Endurance training reduces circulating asymmetric dimethylarginine and myeloperoxidase levels in persons at risk of coronary events

Summary

Asymmetric dimethylarginine (ADMA), myeloperoxidase (MPO) and paraoxonase 1 (PON1) are directly involved in the pathogenesis of atherosclerosis by modulation of oxidative stress and/or NO bioavailability. We aimed to assess whether endurance exercise which is known to be cardioprotective could beneficially affect these novel risk markers. Thirty-two subjects (31–68 yrs, 56% males) with elevated cardiovascular risk including ten patients with coronary artery disease volunteered for a supervised 12-week endurance training (196 ± 15 min/week).Their fitness evaluated by 2 km test runs improved significantly after training (pre: 17.3±0.8 vs. post: 15.7±0.9min, p<0.001). ADMA (pre: 0.94±0.03 vs. post: 0.75±0.04 μmol l⁻¹) and MPO (pre:296.8±22.2 vs.post:185.7±19.5 ng ml⁻¹) serum levels decreased significantly by 17.6±4.6% and 28.5±7.5%, respectively, after training (both p<0.001).Their down-regulation was inversely correlated (ADMA: r=-0.609, p<0.001, MPO: r=-0.437, p=0.014) with the up-regulation of plasma cGMP levels (Cyclic-guanosine 3`,5`-monophosphate; pre: 1.6±0.12 vs. post: 2.21±0.2 μmol ml⁻¹, p=0.001) reflecting NO production. PON1 activity towards phenylacetate was not significantly influenced by training (pre: 133±6 vs. post: 130±5 μmol ml⁻¹ min⁻¹, p=0.375). In a matched inactive control group (n=16) ADMA, MPO, cGMP levels and PON1 activity did not change over time. ADMA, MPO and cGMP changes were significantly different between participants and controls (all p<0.05). Regular endurance exercise was successful in reducing the circulating levels of two promising cardiovascular risk markers, ADMA and MPO, in persons prone to cardiac events. These changes may result in numerous antiatherosclerotic effects such as improvement of NO bioavailability, reduction of oxidative stress and lipid peroxidation.

Keywords

Exercise - atherosclerosis - asymmetric dimethylarginine - myeloperoxidase - paraoxonase 1

^* Both authors equally contributed to this study None of the authors has a conflict of interest

