Exercise and Atherogenesis

John Kelly Smith


According to the World Health Organization, ischemic heart disease and stroke are the top two causes of mortality worldwide, accounting for a total of 14.1 million deaths in 2012. A number of studies have shown that regularly performed moderate-intensity physical exercise reduces the risk of dying from atherosclerotic cardiovascular disease (ASCVD), in part by reducing the impact of risk factors such as hypertension, hyperlipidemia, obesity, and type 2 diabetes mellitus. How physical exercise affects atherogenesis at the molecular level, however, is incompletely understood. This review examines what is currently known about the role that myokines, adipokines, endothelial cells, macrophages, interleukins and telomeres play in atherogenesis and how their activities are modified by regularly performed physical exercise. The evidence suggests that in persons at risk of ASCVD, exercise changes the balance between the proportion of immune cells producing atherogenic cytokines and those producing atheroprotective cytokines. There are likely multiple contributors to this change, including shear stress-related normalization of endothelial cell function, the production of anti-inflammatory myokines, adipokines and cytokines, and the influence of exercise on telomere length.


exercise; atherogenesis; atherosclerosis; myokines; adipokines; vascular endothelial cells; monocytes; macrophages; telomeres; interleukins

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World Health Organization Media Center. The top 10 leading causes of death in the world. 2012.

Heron M. Deaths: Leading Causes for 2013. Natl Vital Stat Rep. 2016; 65: 1-95.

Chen L, Magliano DJ, Zimmet PZ. The worldwide epidemiology of type 2 diabetes mellitus—present and future perspectives. Nat Rev Endocrinol. 2011; 8: 228-236.

Laslett LJ, Alagona P Jr, Clark BA 3rd, Drozda JP Jr, Saldivar F, et al. The worldwide environment of cardiovascular disease: prevalence, diagnosis, therapy, and policy issues: a report from the American College of Cardiology. J Am Coll Cardiol. 2012; 60: S1-49.

Blair SN, Kampert JB, Kohl HW 3rd, Barlow CE, Macera CA, et al. Influences of cardiorespiratory fitness and other precursors on cardiovascular disease and all-cause mortality in men and women. JAMA. 1996; 276: 205-210.

Kujala UM, Kaprio J, Sarna S, Koskenvuo M. Relationship of leisure-time physical activity and mortality: the Finnish twin cohort. JAMA. 1998; 279:440-444.

Leeper NJ, Myers J, Zhou M, Nead KT, Syed A, et al. Exercise capacity is the strongest predictor of mortality in patients with peripheral arterial disease. J Vasc Surg. 2013; 57: 728-733.

Park S, Lee J, Kang DY, Rhee CW, Park BJ, et al. Indoor physical activity reduces all-cause and cardiovascular disease mortality among elderly women. J Prev Med Public Health. 2012; 45: 21-28.

Sigal RJ, Kenny GP, Wasserman DH, Castaneda-Sceppa C, White RD, et al. Physical activity/exercise and type 2 diabetes: a consensus statement from the American Diabetes Association. Diabetes Care. 2006; 29: 1433-1438.

Hamer M. The anti-hypertensive effects of exercise: integrating acute and chronic mechanisms. Sports Med. 2006; 36: 109-116.

Bouchard C, Depres JP, Tremblay A. Exercise and obesity. Obes Res. 1993; 1: 133-147.

Blair SN. Evidence for success of exercise in weight loss and control. Ann Intern Med. 1993;

: 702-706.

Stefanick ML, Wood PD. Physical activity, lipid and lipoprotein metabolism, and lipid transport. In: Bouchard C, Shephard RJ, Stephens T, eds. Physical Activity, Fitness, and Health: International Proceedings and Consensus Statement. Champaign, Ill: Human Kinetics Publishers Inc. 1994; 417-443.

Ahmed HM, Blaha MJ, Nasir K, Rivera JJ, Blumenthal RS, et al. Effects of physical activity on cardiovascular disease. Am J Cardiol. 2012; 109:288-295.

Mayer-Davis EJ, D’Agostino R Jr, Karter AJ, Haffner SM, Rewers MJ, et al. Intensity and amount of physical activity in relation to insulin sensitivity. The insulin resistance atherosclerosis study. JAMA. 1998; 279: 669-674.

