Subscribe to RSS
Exercise training in intermittent claudication: Effects on antioxidant genes, inflammatory mediators and proangiogenic progenitor cellsFinancial support: This work was supported by grants POIG 01.01.02–00–109/09 and 01.01.02.069/09 from the European Union structural funds.
30 April 2012
Accepted after major revision: 28 July 2012
29 November 2017 (online)
Exercise training remains a therapy of choice in intermittent claudication (IC). However, too exhaustive exercise may cause ischaemic injury and inflammatory response. We tested the impact of three-month treadmill training and single treadmill exercise on antioxidant gene expressions, cytokine concentrations and number of marrow-derived proangiogenic progenitor cells (PPC) in the blood of IC patients. Blood samples of 12 patients were collected before and after training, before and 1, 3 and 6 hours after the single exercise. PPCs were analysed with flow cytometry, cytokine concentrations were checked with Milliplex MAP, while expression of mRNAs and miRNAs was evaluated with qRT-PCR. Treadmill training improved pain-free walking time (from 144 ± 44 seconds [s] to 311 ± 134 s, p=0.02) and maximum walking time (from 578 ± 293 s to 859 ± 423 s, p=0.01) in IC patients. Before, but not after training, the single treadmill exercise increased the number of circulating CD45dimCD34+CD133-KDR+ PPCs (p=0.048), decreased expression of HMOX1 (p=0.04) in circulating leukocytes, reduced tumour necrosis factor-α (p=0.03) and tended to elevate myeloperoxidase (p=0.06) concentrations in plasma. In contrast, total plasminogen activator inhibitor-1 was decreased by single exercise only after, but not before training (p=0.02). Both before and after training the single exercise decreased monocyte chemoattractant protein (MCP)-1 (p=0.006 and p=0.03) concentration and increased SOD1 (p=0.001 and p=0.01) expression. Patients after training had also less interleukin-6 (p=0.03), but more MCP-1 (p=0.04) in the blood. In conclusion, treadmill training improves walking performance of IC patients, attenuates the single exercise-induced changes in gene expressions or PPC mobilisation, but may also lead to higher production of some proinflammatory cytokines.
# These authors contributed equally as senior authors.
* These authors contributed equally as first authors.
- 1 Meru AV, Mittra S, Thyagarajan B. et al. Intermittent claudication: an overview. Atherosclerosis 2006; 187: 221-237.
- 2 Murabito JM, D'Agostino RB, Silbershatz H. et al. Intermittent claudication. A risk profile from The Framingham Heart Study. Circulation 1997; 96: 44-49.
- 3 Nawaz S, Walker RD, Wilkinson CH. et al. The inflammatory response to upper and lower limb exercise and the effects of exercise training in patients with claudication. J Vasc Surg 2001; 33: 392-399.
- 4 Turton EP, Spark JI, Mercer KG. et al. Exercise-induced neutrophil activation in claudicants: a physiological or pathological response to exhaustive exercise?. Eur J Vasc Endovasc Surg 1998; 16: 192-196.
- 5 Hickey NC, Shearman CP, Gosling P. et al. Assessment of intermittent claudication by quantitation of exercise-induced microalbuminuria. Eur J Vasc Surg 1990; 4: 603-606.
- 6 Diamantopoulos EJ, Charitos D, Georgopoulos V. et al. Oxygen Free Radicals and the Effect of a Free Radical Scavenger in Patients with Intermittent Claudication. Vasc Endovasc Surg 2000; 34: 167-174.
- 7 Edwards AT, Blann AD, Suarez-Mendez VJ. et al. Systemic responses in patients with intermittent claudication after treadmill exercise. Br J Surg 1994; 81: 1738-1741.
- 8 Finaud J, Lac G, Filaire E. Oxidative stress: relationship with exercise and training. Sports Med 2006; 36: 327-358.
- 9 Hulsmans M, De Keyzer D, Holvoet P. MicroRNAs regulating oxidative stress and inflammation in relation to obesity and atherosclerosis. FASEB J 2011; 25: 2515-2527.
- 10 Zernecke A. MicroRNAs in the regulation of immune cell functions - implications for atherosclerotic vascular disease. Thromb Haemost 2012; 107: 626-633.
- 11 Stewart AHR, Lamont PM. Exercise training for claudication. Surgeon 2007; 5: 291-299.
- 12 Regensteiner JG, Steiner JF, Hiatt WR. Exercise training improves functional status in patients with peripheral arterial disease12. J Vasc Surg 1996; 23: 104-115.
- 13 Norgren L, Hiatt WR, Dormandy JA. et al. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). Eur J Vasc Endovasc Surg 2007; (Suppl. 45) S5-S6.
- 14 Hiatt WR, Hirsch AT, Regensteiner JG. et al. Clinical trials for claudication. Assessment of exercise performance, functional status, and clinical end points. Vascular Clinical Trialists. Circulation 1995; 92: 614-621.
- 15 Corretti MC, Anderson TJ, Benjamin EJ. et al. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol 2002; 39: 257-265.
- 16 McDermott MM, Ades P, Guralnik JM. et al. Treadmill exercise and resistance training in patients with peripheral arterial disease with and without intermittent claudication: a randomized controlled trial. J Am Med Assoc 2009; 301: 165-174.
