Erythrocyte sodium/lithium countertransport is associated with thrombotic and fibrinolytic factors in 58-year-old men

Summary

The metabolic syndrome, in which insulin resistance is the core feature, is associated both with dysregulation of thrombosis/ fibrinolysis and erythrocyte sodium/lithium countertransport (SLC).To investigate this further we designed a cross-sectional study to examine whether factors involved in coagulationand fibrinolysis systems were associated with SLC independently of insulin resistance in 93 58-year-old men. SLC was in univariate analysis positively correlated with PAI-1 activity (r = 0.35, p <0.01), tPA antigen (r = 0.38, p <0.01), von Willebrand factor (r = 0.25, p <0.05), protein S (r = 0.26, p <0.05), and C (r = 0.30, p <0.01), and negatively associated with tPA activity(r = −0.28, p <0.01). Since these correlations could be influenced by the components of the metabolic syndrome itself, a separate analysis with adjustment for glucose infusion rate (GIR), plasma insulin, body fat, sagittal diameter of the abdomen (SD) and log serum triglyceride concentration (TG) was conducted. Then SLC was associated with tPA antigen independent of GIR, plasma insulin, body fat, SD and TG. SLC was also associated with protein C independent of GIR, insulin, body fat and SD but not TG. In conclusion, we found a relationship between SLC and the fibrinolytic system that was not related to the metabolic syndrome.

Keywords

Sodium/lithium countertransport - fibrinolysis - coagulation - metabolic syndrome - renin-angiotensin system