• References

• 1 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: 605-13.
• 2 Thompson PD, Buchner D, Pina IL. et al Exercise and physical activity in the prevention and treatment of atherosclerotic cardiovascular disease: a statement from the Council on Clinical Cardiology (Subcommittee on Exercise, Rehabilitation, and Prevention) and the Council on Nutrition, Physical Activity, and Metabolism (Subcommittee on Physical Activity). Circulation 2003; 107: 3109-16.
• 3 Ridker PM, Brown NJ, Vaughan DE. et al Established and emerging plasma biomarkers in the prediction of first atherothrombotic events. Circulation 2004; 109 (Suppl. 25) IV6-19.
• 4 Reiner AP, Siscovick DS, Rosendaal FR. Hemostatic risk factors and arterial thrombotic disease. Thromb Haemost 2001; 85: 584-95.
• 5 Maas R, Boger RH. Old and new cardiovascular risk factors: from unresolved issues to new opportunities. Atheroscler Suppl 2003; 4: 5-17.
• 6 Wannamethee SG, Lowe GD, Whincup PH. et al Physical activity and hemostatic and inflammatory variables in elderly men. Circulation 2002; 105: 1785-90.
• 7 Milani RV, Lavie CJ, Mehra MR. Reduction in C-reactive protein through cardiac rehabilitation and exercise training. J Am Coll Cardiol 2004; 43: 1056-61.
• 8 Geffken DF, Cushman M, Burke GL. et al Association between physical activity and markers of inflammation in a healthy elderly population. Am J Epidemiol 2001; 153: 242-50.
• 9 Fatouros IG, Jamurtas AZ, Villiotou V. et al Oxidative stress responses in older men during endurance training and detraining. Med Sci Sports Exerc 2004; 36: 2065-72.
• 10 Niebauer J, Clark AL, Webb-Peploe KM. et al Home-based exercise training modulates pro-oxidant substrates in patients with chronic heart failure. Eur J Heart Fail 2005; 7: 183-8.
• 11 Boger RH, Bode-Boger SM, Szuba A. et al Asymmetric dimethylarginine (ADMA): a novel risk factor for endothelial dysfunction: its role in hypercholesterolemia. Circulation 1998; 98: 1842-7.
• 12 Ruef J, Peter K, Nordt TK. et al Oxidative stress and atherosclerosis: its relationship to growth factors, thrombus formation and therapeutic approaches. Thromb Haemost 1999; 82 (Suppl. 01) 32-7.
• 13 Wassmann S, Wassmann K, Nickenig G. Modulation of oxidant and antioxidant enzyme expression and function in vascular cells. Hypertension 2004; 44: 381-6.
• 14 Cooke JP, Dzau VJ. Nitric oxide synthase: role in the genesis of vascular disease. Annu Rev Med 1997; 48: 489-509.
• 15 Vita JA, Brennan ML, Gokce N. et al Serum myeloperoxidase levels independently predict endothelial dysfunction in humans. Circulation 2004; 110: 1134-9.
• 16 Sydow K, Munzel T. ADMA and oxidative stress. Atheroscler Suppl 2003; 4: 41-51.
• 17 Edwards DG, Schofield RS, Lennon SL. et al Effect of exercise training on endothelial function in men with coronary artery disease. Am J Cardiol 2004; 93: 617-20.
• 18 Hambrecht R, Adams V, Erbs S. et al Regular physical activity improves endothelial function in patients with coronary artery disease by increasing phosphorylation of endothelial nitric oxide synthase. Circulation 2003; 107: 3152-8.
• 19 Vallance P, Leone A, Calver A. et al Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet 1992; 339: 572-5.
• 20 Zoccali C, Bode-Boger S, Mallamaci F. et al Plasma concentration of asymmetrical dimethylarginine and mortality in patients with end-stage renal disease: a prospective study. Lancet 2001; 358: 2113-7.
• 21 Cooke JP. Asymmetrical dimethylarginine: the Uber marker?. Circulation 2004; 109: 1813-8.
• 22 Fliser D. Asymmetric dimethylarginine (ADMA): the silent transition from an ‘uraemic toxin’ to a global cardiovascular risk molecule. Eur J Clin Invest 2005; 35: 71-9.
• 23 Klebanoff SJ. Myeloperoxidase. Proc Assoc Am Physicians 1999; 111: 383-9.
• 24 Brennan ML, Penn MS, Van Lente F. et al Prognostic value of myeloperoxidase in patients with chest pain. N Engl J Med 2003; 349: 1595-604.
• 25 Mackness B, Durrington P, McElduff P. et al Low paraoxonase activity predicts coronary events in the Caerphilly Prospective Study. Circulation 2003; 107: 2775-9.