- 17 Fleming I. Role of PECAM-1 in the shear-stress-induced activation of Akt and the endothelial nitric oxide synthase (eNOS) in endothelial cells. J Cell Sci 2005; 118: 4103-4111.
- 18 Obi S, Masuda H, Shizuno T, Sato A, Yamamoto K, Ando J. et al. Fluid shear stress induces differentiation of circulating phenotype endothelial progenitor cells. AJP: Cell Physiology. 2012 epub ahead of print.
- 19 Shaffer RG, Greene S, Arshi A. et al. Effect of acute exercise on endothelial progenitor cells in patients with peripheral arterial disease. Vasc Med 2006; 11: 219-226.
- 20 Schlager O, Giurgea A, Schuhfried O. et al. Exercise training increases endothelial progenitor cells and decreases asymmetric dimethylarginine in peripheral arterial disease: A randomized controlled trial. Atherosclerosis 2011; 217: 240-248.
- 21 Taha H, Skrzypek K, Guevara I. et al. Role of heme oxygenase-1 in human endothelial cells: lesson from the promoter allelic variants. Arterioscl Thromb Vasc Biol 2010; 30: 1634-1641.
- 22 Thompson D, Basu-Modak S, Gordon M. et al. Exercise-induced expression of heme oxygenase-1 in human lymphocytes. Free Radic Res 2005; 39: 63-69.
- 23 Niess A, Sommer M, Schneider M. et al. Physical exercise-induced expression of inducible nitric oxide synthase and heme oxygenase-1 in human leukocytes: effects of RRR-a-tocopherol supplementation. Antioxid Redox Signal 2000; 2: 113-126.
- 24 Tauler P, Sureda A, Cases N. et al. Increased lymphocyte antioxidant defences in response to exhaustive exercise do not prevent oxidative damage. J Nutr Biochem 2006; 17: 665-671.
- 25 Murabito JM, Keyes MJ, Guo C-Y. et al. Cross-sectional relations of multiple inflammatory biomarkers to peripheral arterial disease: The Framingham Offspring Study. Atherosclerosis 2009; 203: 509-514.
- 26 Chaparala RPC, Orsi NM, Lindsey NJ. et al. Inflammatory profiling of peripheral arterial disease. Ann Vasc Surg 2009; 23: 172-178.
- 27 McDermott MM, Liu K, Ferrucci L. et al. Circulating Blood Markers and Functional Impairment in Peripheral Arterial Disease. J Am Geriatr Soc 2008; 56: 1504-1510.
- 28 Hoogeveen RC, Morrison A, Boerwinkle E. et al. Plasma MCP-1 level and risk for peripheral arterial disease and incident coronary heart disease: Atherosclerosis Risk in Communities study. Atherosclerosis 2005; 183: 301-307.
- 29 Heil M, Ziegelhoeffer T, Pipp F. et al. Blood monocyte concentration is critical for enhancement of collateral artery growth. Am J Physiol Heart Circ Physiol 2002; 283: H2411-H2419.
- 30 Park H-J, Chang K, Park CS. et al. Coronary collaterals: The role of MCP-1 during the early phase of acute myocardial infarction. Intern J Cardiol 2008; 130: 409-413.
- 31 Melanson SEF, Green SM, Wood MJ. et al. Elevation of Myeloperoxidase in Conjunction With Cardiac-Specific Markers After Marathon Running. Am J Clin Pathol 2006; 126: 888-893.
- 32 Niess AM, Passek F, Lorenz I. et al. Expression of the antioxidant stress protein heme oxygenase-1 (HO-1) in human leukocytes. Free Radic Biol Med 1999; 26: 184-192.
- 33 Brevetti G, Schiano V, Laurenzano E. et al. Myeloperoxidase, but not C-reactive protein, predicts cardiovascular risk in peripheral arterial disease. Eur Heart J 2008; 29: 224-230.
- 34 Turton EPL, Coughlin PA, Kester RC. et al. Exercise training reduces the acute inflammatory response associated with claudication. Eur J Vasc Endovasc Surg 2002; 23: 309-316.
- 35 Killewich LA, Macko RF, Montgomery PS. et al. Exercise training enhances endogenous fibrinolysis in peripheral arterial disease. J Vasc Surg 2004; 40: 741-745.
- 36 Brevetti G, De Caterina M, Martone VD. et al. Exercise increases soluble adhesion molecules ICAM-1 and VCAM-1 in patients with intermittent claudication. Clin Hemorheol Microcirc 2001; 24: 193-199.
- 37 Andreozzi GM, Martini R, Cordova R. et al. Circulating levels of cytokines (IL-6 and IL-1beta) in patients with intermittent claudication, at rest, after maximal exercise treadmill test and during restore phase. Could they be progression markers of the disease?. Int Angiol 2007; 26: 245-252.
- 38 Kirk G, Hickman P, McLaren M. et al. Interleukin-8 (IL-8) may contribute to the activation of neutrophils in patients with peripheral arterial occlusive disease (PAOD). Eur J Vasc Endovasc Surg 1999; 18: 434-438.
- 39 Palmer-Kazen U, Religa P, Wahlberg E. Exercise in patients with intermittent claudication elicits signs of inflammation and angiogenesis. Eur J Vasc Endovasc Surg 2009; 38: 689-696.