Golbidi S, Mesdaghinia A, Laher I. Exercise in the metabolic syndrome. Oxid Med Cell Longev. 2012; 2012: 349710.

Hamer M, Lavoie KL, Bacon SL. Taking up physical activity in later life and healthy ageing: the English longitudinal study of ageing. Br J Sports Med. 2014; 48: 239-243.

Liu SS, Monti J, Kargbo HM, Athar MW, Parakh K, et al. Frontiers of therapy for patients with heart failure. Am J Med. 2013; 126: 6-12.

Goldhammer E, Tanchilevitch A, Maor I, Beniamini Y, Rosenschein U, et al. Exercise training modulates cytokines activity in coronary heart disease patients. Int J Cardiol. 2005; 100: 93-99.

Guidon M, McGee H. One-year effect of a supervised exercise programme on functional capacity and quality of life in peripheral arterial disease. Disabil Rehabil. 2013; 35: 397-404.

Hansson GK, Hermansson A. The immune system in atherosclerosis. Nat Immunol. 2011; 12:204-212.

Smith JK. Exercise and cardiovascular disease. Cardiovasc Hematol Disord Drug Targets. 2010;10: 269-272.

Frostegard J, Ulfgren AK, Nyberg P, Hedin U, Swedenborg J, et al. Cytokine expression in advanced human atherosclerotic plaques: dominance of proinflammatory (Th1) and macrophage-stimulating cytokines. Atherosclerosis. 1999; 145: 33-43.

Raschke S, Eckel J. Adipo-myokines: two sides of the same coin--mediators of inflammation and mediators of exercise. Mediators Inflamm. 2013;2013: 320724.

Walsh NP, Gleeson M, Shephard RJ, Gleeson M, Woods JA, et al. Position statement. Part one: Immune function and exercise. Exerc Immunol Rev. 2011; 17: 6-63.

Pedersen BK. Muscles and their myokines. J Exp Biol. 2011; 214: 337-346.

van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JM, Kemerink GJ, et al. Cold-activated brown adipose tissue in healthy men. N Engl J Med. 2009; 360: 1500-1508.

Xin C, Liu J, Zhang J, Zhu D. Irisin improves fatty acid oxidation and glucose utilization in type 2 diabetes by regulating the AMPK signaling pathway. Int J Obes (Lond). 2016; 40: 443-451.

Hecksteden A, Wegmann M, Steffen A, Kraushaar J, Morsch A, et al. Irisin and exercise training in humans - results from a randomized controlled training trial. BMC Med. 2013; 11: 235.

Kim HJ, Lee HJ, So B, Son JS, Yoon D, et al. Effect of aerobic and resistance training on circulating irisin levels and their association with change of body composition in overweight/obese adults: a pilot study. Physiol Res. 2016; 65: 271-279.

Daskalopoulou SS, Cooke AB, Gomez YH, Mutter AF, Filippaios A, et al. Plasma irisin levels progressively increase in response to increasing exercise workloads in young, healthy, active subjects. Eur J Endocrinol. 2014; 171: 343-352.

Tsuchiya Y, Ando D, Takamatsu K, Goto K. Resistance exercise induces a greater irisin response than endurance exercise. Metabolism. 2015; 64:1042-1050.

Huh JY, Siopi A, Mougios V, Park KH, Mantzoros CS, et al. Irisin in response to exercise in humans with and without metabolic syndrome. J Clin Endocrinol Metab. 2015; 100: E453-457. 34. Greenberg AS, Obin MS. Obesity and the role of adipose tissue in inflammation and metabolism. Am J Clin Nutr. 2006; 83: 461S-465S.

Lu L, Zhang RY, Wang XQ, Liu ZH, Shen Y, et al. C1q/TNF-related protein-1: an adipokine marking and promoting atherosclerosis. Eur Heart J. 2016; 37: 1762-1771.

Lee S, Park Y, Dellsperger KC, Zhang C. Exercise training improves endothelial function via adiponectin-dependent and independent pathways in type 2 diabetic mice. Am J Physiol Heart Circ Physiol. 2011; 301: H306-314.

Chang RY, Koo M, Chen CK, Lu YC, Lin YE, et al. Effects of habitual Tai Chi exercise on adiponectin, glucose homeostasis, lipid profile, and atherosclerotic burden in individuals with cardiovascular risk factors. J Altern Complement Med. 2013;19: 697-703.

