Increased plasma levels of plasminogen activator inhibitor-1 and soluble vascular cell adhesion molecule after triacylglycerol infusion in man

Summary

Increased plasma plasminogen activator inhibitor-1 (PAI-1) has been implicated in the development of vascular disease. In type 2 diabetes mellitus high PAI-1 levels are associated with increased plasma concentrations of free fatty acids (FFA) and triacylglycerol indicating an association or a causal relationship. To answer that question, the effect of FFA/triacylglycerol on plasma PAI-1 was examined. Ten healthy male volunteers were studied for 6 h during infusion of triacylglycerol [1.5 ml/min]/heparin [0.2 IU/(kg·min)] (LIP; n=10), saline only (SAL; n=10), and saline/heparin (HEP; n=5). Plasma insulin concentrations were kept constant at ~35 pmol/l by intravenous soma-tostatin-insulin infusions and there was no significant change in plasma glucose levels during any of the study protocols. LIP increased plasma triacylglycerol and FFA ~3- (p<0.001) and ~8-(p<0.000001) fold, respectively, within 90 min. Baseline plasma PAI-1 measured by a bio-immunoassay was similar in HEP (11.4±2.8 ng/ml), SAL (16.6±3.6 ng/ml), and LIP studies (15.2±3.4 ng/ml). Since studies were initiated in the morning, PAI-1 decreased (p<0.025) over time following its normal diurnal variation to 6.4±2.0 ng/ml and 4.0±2.4 ng/ml at 360 min in SAL and HEP, respectively. During LIP, however, PAI-1 increased to ~2.6 fold higher levels than during SAL at 360 min (16.4±4.0 ng/ml, p<0.01). While tissue plasminogen activator (tPA) and adipsin, an adipocyte derived protease, were unaffected by LIP, changes in soluble vascular cell adhesion molecule-1 (sVCAM-1) were significantly correlated (p=0.02) with those seen for PAI-1. This suggests that hyperlipidemia independent of insulin and plasma glucose levels stimulates vascular tissue and in turn might induce an increase in plasma PAI-1. PAI-1 then could contribute to the development of atherothrombotic vascular disease.

Keywords

Fibrinolysis - PAI-1 - VCAM-1 - adhesion molecules - vascular disease - insulin resistance - free fatty acids

