Regular Exercise, Plasminogen Activator Inhibitor-1 (PAI-1) Activity and the 4G/5G Promoter Polymorphism in the PAI-1 Gene

Summary

The aim of this controlled randomised clinical trial was to investigate the effects of regular low to moderate intensity physical activity on plasminogen activator inhibitor-1 (PAI-1) activity during three years while taking into account the 4G/5G polymorphism in the promoter of the PAI-1 gene. Male subjects (age 52-62 years, n = 132) were randomised into an exercise or a (non-intervention) reference group. Aerobic threshold increased by 8.8% (p = 0.025) in the exercise group, and decreased by 1.1% in the non-intervention group, while PAI-1 activity did not change significantly in either study group. However, homozygotes for the 4G allele in the exercise group showed a 36% reduction in PAI-1 (p = 0.025). In conclusion, although regular moderate physical activity did not decrease PAI-1 activity in the whole group, regular exercise may be effective for controlling elevated PAI-1 level in subjects homozygous for the 4G allele.

Key words

Plasminogen activator inhibitor-1 - DNA polymorphism - exercise training - randomised clinical trial - population based study

• References

• 1 Cortellaro M, Cofrancesco E, Boschetti C, Mussoni L, Donati MB, Cardillo M, Catalano M, Gabrielli L, Lombardi B, Specchia G, Tavazzi L, Tremoli E, Pozzoli E, Turri M. Increased fibrin turnover and high PAI-1 activity as predictors of ischemic events in atherosclerotic patients. A case-control study. Arterioscler Thromb 1993; 13: 1412-7.
• 2 Salomaa V, Stinson V, Kark JD, Folsom AR, Davis CE, Wu KK. Association of fibrinolytic parameters with early atherosclerosis. The ARIC Study. Atherosclerosis Risk in Communities Study. Circulation 1995; 91: 284-90.
• 3 Rankinen T, Väisänen S, Penttilä I, Rauramaa R. Acute dynamic exercise increases fibrinolytic activity. Thromb Haemost 1995; 73: 281-6.
• 4 van den Burg PJ, Hospers JE, van Vliet M, Mosterd WL, Bouma BN, Huisveld IA. Effect of endurance training and seasonal fluctuation on coagulation and fibrinolysis in young sedentary men. J Appl Physiol 1997; 82: 613-20.
• 5 Chandler WL, Schwartz RS, Stratton JR, Vitiello MV. Effects of endurance training on the circadian rhythm of fibrinolysis in men and women. Med Sci Sports Exerc 1996; 28: 647-55.
• 6 Kluft C, Verheijen JH. Leiden fibrinolysis working party: blood collection and handling procedures for assessment of tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1). Fibrinolysis 1990; 4 (Suppl. 02) 155-61.
• 7 Juhan-Vague I, Alessi MC, Raccah D, Aillaud MF, Billerey M, Ansaldi J, Philip-Joet C, Vague P. Daytime fluctuations of plasminogen activator inhibitor 1 (PAI-1) in populations with high PAI-1 levels. Thromb Haemost 1992; 67: 76-82.
• 8 Dawson SJ, 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 HepG2 cells. J Biol Chem 1993; 268: 10739-45.
• 9 Eriksson P, Kallin B, van’t Hooft FM, Båvenholm P, Hamsten A. Allele-specific increase in basal transcription of the plasminogen-activator inhibitor 1 gene is associated with myocardial infarction. Proc Natl Acad Sci U S A 1995; 92: 1851-5.
• 10 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.
• 11 Ye S, Green FR, Scarabin PY, Nicaud V, Bara L, Dawson SJ, Humphries SE, Evans A, Luc G, Cambou JP, Arveiler D, Henney AM, Cambien F. The 4G/5G genetic polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene is associated with differences in plasma PAI-1 activity but not with risk of myocardial infarction in the ECTIM study. Thromb Haemost 1995; 74: 837-41.
• 12 Margaglione M, Cappucci G, d’Addedda M, Colaizzo D, Giuliani N, Vecchione G, Mascolo G, Grandone E, Di Minno G. PAI-1 plasma levels in a general population without clinical evidence of atherosclerosis. Relation to environmental and genetic determinants. Arterioscler Thromb Vasc Biol 1998; 18: 562-7.
• 13 Mussoni L, Mannucci L, Sirtori M, Camera M, Maderna P, Sironi L, Tremoli E. Hypertriglyceridemia and regulation of fibrinolytic activity. Arterioscler Thromb 1992; 12: 19-27.
• 14 Väisänen S, Baumstark MW, Penttilä I, Bouchard C, Halonen P, Rankinen T, Berg A, Rauramaa R. Small, dense LDL particle concentration correlates with plasminogen activator inhibitor type-1 (PAI-1) activity. Thromb Haemost 1997; 78: 1495-9.
• 15 Juhan-Vague I, Thompson SG, Jespersen J. Involvement of the hemostatic system in the insulin resistance syndrome. A study of 1500 patients with angina pectoris. The ECAT Angina Pectoris Study Group. Arterioscler Thromb 1993; 13: 1865-73.
• 16 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 non-insulin-dependent diabetes mellitus. Thromb Haemost 1995; 74: 842-7.
• 17 Ossei-Gerning N, Mansfield MW, Stickland MH, Wilson IJ, Grant PJ. Plasminogen activator inhibitor-1 promoter 4G/5G genotype and plasma levels in relation to a history of myocardial infarction in patients characterized by coronary angiography. Arterioscler Thromb Vasc Biol 1997; 17: 33-7.
• 18 Rauramaa R, Rankinen T, Tuomainen P, Väisänen S, Mercuri M. Inverse relationship between cardiorespiratory fitness and carotid atherosclerosis. Atherosclerosis 1995; 112: 213-21.
• 19 Humphries SE, Luong LA, Talmud PJ, Frick MH, Kesäniemi YA, Pastermack A, Taskinen M-R. Syvänne M for the LOCAT Study Group. The 5A/6A polymorphism in the promoter of the stromelysin-1 (MMP-3) gene predicts progression of angiographically determined coronary artery disease in men in the LOCAT gemfibrozil study. Atherosclerosis 1998; 139: 49-56.
• 20 Weir BS. Genetic data analysis. Methods for discrete population genetic data. Sinauer Associates, Inc. Publishers; Sunderland, Massachusetts: 1990
• 21 Szymanski LM, Pate RR. Effects of exercise intensity, duration, and time of day on fibrinolytic activity in physically active men. Med Sci Sports Exerc 1994; 26: 1102-8.
• 22 de Geus EJC, Kluft C, de Bart ACW, van Doornen LJP. Effects of exercise training on plasminogen activator inhibitor activity. Med Sci Sports Exerc 1992; 24: 1210-9.
• 23 Stegnar M, Mavri A. Reproducibility of fibrinolytic response to venous occlusion in healthy subjects. Thromb Haemost 1995; 73: 453-7.
• 24 Chandler WL, Levy WC, Stratton JR. The circulatory regulation of TPA and UPA secretion, clearance, and inhibition during exercise and during the infusion of isoproterenol and phenylephrine. Circulation 1995; 92: 2984-94.