Nascimento H, Alves AI, Medeiros AF, Coimbra S, Catarino C, et al. Impact of a school-based intervention protocol “ACORDA project” on adipokines in an overweight and obese pediatric population. Pediatr Exerc Sci. 2016; 28: 407-416.

Sturgeon K, Digiovanni L, Good J, Salvatore D, Fenderson D, et al. Exercise-induced dose-response alterations in adiponectin and leptin levels are dependent on body fat changes in women at risk for breast cancer. Cancer Epidemiol Biomarkers Prev. 2016.

Sjogren P, Sierra-Johnson J, Kallings LV, Cederholm T, Kolak M, et al. Functional changes in adipose tissue in a random controlled trial of physical activity. Lipids Health Dis. 2012.

Gondim OS, de Camargo VT, Gutierrez FA, Martins PF, Passos ME, et al. Benefits of Regular Exercise on Inflammatory and Cardiovascular Risk Markers in Normal Weight, Overweight and Obese Adults. PLoS One. 2015; 10: e0140596.

Witzum JL. Immunological responses to oxidized LDL. Atherosclerosis. 1997; 131: S9-S1.

Johnson BD, Mather KJ, Wallace JP. Mechanotransduction of shear in the endothelium: basic studies and clinical implications. Vasc Med. 2011; 16: 365-377.

Adam E, Melnick JL, Probtsfield JL, Petrie BL, Burek J, et al. High levels of cytomegalovirus antibody in patients requiring vascular surgery for atherosclerosis. Lancet. 1987; 2: 291-293.

Porter KM, Sutliff RL. HIV-, reactive oxygen species, and vascular complications. Free Radic Biol Med. 2012; 53: 143-159.

Kuo CC, Grayston JT, Campbell LA, Goo YA, Wissler RW, et al. Chlamydia pneumoniae

(TWAR) in coronary arteries of young adults (15-34 years old). Proc Natl Acad Sci U S A. 1995; 92:6911-6914.

Yokota T, Hansson GK. Immunological mechanisms in atherosclerosis. J Intern Med. 1995; 238:479-489.

Watanabe T, Haraoka S, Shimokama T. Inflammatory and immunological nature of atherosclerosis. Int J Cardiol. 1996; 54 Suppl: S51-60.

Labarrere CA, Nelson DR, Faulk WP. Endothelial activation and development of coronary artery disease in transplanted human hearts. JAMA. 1997; 278: 1169-1175.

Malek AM, Alper SL, Izumo S. Hemodynamic shear stress and its role in atherosclerosis. JAMA. 1999; 282: 2035-2042.

Davignon J, Ganz P. Role of endothelial dysfunction in atherosclerosis. Circulation. 2004; 109:III27-32.

Hambrecht R, Wolf A, Gielen S, Linke A, Hofer J, et al. Effect of exercise on coronary endothelial function in patients with coronary artery disease. N Engl J Med. 2000; 342: 454-460.

Smith JK. Exercise and atherogenesis. Exerc Sport Sci Rev. 2001; 29: 49-53.

Vita JA, Keaney JF Jr. Exercise--toning up the endothelium? N Engl J Med. 2000; 342: 503-505.

Guizoni DM, Dorighello GG, Oliveira HC, Delbin MA, Krieger MH, et al. Aerobic exercise training protects against endothelial dysfunction by increasing nitric oxide and hydrogen peroxide production in LDL-receptor deficient mice. J Transl Med. 2016; 14: 213.

Mahmoud MM, Kim HR, Xing R, Hsiao S, Mammoto A, et al. TWIST1 Integrates Endothelial Responses to Flow in Vascular Dysfunction and Atherosclerosis. Circ Res. 2016; 119: 450-462.

Restaino RM, Walsh LK, Morishima T, Vranish JR, Martinez-Lemus LA, et al. Endothelial dysfunction following prolonged sitting is mediated by a reduction in shear stress. Am J Physiol Heart Circ Physiol. 2016; 310: H648-653.

Seawright JW, Luttrell M, Trache A, Woodman CR. Short-term increases in pressure and shear stress attenuate age-related declines in endothelial function in skeletal muscle feed arteries. Eur J Appl Physiol. 2016; 116: 1305-1311.

