Effects of high-amount–high-intensity exercise on in vivo platelet activation: Modulation by lipid peroxidation and AGE/RAGE axis

Francesca Santilli; Natale Vazzana; Pierpaolo Iodice; Stefano Lattanzio; Rossella Liani; Rosa Grazia Bellomo; Gianfranco Lessiani; Francesca Perego; Raoul Saggini; Giovanni Davì

doi:10.1160/TH13-04-0295

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2013; 110(06): 1232-1240
DOI: 10.1160/TH13-04-0295

Platelets and Blood Cells

Schattauer GmbH

Effects of high-amount–high-intensity exercise on in vivo platelet activation: Modulation by lipid peroxidation and AGE/RAGE axis

Francesca Santilli

¹Internal Medicine and Center of Excellence on Aging, “G. d’Annunzio” University of Chieti, Chieti, Italy

,

Natale Vazzana

¹Internal Medicine and Center of Excellence on Aging, “G. d’Annunzio” University of Chieti, Chieti, Italy

,

Pierpaolo Iodice

²Department of Neuroscience and Imaging, “G. d’Annunzio” University of Chieti, Chieti, Italy

,

Stefano Lattanzio

¹Internal Medicine and Center of Excellence on Aging, “G. d’Annunzio” University of Chieti, Chieti, Italy

,

Rossella Liani

¹Internal Medicine and Center of Excellence on Aging, “G. d’Annunzio” University of Chieti, Chieti, Italy

,

Rosa Grazia Bellomo

³Department of Human Movement, “G. d’Annunzio” University of Chieti

,

Gianfranco Lessiani

¹Internal Medicine and Center of Excellence on Aging, “G. d’Annunzio” University of Chieti, Chieti, Italy

,

Francesca Perego

⁴Internal Medicine III, Luigi Sacco Hospital, University of Milan, Milan, Italy

,

Raoul Saggini

²Department of Neuroscience and Imaging, “G. d’Annunzio” University of Chieti, Chieti, Italy

,

Giovanni Davì

¹Internal Medicine and Center of Excellence on Aging, “G. d’Annunzio” University of Chieti, Chieti, Italy

› Author Affiliations

Abstract

Summary

Physical activity is associated with cardiovascular risk reduction, but the effects of exercise on platelet activation remain controversial. We investigated the effects of regular high-amount, high intensity aerobic exercise on in vivo thromboxane (TX)-dependent platelet activation and plasma levels of platelet-derived proteins, CD40L and P-selectin, and whether platelet variables changes may be related to changes in high-density lipoprotein (HDL) and in the extent of oxidative stress and oxidative stress-related inflammation, as reflected by urinary isoprostane excretion and endogenous soluble receptor for advanced glycation end-products (esRAGE), respectively. Urinary excretion of 11-dehydro-TXB₂ and 8-iso-prostaglandin (PG)F_2α and plasma levels of P-selectin, CD40L and esRAGE were measured before and after a eight-week standardised aerobic high-amount–high-intensity training program in 22 sedentary subjects with low-to-intermediate risk. Exercise training had a clear beneficial effect on HDL cholesterol (+10%, p=0.027) and triglyceride (-27%, p=0.008) concentration. In addition, a significant (p<0.0001) decrease in urinary 11-dehydro-TXB₂ (26%), 8-iso-PGF_2α (21 %), plasma P-selectin (27%), CD40L (35%) and a 61% increase in esRAGE were observed. Multiple regression analysis revealed that urinary 8-iso-PGF_2α [beta=0.33, SEM=0.116, p=0.027] and esRAGE (beta=-0.30, SEM=31.3, p=0.046) were the only significant predictors of urinary 11-dehydro-TXB₂ excretion rate over the training period. In conclusion, regular high-amount–high-intensity exercise training has broad beneficial effects on platelet activation markers, paralleled and possibly associated with changes in the lipoprotein profile and in markers of lipid peroxidation and AGE/RAGE axis. Our findings may help explaining why a similar amount of exercise exerts significant benefits in preventing cardiovascular events.