• References

• 1 Canessa M, Adragna N, Solomon HS. et al. Increased sodium-lithium countertransport in red cells of patients with essential hypertension. N Engl J Med 1980; 302: 772-6.
• 2 Laurenzi M, Cirillo M, Panarelli W. et al. Baseline sodium-lithium countertransport and 6-year incidence of hypertension. The Gubbio Population Study. Circulation 1997; 95: 581-7.
• 3 Strazzullo P, Siani A, Cappuccio FP. et al. Red blood cell sodium-lithium countertransport and risk of future hypertension: the Olivetti Prospective Heart Study. Hypertension 1998; 31: 1284-9.
• 4 Redgrave J, Canessa M, Gleason R. et al. Red blood cell lithium-sodium countertransport in non-modulating essential hypertension. Hypertension 1989; 13: 721-6.
• 5 Doria A, Fioretto P, Avogaro A. et al. Insulin resistance is associated with high sodium-lithium countertransport in essential hypertension. Am J Physiol 1991; 261: 684-91.
• 6 Trevisan M, Laurenzi M. Correlates of sodium-lithium countertransport. Findings from the Gubbio Epidemiological Study. The Gubbio Collaborative Study Group. Circulation 1991; 84: 2011-9.
• 7 Ferrannini E, Buzzigoli G, Bonadonna R. et al. Insulin resistance in essential hypertension. N Engl J Med 1987; 317: 350-7.
• 8 Alberti KGMM, Zimmet PZ. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 1998; 15: 539-53.
• 9 Agewall S, Bokemark L, Wikstrand J. et al. Insulin sensitivity and hemostatic factors in clinically healthy 58-year-old men. Thromb Haemost 2000; 84: 571-5.
• 10 Herlitz H, Bokemark L, Alenhag EL. et al. Sodium/lithium countertransport, insulin resistance, insulin peptides and micoralbuminuria in clinically healthy 58-year-old men. Clin Sci 2001; 100: 443-9.
• 11 Wilhelmsen L, Svärdsudd K, Korsan-Bengtsen K. et al. Fibrinogen as a risk factor for stroke and myocardial infarction: The study of men born in 1913. N Engl J Med 1984; 311: 501-5.
• 12 Kannel WB, Wolf PA, Castelli WP. et al. Fibrinogen and risk of cardiovascular disease. JAMA 1987; 258: 1183-6.
• 13 Bokemark L, Wikstrand J, Attvall S. et al. Insulin resistance and intima-media thickness in the carotid and femoral arteries of clinically healthy 58-year-old men. J Intern Med 2001; 249: 59-67.
• 14 Klose S, Borner K. Enzymatische bestimmung des gesamtcholesterins mit dem greiner selective analyzer (GSA-II). J Clin Chem Clin Biochem 1978; 15: 121-30.
• 15 Wahlefeld AW. Triglycerides: determination after enzymatic hydrolysis. In Methods of Enzymatic Analysis. Bermeyer HU. Academic Press Inc; New York: 1974: 18-31.
• 16 Agewall S, Fagerberg B, Samuelsson O. et al. Multiple cardiovascular risk factor intervention in treated hypertensive men: What can be achieved?. Nutr Metab Cardiovasc Dis 1993; 03: 128-35.
• 17 DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 1979; 237: E214-E223.
• 18 Ingerslev J. A sensitive ELISA for von Willebrand factor (vWF.ag). Scand J Clin Lab Invest 1987; 47: 143-9.
• 19 Nilsson IM, Olow B. Determination of fibrinogen and fibrinogenolytic activity. Thromb Diath Haemorrh 1962; 08: 297-309.
• 20 Gaffney PJ, Curtis AD. A collaborative study to establish the 2^nd international standard for tissue plasminogen activator (t-PA). Thromb Haemost 1987; 58: 1085-7.
• 21 Holvoet P, Cleemput H, Collen D. Assay of human tissue-type plasminogen activator (t-PA) with an enzyme-linked immunosorbent assay (ELISA) based on three murine monoclonal antibodies to t-PA. Thromb Haemost 1985; 54: 684-7.
• 22 Martinoli JL, Stocker K. Fast functional protein C assay using Protac, a novel protein C activator. Thromb Res 1986; 43: 253-64.
• 23 Wolf M, Boyer-Neumann C, Peynaud-Debayle E. et al. Clinical applications of a direct assay of free protein S antigen using monoclonal antibodies. A study of 59 cases. Blood Coagul Fibrinolysis 1994; 05: 187-92.
• 24 Chandler WL, Alessi MC, Aillaud MF. et al. Clearance of tissue plasminogen activator (TPA) and TPA/plasminogen activator inhibitor type 1 (PAI-1) complex: relationship to elevated TPA antigen in patients with high PAI-1 activity levels. Circulation 1997; 96: 761-8.
• 25 Morange PE, Alessi MC, Verdier M. et al. PAI-1 produced ex vivo by human adipose tissue is relevant to PAI-1 blood level. Arterioscler Thromb Vasc Biol 1999; 19: 1361-5.
• 26 Engelmann B, Duhm J, Schonthier UM. et al. Relations of sodium-lithium countertransport kinetics to plasma and red cell membrane phospholipids in hyperlipidemia. Atherosclerosis 1993; 99: 151-63.
• 27 Watkins SL, West IC, Wilkinson R, Thomas TH. Abnormal thiol reactivity of tropomyosin in essential hypertension and its association with abnormal sodium-lithium countertransport kinetics. J Hypertens 2001; 19: 485-93.
• 28 Pontremoli R, Zerbini G, Rivera A. et al. Insulin activation of red blood cell Na⁺/K⁺ exchange decreases the affinity of sodium sites. Kidney Int 1994; 46: 365-75.
• 29 Rutherford PA, Thomas TH, Hardman T. et al. Sodium-lithium countertransport activity is not affected by short-term insulin exposure in vivo or in a physiologic medium in vitro. Metabolism 1993; 42: 1087-9.
• 30 De la ASierra, Insa R, Compte M. et al. Effect of long term antihypertensive therapy with angiotensin converting enzyme inhibitors on red cell sodium transport. Am J Hypertens 1995; 08: 622-5.
• 31 Sánchez RA, Giménez MI, Migliorini M. et al. Erythrocyte sodium-lithium countertransport in non-modulating offspring and essential hypertensive individuals. Response to enalapril. Hypertension 1997; 30: 99-105.
• 32 Berk BC, Aronow MS, Brock TA. et al. Angiotensin II-stimulated Na⁺/H⁺ exchange in cultured vascular smooth muscle cells. Evidence for protein kinase C-dependent and -independent pathways. J Biol Chem 1987; 262: 5057-64.
• 33 Zerbini G, Maestroni A, Breviario D. et al. Alternative splicing of NHE-1 mediates Na-Li countertransport and associates with activity rate. Diabetes 2003; 52: 1511-8.
• 34 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.
• 35 Ridker PM, Gaboury CL, Conlin PR. et al. Stimulation of plasminogen activator inhibitor in vivo by infusion of angiotensin II. Evidence of a potential interaction between the reninangiotensin system and fibrinolytic function. Circulation 1993; 87: 1969-73.
• 36 Brown NJ, Kumar S, Painter CA. et al. ACE inhibition versus angiotensin type I receptor antagonism. Differential effects on PAI-I over time. Hypertension 2002; 40: 859-65.
• 37 Karlsson C, Lindell K, Ottosson M. et al. Human adipose tissue expresses angiotensinogen and enzymes required for its conversion to angiotensin II. J Clin Endocrinol Metab 1998; 83: 3925-9.