Laughlin MH, Newcomer SC, Bender SB. Importance of hemodynamic forces as signals for

exercise-induced changes in endothelial cell phenotype. J Appl Physiol (1985). 2008; 104: 588-600.

Kim B, Lee H, Kawata K, Park JY. Exercise-mediated wall shear stress increases mitochondrial biogenesis in vascular endothelium. PLos One. 2014;9: e111409.

Lin J, Kakkar V, Lu X. Essential Roles of Toll-Like Receptors in Atherosclerosis. Curr Med Chem. 2016; 23: 431-454.

Osterud B, Bjorklid E. Role of monocytes in atherogenesis. Physiol Rev. 2003; 83: 1069-1112.

Yakeu G, Butcher L, Isa S, Webb R, Roberts AW, et al. Low-intensity exercise enhances expression of markers of alternative activation in circulating leukocytes: roles of PPARI3 and Th2 cytokines. Atherosclerosis. 2010; 212: 668-673.

Ikeda S, Tamura Y, Kakehi S, Takeno K, Kawaguchi M, et al. Exercise-induced enhancement of insulin sensitivity is associated with accumulation of M2-polarized macrophages in mouse skeletal muscle. Biochem Biophys Res Commun. 2013;441: 36-41.

Kawanishi N, Mizokami T, Yano H, Suzuki K. Exercise attenuates M1 macrophages and CD8+ T cells in the adipose tissue of obese mice. Med Sci Sports Exerc. 2013; 45: 1684-1693.

Oliveira AG, Araujo TG, Carvalho BM, Guadagnini D, Rocha GZ, et al. Acute exercise induces a phenotype switch in adipose tissue macrophage polarization in diet-induced obese rats. Obesity. 2013; 21: 2545-2556.

Goh J, Ladiges WC. Exercise enhances wound healing and prevents cancer progression during aging by targeting macrophage polarity. Mech Ageing Dev. 2014; 139: 41-48.

Ikeda Y, Kumagai H, Motozawa Y, Suzuki J, Akazawa H, et al. Understanding Vascular Diseases: Lessons From Premature Aging Syndromes. Can J Cardiol. 2016; 32: 650-658.

Fernandez-Alvira JM, Fuster V, Dorado B, Soberon N, Flores I, et al. Short Telomere Load,

Telomere Length, and Subclinical Atherosclerosis: The PESA Study. J Am Coll Cardiol. 2016; 67:2467-2476.

Mundstock E, Zatti H, Louzada FM, Oliveira SG, Guma FT, et al. Effects of physical activity in telomere length: Systematic review and meta-analysis. Ageing Res Rev. 2015; 22: 72-80.

Denham J, O Brien BJ, Prestes PR, Brown NJ, Charchar FJ, et al. Increased expression of telomere-regulating genes in endurance athletes with long leukocyte telomeres. J Appl Physiol.

; 120: 148-158.

Ray KK. Interleukin-1 revisited: further insights into its role in atherosclerosis and as a potential therapeutic target for treatment. J Am Coll Cardiol. 2014; 63: 1735-1738.

Akdis M, Burgler S, Crameri R, Eiwegger T, Fujita H, et al. Interleukins, from 1 to 37, and interferon-γ: receptors, functions, and roles in diseases. J Allergy Clin Immunol. 2011; 127: 701-721.

Gardner SE, Humphry M, Bennett MR, Clarke MC. Senescent vascular smooth muscle cells

drive inflammation through an interleukin-γ-dependent senescence-associated secretory phenotype. Arterioscler Thromb Vasc Biol. 2015; 35:1963-1974.

Eun SY, Ko YS, Park SW, Chang KC, Kim HJ, et al. IL-1α enhances vascular smooth muscle cell proliferation and migration via P2Y2 receptor mediated RAGE expression and HMGB1 release. Vascul Pharmacol. 2015; 72: 108-117.

Blirando K, Blaise R, Gorodnaya N, Rouxel C, Meilhac O, et al. The stellate vascular smooth

muscle cell phenotype is induced by IL-1α via the secretion of PGE2 and subsequent cAMP-dependent protein kinase A activation. Biochim Biophys Acta. 2015; 1853: 3235-3247.