Keywords

Aerobic exercise - platelet activation - oxidative stress - esRAGE

Full Text

References

References
1 Thompson PD, Franklin BA, Balady GJ. et al. Exercise and acute cardiovascular events placing the risks into perspective: a scientific statement from the American Heart Association Council on Nutrition, Physical Activity, and Metabolism and the Council on Clinical Cardiology. Circulation 2007; 115: 2358-2368.
2 Blair SN, Kohl 3rd HW, Barlow CE. et al. Changes in physical fitness and all-cause mortality. A prospective study of healthy and unhealthy men. J Am Med Assoc 1995; 273: 1093-1098.
3 Kokkinos P, Myers J, Faselis C. et al. Exercise capacity and mortality in older men: a 20-year follow-up study. Circulation 2010; 122: 790-797.
4 Leon AS, Connett J, Jacobs Jr DR. et al. Leisure-time physical activity levels and risk of coronary heart disease and death. The Multiple Risk Factor Intervention Trial. J Am Med Assoc 1987; 258: 2388-2395.
5 Paffenbarger Jr RS, Hyde RT, Wing AL. et al. Physical activity, all-cause mortality, and longevity of college alumni. N Engl J Med 1986; 314: 605-613.
6 Leon AS, Sanchez OA. Response of blood lipids to exercise training alone or combined with dietary intervention. Med Sci Sports Exerc 2001; 33 (Suppl. 06) S502-515 discussion S528-529.
7 Zoppini G, Targher G, Zamboni C. et al. Effects of moderate-intensity exercise training on plasma biomarkers of inflammation and endothelial dysfunction in older patients with type 2 diabetes. Nutr Metab Cardiovasc Dis 2006; 16: 543-549.
8 Kodama S, Tanaka S, Saito K. et al. Effect of aerobic exercise training on serum levels of high-density lipoprotein cholesterol: a meta-analysis. Arch Intern Med 2007; 167: 999-1008.
9 Kraus WE, Houmard JA, Duscha BD. et al. Effects of the amount and intensity of exercise on plasma lipoproteins. N Engl J Med 2002; 347: 1483-1492.
10 Kraus WE, Torgan CE, Duscha BD. et al. Studies of a targeted risk reduction intervention through defined exercise (STRRIDE). Med Sci Sports Exerc 2001; 33: 1774-1784.
11 Slentz CA, Houmard JA, Johnson JL. et al. Inactivity, exercise training and detraining, and plasma lipoproteins. STRRIDE: a randomized, controlled study of exercise intensity and amount. J Appl Physiol 2007; 103: 432-442.
12 Kestin AS, Ellis PA, Barnard MR. et al. Effect of strenuous exercise on platelet activation state and reactivity. Circulation 1993; 88: 1502-1511.
13 Li N, Wallén NH, Hjemdahl P. Evidence for prothrombotic effects of exercise and limited protection by aspirin. Circulation 1999; 100: 1374-1379.
14 Wang JS, Li YS, Chen JC. et al. Effects of exercise training and deconditioning on platelet aggregation induced by alternating shear stress in men. Arterioscler Thromb Vasc Biol 2005; 25: 454-460.
15 Thrall G, Lip GY. Exercise and the prothrombotic state: a paradox of cardiovascular prevention or an enhanced prothrombotic state?. Arterioscler Thromb Vasc Biol 2005; 25: 265-266.
16 Ferroni P, Riandino S, Vazzana N. et al. Biomarkers of platelet activation in acute coronary syndromes. Thromb Haemost 2012; 108: 1109-1123.
17 Davì G, Patrono C. Platelet activation and atherothrombosis. N Engl J Med 2007; 357: 2482-2494.
18 Davì G, Guagnano MT, Ciabattoni G. et al. Platelet activation in obese women: role of inflammation and oxidant stress. J Am Med Assoc 2002; 288: 2008-2014.
19 Patrono C, Falco A, Davì G. Isoprostane formation and inhibition in athero-thrombosis. Curr Opin Pharmacol 2005; 5: 198-203.
20 Basili S, Pacini G, Guagnano MT. et al. Insulin resistance as a determinant of platelet activation in obese women. J Am Coll Cardiol 2006; 48: 2531-2538.
