kluft C, Radder JK, Blankenstein MA, Meinders AE. The cardiovascular risk factor plasminogen activator inhibitor type 1 is related to insulin resistance. Metabolism 1993 : 42 : 945-9. 71 Raccah D, Alessi MC, Scelles V, Menard C, Juhar-Vague I, Vague P. Plamsinogen activator inhibitor activity in various types of endogenous hypertriglyceridemia. Fibrinolysis 1993 ; 7 : 171-6. 72 Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes 1988 ; 37 : 1595607. 73 Reaven GM. Pathogenesis of insulin resistance in human disease. Physiol Rev 1995 ; 75 : 473-86. 74 Ridker PM, Gaboury CL, Conlin PR, Seely EW, Williams GH, Vaughan DE. Stimulation of plasminogen activator inhibitor in vivo by infusion of angiotensin II. Evidence of a potential interaction between the renin-angiotensin system and fibrinolytic function. Circulation 1993 ; 87 : 1969-73. 75 Samad F, Yamamoto K, Lostkutoff DJ. Distribution and regulation of plasminogen activator inhibitor 1 in murine adipose tissue in viva: induction by tumor necrosis factor-a and lipopolysaccharide. J Clin Invest 1996 ; 97 : 37-46. 76 Samad F, Loskutoff DJ. Tissue distribution and regulation of plasminogen activator inhibitor 1 in obese mice. Mol Med 1996 ; 2 : 568-82. 77 Sawdey S, Loskutoff DJ. Regulation of murine type 1 plasminogen activator inhibitor (PAI-1) gene expression in vivo. Tissue specificity and induction by lipopolysaccharide, tumor necrosis factor a and transforming growth factor-p. J Clin Invest 1991 ; 88 : 1346-53. 78 Schneider DJ, Sobel BE. Augmentation of synthesis of plasminogen activator inhibiror type 1 by insulin and insulin-like growth factor type 1: implications for vascular disease in hyperinsulinemic states. Proc Nat1 Acad Sci USA 1991 ; 88 : 9959-63. 79 Schneider DJ, Nordt TK, Sobel BE. Attenuated fibrinolysis and accelerated atherogenesis in type II diabetic patients. Diabetes 1993 ; 42 : l-7. 80 Schneider DJ, Absher PM, Ricci MA. Dependence of augmentation of arterial endothelial cell expression of plasminogen activator inhibitor type 1 by insulin on soluble factors released from vascular smooth muscle cells. Circulation 1997 ; 96 : 2868-76. 81 Shimomura I, Funahashi T, Takahashi M, Maeda K, Kotani K, Nakamura T, et al. Enhanced expression of PAI- in visceral fat: possible contributor to vascular disease in obesity. Nat Med 1996 ; 2 : 800-3. 82 Sitko-Rahm A, Wiman B, Hamsten A, Nilsson J. Secretion of plasminogen activator inhibitor 1 from cultured human umbilical vein endothelial cells induced by very low density lipoprotein. Arteriosclerosis 1990 ; 10 : 1067-73. 83 Smith EB, Cochran S. Factors influencing the accumulation in fibrous plaque of lipid derived from low density lipoprotein. Part II. Preferential immobilization of lipoprotein (a). Atherosclerosis 1990 ; 84 : 173-81.

461

84 Spiegelman BM. PPAR-y: adipogenic regulator and thiazolidindione receptor. Diabetes 1998 ; 47 : 507-14. 85 Svendsen OL, Hassger C, Christiansen C, Nielsen JD, Winther K. Plasminogen activator inhibitor 1, tissuetype plasminogen activator, and fibrinogen. Effect of dieting with or without exercise in overweight postmenopausal women. Arterioscler Thromb Vast Biol 1996 ; 16 : 381-5. 86 Sylvan A, Rutergard JN, Janunger KG, Sjolund B, Nilsson TK. Normal plasminogen activator inhibitor levels at long-term follow-up after jejuno-ileal bypass in morbidly obese individuals. Metabolism 1992 ; 41 : 1370-2. 87 Thompson WD, Smith EB. Atherosclerosis and the coagulation system. J Path01 1989 ; 159 : 97-106. 88 Toft I. Bonaa KH. Ingebretsen OC. Nordov A, Birkeland KI, Jenssen T. Gender drfferences in the relaiionships between plasma plasminogen activator inhibitor 1 activity and factors linked to the insulin resistance syndrome in essential hypertension. Arterioscler Thromb Vast Biol 1997 ; 17 : 553-9.89 Vague P. Juhan-Vague I. Aillaud MF, Badier C, Viard R. Alessi MC, et al. Correlation between blood fibrinolytic activity, plasminogen activator inhibitor level, plasma insulin level and relative body weight in normal and obese subjects. Metabolism 1986 ; 35 : 250-3. 90 Vague P, Juhan-Vague I, Chabert V, Alessi MC, Atlan C. Fat distribution and plasminogen activator inhibitor activity in non diabetic obese women. Metabolism 1989 ; 38 : 913-5. 91 Vague P, Raccah D, Scelles V. Hypofibrinolysis and the insulin resistance syndrome. Int J Obesity 1995 ; 19 Suppl 1 : Sll-5. 92 Van Steenbergen W, Lanckmans S. Liver disturbances in obesity and diabetes mellitus. Int J Obesity 1995 ; 19 Suppl 3 : S27-36. 93 Van Meijer, M, Pannehoek, H. Structure of plasminogen activator inhibitor 1 (PAI-1) and its function in fibrinolysis: an update. Fibrinolysis 1995 ; 9 : 263-76. 94 Vaughan DE, Declerck PJ, Van Houtte E, De Mol M, Collen D. Reactivated recombinant plasminogen activator inhibitor 1 (rPAI-1) effectively prevents thrombolysis in viva. Thromb Haemost 1992 ; 68 : 60-3. 95 Vaughan DE, Lazos SA, Tong K. Angiotensin II regulates the expression of plasminogen activator inhibitor 1 in cultured endothelial cells: a potential link between the renin angiotensin system and thrombosis. J Clin Invest 1995 ; 95 : 995-1001. 96 Vuorinen-Markkola H, Puhakainen I, Yki-Jarvinen H. No evidence for short-term regulation of plasminogen activator inhibitor activity by insulin in man. Thromb Haemost 1992 ; 67 : 117-20. 97 Wanless IR, Lentz JS. Fatty liver hepatitis (steatohepatitis) and obesity: an autopsy study with analysis of risk factors. Hepatology 1990 ; 12 : 1106-10. 98 Ye S, Green FR, Scarabin PY, Nicaud V, Bara L, Dawson SJ, et al. The 4G/5G genetic polymorphism in the promoter of the plasminogen activator inhibitor 1 (PAI-1) associated with differences in plasma PAI- activity but not with risk of myocar dial infarction in the ECTIM study. Thromb Haemostas 1995 ; 74 : 837-41.