Tsimikas S, Duff GW, Berger PB, Rogus J, Huttner K, et al. Pro-inflammatory interleukin-1 genotypes potentiate the risk of coronary artery disease and cardiovascular events mediated by oxidized phospholipids and lipoprotein(a). J Amer Coll Cardiol. 2014; 63: 1724-1734.

Enayati S, Seifirad S, Amiri P, Abolhalai M, Mohammad-Amoli M, et al. Interleukin-1 beta, interferon-gamma, and tumor necrosis factor-alpha gene expression in peripheral blood mononuclear cells of patients with coronary artery disease. ARYA Atheroscler. 2015; 11: 267-274.

Aghagolzadeh P, Bachtler M, Bijarnia R, Jackson C, Smith ER, et al. Calcification of vascular smooth muscle cells is initiated by secondary calciprotein particles and enhanced by tumor necrosis factor-Iα. Atherosclerosis. 2016; S0021-9150(16)30221-0.

Chen X, Zhang H, Hill MA, Zhang C, Park Y, et al. Regulation of Coronary Endothelial Function by Interactions between TNF-Iα, LOX-1 and Adiponectin in Apolipoprotein E Knockout Mice. J Vasc Res. 2015; 52: 372-382.

de Boer OJ, van der Wal AC, Verhagen CE, Becker AE. Cytokine secretion profiles of cloned T cells from human aortic atherosclerotic plaques. J Pathol. 1999; 188: 174-179.

Moss JW, Ramji DP. Interferon-I3: Promising therapeutic target in atherosclerosis. World J Exp Med. 2015; 5: 154-159.

Gupta S, Pablo AM, Jiang Xc, Wang N, Tall AR, et al. IFN-gamma potentiates atherosclerosis in ApoE knock-out mice. J Clin Invest. 1997; 99:2752-2761.

Zhao XN, Li YN, Wang YT. Interleukin-4 regulates macrophage polarization via the MAPK signaling pathway to protect against atherosclerosis. Genet Mol Res. 2016; 15.

Bogdan C, Nathan C. Modulation of macrophage function by transforming growth factor beta, interleukin-4, and interleukin-10. Ann N Y Acad Sci. 1993; 685: 713-739.

Okamura T, Morita K, Iwasaki Y, Inoue M, Komai T, et al. Role of TGF-β in the regulation of immune responses. Clin Exp Rheumatol. 2015; 33:S63-69.

Smith JK, Dykes R, Douglas JE, Krishnaswamy G, Berk S, et al. Long-term exercise and atherogenic activity of blood mononuclear cells in persons at risk of developing ischemic heart disease. JAMA. 1999; 81: 1722-1727.

Hopps E, Canino B, Caimi G. Effects of exercise on inflammation markers in type 2 diabetic subjects. Acta Diabetol. 2011; 48: 183-189.

Tartibian B, FitzGerald LZ, Azadpour N, Maleki BH. A randomized controlled study examining the effect of exercise on inflammatory cytokine levels in post-menopausal women. Post Reprod Health. 2015; 21: 9-15.

Ahmadi N, Eshaghian S, Huizenga R, Sosnin K, Ebrahimi R, et al. Effects of intense exercise and moderate caloric restriction on cardiovascular risk factors and inflammation. Am J Med. 2011;124: 978-982.

Kim YJ, Shin YO, Bae JS, Lee JB, Ham JH, et al. Beneficial effects of cardiac rehabilitation and exercise after percutaneous coronary intervention on CRP and inflammatory cytokines in CAD patients. Eur J Physiol. 2008; 455: 1081-1088.

Zanetti HR, Cruz LG, Lourenco CL, Neves FF, Silva-Vergara ML, et al. Non-linear resistance training reduces inflammatory biomarkers in persons living with HIV: a randomized controlled trial. Eur J Sport Sci. 2016; 1-8.

Silveira Martins M, Boufleur Farinha J, Basso Benetti C, Alves Courtes A, Duarte T, et al. Positive effects of resistance training on inflammatory parameters in men with metabolic risk factors. Nutr Hosp. 2015; 32: 792-798.

World Health Organization. Global status report on noncommunicable diseases. 2014.

DOI: http://dx.doi.org/10.18103/imr.v3i5.475


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