21 Santilli F, Vazzana N, Liani R. et al. Platelet activation in obesity and metabolic syndrome. Obes Rev 2012; 13: 27-42.
22 Santilli F, Basili S, Ferroni P. et al. CD40/CD40L system and vascular disease. Intern Emerg Med 2007; 2: 256-268.
23 Santilli F, Vazzana N, Bucciarelli LG. et al. Soluble forms of RAGE in human diseases: clinical and therapeutical implications. Curr Med Chem 2009; 16: 940-952.
24 D'Agostino Sr RB, Vasan RS, Pencina MJ. et al. General cardiovascular risk profile for use in primary care: the Framingham Heart Study. Circulation 2008; 117: 743-753.
25 Wang Z, Ciabattoni G, Créminon C. et al. Immunological characterization of urinary 8-epi-prostaglandin F2 alpha excretion in man. J Pharmacol Exp Ther 1995; 275: 94-100.
26 Ciabattoni G, Pugliese F, Davi G. et al. Fractional conversion of thromboxane B2 to urinary 11-dehydrothromboxane B2 in man. Biochim Biophys Acta 1989; 992: 66-70.
27 Davì G, Averna M, Catalano I. et al. Increased thromboxane biosynthesis in type IIa hypercholesterolemia. Circulation 1992; 85: 1792-1798.
28 Santilli F, Formoso G, Sbraccia P. et al. Postprandial hyperglycemia is a determinant of platelet activation in early type 2 diabetes mellitus. J Thromb Haemost 2010; 8: 828-837.
29 Varo N, Nuzzo R, Natal C. et al. Influence of pre-analytical and analytical factors on soluble CD40L measurements. Clin Sci (Lond) 2006; 111: 341-347.
30 Davì G, Romano M, Mezzetti A. et al. Increased levels of soluble P-selectin in hypercholesterolemic patients. Circulation 1998; 17 (97) 953-957.
31 Santilli F, Rocca B, De Cristofaro R. et al. Platelet cyclooxygenase inhibition by low-dose aspirin is not reflected consistently by platelet function assays: implications for aspirin "resistance". J Am Coll Cardiol 2009; 53: 667-677.
32 Barlow CE, Defina LF, Radford NB. et al. Cardiorespiratory fitness and long-term survival in “low-risk” adults. J Am Heart Assoc 2012; 1: e001354.
33 El-Sayed MS, Ali N, El-Sayed Ali Z. Aggregation and activation of blood platelets in exercise and training. Sports Med 2005; 35: 11-22.
34 Gibbs CR, Blann AD, Edmunds E. et al. Effects of acute exercise on hemorheological, endothelial, and platelet markers in patients with chronic heart failure in sinus rhythm. Clin Cardiol 2001; 24: 724-729.
35 Li-Saw-Hee FL, Blann AD, Edmunds E. et al. Effect of acute exercise on the raised plasma fibrinogen, soluble P-selectin and von Willebrand factor levels in chronic atrial fibrillation. Clin Cardiol 2001; 24: 409-414.
36 Ahmadizad S, El-Sayed MS, Maclaren DP. Responses of platelet activation and function to a single bout of resistence exercise and racovery. Clin Hemorheol Microcirc 2006; 25: 159-168.
37 Rauramo I, Ilmonen S, Viinikka L. et al. Prostacyclin and thromboxane in pregnant and nonpregnant women in response to exercise. Obstet Gynecol 1995; 85: 1027-1030.
38 Wennmalm A, Nowalk J, Bjuro T. Excretion of thromboxane A2 and prostacyclin metabolites before and after exercise testing in patients with and without signs of ischemic heart disease. Circulation 1990; 82: 1737-1743.
39 Gangemi S, Luciotti G, D'Urbano E. et al. Physical exercise increases urinary excretion of lipoxin A4 and related compounds. J Appl Physiol 2003; 94: 2237-2240.
40 Li N, Wallen NH, Hjemdahl P. Evidence for prothrombotic effects of exercise and limited protection by aspirin. Circulation 1999; 100: 1374-1379.
41 Stewart JK. Exercise training and the cardiovascular consequences of type diabetes and hypertension: plausible mechanisms for improving cardiovascular health. J Am Med Assoc 2002; 288: 1622-1631.