• References

• 1 Binder BR. Physiology and pathophysiology of the fibrinolytic system. Fibrinolysis 1995; 9 (Suppl. 01) Suppl 3-8.
• 2 Hamsten A. et al. Increased plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction. N Engl J Med 1985; 313: 1557-63.
• 3 Juhan-Vague I, Alessi MC.. Fibrinolysis and risk for coronary artery disease. Fibrinolysis 1996; 10: 127-36.
• 4 Eitzman DT. et al. Plasminogen activator inhibitor-1 deficiency protects against atherosclerosis progression in the mouse carotid artery. Blood 2000; 96: 4212-5.
• 5 Juhan-Vague I, Alessi MC. Plasminogen activator inhibitor 1 and atherothrombosis. Thromb Haemost 1993; 70: 138-43.
• 6 Byberg L. et al. Plasminogen activator inhibitor-1 activity is independently related to both insulin sensitivity and serum triglyce-rides in 70-year-old men. Arterioscler Thromb Vasc Biol 1998; 18: 258-64.
• 7 Juhan-Vague I, Alessi MC. PAI-1, obesity, insulin resistance and risk of cardiovascular events. Thromb Haemost 1997; 78: 656-60.
• 8 McGarry JD. What if Minowski had been ageusic? An alternative angle an diabetes. Science 1992; 258: 766-70.
• 9 Reaven GM. Role of insulin resistance in human disease. Diabetes 1988; 37: 1595-607.
• 10 Alessi MC. et al. Up-regulation of PAI-1 synthesis by insulin and proinsulin in Hep G2 cells but not in endothelial cells. Fibrinolysis 1995; 9: 237-42.
• 11 Kooistra T. et al. Plasminogen activator inhibitor 1: Biosynthe-sis and mRNA levels are increased by insulin in cultured human hepatocytes. Thromb Haemost 1989; 62: 723-8.
• 12 Banfi C. et al. Linoleic acid enhances the secretion of plasminogen activator inhibitor type 1 by Hep G2 cells. J Lipid Res 1997; 38: 860-9.
• 13 Schneider DJ, Sobel BE. Synergistic augmentation of expression of plasminogen activator inhibitor type-1 induced by insulin, very-low-density lipoproteins, and fatty acids. Coron Art Dis 1996; 7: 813-7.
• 14 Eriksson P. et al. Very-low-density lipoprotein response element in the promoter region of the human plasminogen activator inhibitor-1 gene implicated in the impaired fibrinolysis of hypertriglyceridemia. Arterioscler Thromb Vasc Biol 1997; 18: 20-6.
• 15 Stiko-Rahm A. et al. Secretion of plasminogen activator inhibitor-1 from cultured human umbilical vein endothelial cells is induced by very low density lipoprotein. Arteriosclerosis 1990; 10: 1067-73.
• 16 Karikó K. et al. Stimulatory effect of unsatu-rated fatty acids on the level of plasminogen activator inhibitor-1 mRNA in cultured human endothelial cells. FEBS Lett 1995; 361: 118-22.
• 17 Nilsson L. et al. Unsaturated fatty acids increase plasminogen activator inhibitor-1 expression in endothelial cells. Arterioscler Thromb Vasc Biol 1998; 18: 1679-85.
• 18 Nordt TK. et al. Induction of plasminogen activator inhibitor type-1 (PAI-1) by proinsulin and insulin in vivo. Circulation 1995; 91: 764-70.
• 19 Calles-Escandon J. et al. Induction of hyper-insulinemia combined with hyperglycemia and hypertriglyceridemia increases plasminogen activator inhibitor 1 in blood in normal human subjects. Diabetes 1998; 47: 290-3.
• 20 Vuorinen-Markkola H. et al. No evidence for short-term regulation of plasminogen activator inhibitor activity by insulin in men. Thromb Haemost 1992; 67: 117-20.
• 21 Leeuwenberg JFM. et al. E-selectin and inter-cellular adhesion molecule-1 are released by activated human endothelial cells in vitro. Immunology 1992; 77: 543-9.
• 22 Pigott R. et al. Soluble forms of E-selectin, ICAM-1 and VCAM-1 are present in the supernatants of cytokine activated cultured endothelial cells. Biochem Biophys Res Commun 1992; 187: 584-9.
• 23 Wagner OF, Jilma B. Putative role of adhesion molecules in metabolic disorders. Horm Metab Res 1997; 29: 627-30.
• 24 Huber K. et al. Hepatic synthesis and clearance of components of the fibrinolytic system in healthy volunteers and in patients with different stages of liver cirrhosis. Thromb Res 1991; 62: 491-500.
• 25 van Griensven JM. et al. Effects of increased liver blood flow on the kinetics and dynamics of recombinant tissue-type plasminogen activator. Clin Pharmacol Ther 1996; 60: 504-11.
• 26 Lansink M. et al. Increased clearance explains lower plasma levels of tissue-type plasminogen activator by estradiol: evidence for potently enhanced mannose receptor expression in mice. Blood 1999; 94: 1330-6.
• 27 White RT. et al. Human adipsin is identical to complement factor D and is expressed at high levels in adipose tissue. J Biol Chem 1992; 267: 9210-3.
• 28 Alessi MC. et al. Relation between plasma PAI activity and adipsin levels. Thromb Haemostas 1995; 74: 1200-2.
• 29 Mavri A. et al. Impact of adipose tissue on plasma plasminogen activator inhibitor-1 in dieting obese women. Arterioscler Thromb Vasc Biol 1999; 19: 1582-7.
• 30 Krebs M. et al. Free fatty acids inhibit the glucose stimulated increase of intramuscular glucose-6-phosphate concentrations in humans. J Clin Endocrinol Metab 2001; 86: 2153-60.
• 31 Hultin M. et al. Release of lipoprotein lipase to plasma by triacylglycerol emulsions. Biochim Biophys Acta 1992; 1125: 97-103.