• 26 Draganov DI, La Du BN. Pharmacogenetics of paraoxonases: a brief review. Naunyn Schmiedebergs Arch Pharmacol 2004; 369: 78-88.
• 27 Baldus S, Heeschen C, Meinertz T. et al Myeloperoxidase serum levels predict risk in patients with acute coronary syndromes. Circulation 2003; 108: 1440-5.
• 28 Lu TM, Ding YA, Lin SJ. et al Plasma levels of asymmetrical dimethylarginine and adverse cardiovascular events after percutaneous coronary intervention. Eur Heart J 2003; 24: 1912-9.
• 29 Fletcher GF, Balady GJ, Amsterdam EA. et al Exercise standards for testing and training: a statement for healthcare professionals from the American Heart Association. Circulation 2001; 104: 1694-740.
• 30 Karvonen J, Vuorimaa T. Heart rate and exercise intensity during sports activities. Practical application. Sports Med 1988; 5: 303-11.
• 31 Schulze F, Wesemann R, Schwedhelm E. et al Determination of asymmetric dimethylarginine (ADMA) using a novel ELISA assay. Clin Chem Lab Med 2004; 42: 1377-83.
• 32 Juretic D, Tadijanovic M, Rekic B. et al Serum paraoxonase activities in hemodialyzed uremic patients: cohort study. Croat Med J 2001; 42: 146-50.
• 33 Zhang R, Brennan ML, Fu X. et al Association between myeloperoxidase levels and risk of coronary artery disease. JAMA 2001; 286: 2136-42.
• 34 Boger RH. The emerging role of asymmetric dimethylarginine as a novel cardiovascular risk factor. Cardiovasc Res 2003; 59: 824-33.
• 35 Lu TM, Ding YA, Charng MJ. et al Asymmetrical dimethylarginine: a novel risk factor for coronary artery disease. Clin Cardiol 2003; 26: 458-64.
• 36 Fu X, Kassim SY, Parks WC. et al Hypochlorous acid oxygenates the cysteine switch domain of promatrilysin (MMP-7). A mechanism for matrix metalloproteinase activation and atherosclerotic plaque rupture by myeloperoxidase. J Biol Chem 2001; 276: 41279-87.
• 37 Podrez EA, Febbraio M, Sheibani N. et al Macrophage scavenger receptor CD36 is the major receptor for LDL modified by monocyte-generated reactive nitrogen species. J Clin Invest 2000; 105: 1095-108.
• 38 Podrez EA, Schmitt D, Hoff HF. et al Myeloperoxidase-generated reactive nitrogen species convert LDL into an atherogenic form in vitro . J Clin Invest 1999; 103: 1547-60.
• 39 Abu-Soud HM, Hazen SL. Nitric oxide is a physiological substrate for mammalian peroxidases. J Biol Chem 2000; 275: 37524-32.
• 40 Moncada S, Higgs A. The L-arginine-nitric oxide pathway. N Engl J Med 1993; 329: 2002-12.
• 41 Murad F, Rapoport RM, Fiscus R. Role of cyclic-GMP in relaxations of vascular smooth muscle. J Cardiovasc Pharmacol 1985; 7 (Suppl. 03) S111-8.
• 42 Kielstein JT, Impraim B, Simmel S. et al Cardiovascular effects of systemic nitric oxide synthase inhibition with asymmetrical dimethylarginine in humans. Circulation 2004; 109: 172-7.
• 43 Peake J, Wilson G, Hordern M. et al Changes in neutrophil surface receptor expression, degranulation, and respiratory burst activity after moderate- and highintensity exercise. J Appl Physiol 2004; 97: 612-8.
• 44 Suzuki K, Nakaji S, Yamada M. et al Impact of a competitive marathon race on systemic cytokine and neutrophil responses. Med Sci Sports Exerc 2003; 35: 348-55.
• 45 Naruko T, Ueda M, Haze K. et al Neutrophil infiltration of culprit lesions in acute coronary syndromes. Circulation 2002; 106: 2894-900.
• 46 Buffon A, Biasucci LM, Liuzzo G. et al Widespread coronary inflammation in unstable angina. N Engl J Med 2002; 347: 5-12.
• 47 Niessner A, Richter B, Penka M. et al Endurance training reduces circulating inflammatory markers in persons at risk of coronary events: Impact on plaque stabilization? Atherosclerosis. 2005 Aug 3 Epub ahead of print.
• 48 Osanai T, Saitoh M, Sasaki S. et al Effect of shear stress on asymmetric dimethylarginine release from vascular endothelial cells. Hypertension 2003; 42: 985-90.
• 49 Boger RH, Bode-Boger SM, Brandes RP. et al Dietary L-arginine reduces the progression of atherosclerosis in cholesterol-fed rabbits: comparison with lovastatin. Circulation 1997; 96: 1282-90.