42 Yoshikawa D, Ishii H, Kurebayashi N. et al. Association of cardiorespiratory fitness with characteristics of coronary plaque: Assessment using integrated back-scatter intravascular ultrasound and optical coherence tomography. Int J Cardiol 2013; 162: 123-128.
43 Rauramaa R, Salonen JT, Seppanen K. et al. Inhibition of platelect aggregability by moderate-intensity physical exercise: a randomized clinical trial in overweight men. Circulation 1986; 74: 939-944.
44 FitzGerald GA, Pedersen AK, Patrono C. Analysis of prostacyclin and thromboxane biosynthesis in cardiovascular disease. Circulation 1983; 67: 1174-1177.
45 Patrono C, Ciabattoni G, Pugliese F. et al. Estimated rate of thromboxane secretion into the circulation of normal humans. J Clin Invest 1986; 77: 590-594.
46 Ferroni P, Santilli F, Guadagni F. et al. Contribution of platelet-derived CD40L ligand to inflammation, thrombosis and neoangiogenesis. Curr Med Chem 2007; 14: 2170-2180.
47 Bjornstad HH, Bruvik J, Bjornstad AB. et al. Exercise training decreases plasma levels of soluble CD40 ligand and P-selectin in patients with chronic heart failure. Eur J Cardiovasc Prev Rehabil 2008; 15: 43-48.
48 Campbell PT, Gross MD, Potter JD. et al. Effect of exercise on oxidative stress: a 12-month randomized, controlled trial. Med Sci Sports Exerc 2010; 42: 1448-1453.
49 Choi KM, Han KA, Ahn HJ. et al. Effects of exercise on sRAGE levels and cardiometabolic risk factors in patients with type 2 diabetes: a randomized controlled trial. J Clin Endocrinol Metab 2012; 97: 3751-3758.
50 Vazzana N, Santilli F, Cuccurullo C. et al. Soluble forms or RAGE in internal medicine. Intern Emerg Med 2009; 4: 389-401.
51 Voight BF, Peloso GM, Orho-Melander M. et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet 2012; 380: 572-580.
52 Toth PP, Davidson MH. High-density lipoproteins: marker of cardiovascular risk and therapeutic target. J Clin Lipidol 2010; 4: 359-364.
53 Nofer JR, Walter M, Kehrel B. et al. HDL3-mediated inhibition of thrombin-induced platelet aggregation and fibrinogen binding occurs via decreased production of phosphoinosite-derived second messengers 1,2-diacylglycerol and inositol 1,4,5-tris phosphate. Arterioscler Thromb Vasc Biol 1998; 18: 861-869.
54 Vazzana N, Guagnano MT, Cuccurullo C. et al. Endogenous secretory RAGE in obese women: association with platelet activation and oxidative stress. J Clin Endocrinol Metab 2012; 97: E1726-1730.
55 Sebeková K, Krivošíková Z, Gajdoš M. Total plasma Nε-(carboxymethyl)lysine and sRAGE levels are inversely associated with a number of metabolic syndrome risk factors in non-diabetic young-to-middle-aged medication-free subjects. Clin Chem Lab Med 2013; 18: 1-11.
56 Kotani K, Caccavello R, Sakane N. et al. Influence of Physical Activity Intervention on Circulating Soluble Receptor for Advanced Glycation end Products in Elderly Subjects. J Clin Med Res 2011; 3: 252-257.
57 Lakka TA, Lakka HM, Rankinen T. et al. Effect of exercise training on plasma levels of C-reactive protein in healthy adults: the HERITAGE Family Study. Eur Heart J 2005; 26: 2018-2025.
58 Okita K, Nishijima H, Murakami T. et al. Can exercise training with weight loss lower serum C-reactive protein levels?. Arterioscler Thromb Vasc Biol 2004; 24: 1868-1873.
59 Vanhees L, Geladas N, Hansen D. et al. Importance of characteristics and modalities of physical activity and exercise in the management of cardiovascular health in individuals with cardiovascular risk factors: recommendations from the EACPR. Part II. Eur J Prev Cardiol 2012; 19: 1005-1033.
60 Boden WE, Franklin BA, Wenger NK. Physical Activity and Structured Exercise for Patients With Stable Ischemic Heart Disease. J Am Med Assoc 2013; 309: 143-144.

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