• 32 Gerich JE. et al. Effects of somatostatin on plasma glucose and glucagon levels in human diabetes mellitus. Pathophysiologic and therapeutic implications. N Engl J Med 1974; 291: 544-7.
• 33 Roden M. et al. The roles of insulin and glucagon in the regulation of hepatic glycogen synthesis and turnover in humans. J Clin Invest 1996; 97: 642-8.
• 34 McGowan MW. et al. A peroxidase-coupled method for the colorimetric determination of serum triglycerides. Clin Chem 1983; 29: 538-42.
• 35 Huber K. et al. Circadian fluctuations in plasma levels of tissue plasminogen activator antigen and plasminogen activator inhibitor activity. Fibrinolysis 1989; 3: 41-3.
• 36 Juhan-Vague I. et al. Daytime fluctuations of plasminogen activator inhibitor 1 (PAI-1) in populations with high PAI-1 levels. Thromb Haemost 1992; 67: 76-82.
• 37 Urano T. et al. Fluctuations of tPA and PAI-1 antigen levels in plasma: Difference of their fluctuation patters between male and female. Thromb Res 1990; 60: 133-9.
• 38 Agnelli G. et al. Additive effects of dDAVP and standard heparin in increasing plasma tPA. Thromb Haemost 1989; 61: 507-10.
• 39 Huber K. et al. Heparin induces t-PA antigen plasma levels in patients with unstable angina: no evidence for clinical benefit of heparinization during the initial phase of treatment. Thromb Res 1989; 55: 779-84.
• 40 Myrup B. et al. No effect of unfractionated or low molecular weight heparin treatment on markers of vascular wall and hemostatic function in incipient diabetic nephropathy. Diabetes Care 1997; 20: 1615-9.
• 41 van Hinsberg VW. et al. Tumor necrosis factor increases the production of plasminogen activator inhibitor in human endothelial cells in vitro and in rats in vivo. Blood 1988; 72: 1467-73.
• 42 Loskutoff DJ. et al. The adipocyte and hemostatic balance in obesity. Studies of PAI-1. Arterioscler Thromb Vasc Biol 1998; 18: 1-6.
• 43 Loskutoff DJ. Regulation of PAI-1 gene expression. Fibrinolysis 1991; 5: 197-206.
• 44 Booth NA. et al. Plasminogen activator inhibitor (PAI-1) in plasma and platelets. Br J Haematol 1988; 70: 327-33.
• 45 Asplund-Carlson A. et al. Relationship between plasma plasminogen activator inhibitor-1 activity and VLDL triglyceride concentration, insulin levels and insulin sensitivity: studies in randomly selected normo- and hypertriglyceridaemic men. Diabetologia 1993; 36: 817-25.
• 46 Agnelli G. et al. Effects of standard heparin and low molecular weight heparin (Kabi 2165) on fibrinolysis. Thromb Haemost 1987; 60: 311-3.
• 47 Böhm T. et al. Isolation and characterization of tissue-type plasminogen activator-binding proteoglycans from human umbilical vein endothelial cells. Arterioscler Thromb Vasc Biol 1996; 16: 665-72.
• 48 Rappaport RS. et al. Heparin potentiates endothelial cell growth factor stimulation of plasminogen activator synthesis by dipoloid human lung fibroblasts. Thromb Haemost 1988; 59: 514-22.
• 49 Hackmann A. et al. Levels of soluble cell adhesion molecules in patients with dyslipidemia. Circulation 1996; 93: 1334-8.
• 50 Grainger DJ. et al. Transforming growth factor beta is sequestered into an inactive pool by lipoproteins. J Lipid Res 1997; 38: 2344-52.
• 51 Harris HW. et al. The lipemia of sepsis: triglyceride-rich lipoproteins as agents of innate immunity. J Endotoxin Res 2000; 6: 421-30.
• 52 Kemme MJ. et al. No influence of acute hypertriglyceridemia on plasma t-PA in healthy male volunteers. Thromb Res 2001; 103: 9-16.
• 53 Altomare DF. et al. Reduction of plasma levels of tissue plasminogen activator after infusion of a lipid emulsion in humans. J Parenter Enteral Nutr 1993; 17: 274-6.
• 54 Sironi L. et al. Plasminogen activator inhibitor type-1 synthesis and mRNA expression in HepG2 cells are regulated by VLDL. Arterioscler Thromb Vasc Biol 1996; 16: 89-96.
• 55 Kooner JS. et al. Abdominal obesity, impaired nonesterified fatty acid suppression, and insulin-mediated glucose disposal are early metabolic abnormalities in families with premature myocardial infarction. Arterioscler Thromb Vasc Biol 1998; 18: 1021-6.
• 56 Boden G. et al. Mechanisms of fatty acid-induced inhibition of glucose uptake. J Clin Invest 1994; 93: 2438-46.
• 57 Bonadonna RC. et al. Time dependence of the interaction between lipid and glucose in humans. Am J Physiol 1989; 257: E49-56.
• 58 Yki-Järvinen H. et al. Effect of free fatty acids on glucose uptake and nonoxidative glycolysis across human forearm tissues in the basal state and during insulin stimulation. J Clin Endocrinol Metab 1991; 72: 1268-77.
• 59 Mingrone G. et al. Triglyceride-induced diabetes associated with familial lipoprotein lipase deficiency. Diabetes 1999; 48: 1258-63.
• 60 Meijssen S. et al. In vivo evidence of defective postprandial and postabsorptive free fatty acid metabolism in familial combined hyper-lipidemia. J Lipid Res 2000; 41: 1096-102.
• 61 Kumar S. et al. Suppression of non-esterified fatty acids to treat type A insulin resistance syndrome. Lancet 1994; 343: 1073-4.