Aging promotes accumulation of reactive oxygen/nitrogen species (ROS/RNS) in cardiomyocytes, which leads to contractile dysfunction and cardiac abnormalities. These changes may contribute to increased cardiovascular disease in the elderly. Inducible antioxidant pathways are regulated by nuclear erythroid 2 p45-related factor 2 (Nrf2) through antioxidant response cis-elements (AREs) and are impaired in the aging heart. Whereas acute exercise stress (AES) activates Nrf2 signaling and promotes myocardial antioxidant function in young mice (~2 months), aging mouse (>23 months) hearts exhibit significant oxidative stress as compared to those of the young. The purpose of this study was to investigate age-dependent regulation of Nrf2-antioxidant mechanisms and redox homeostasis in mouse hearts and the impact of exercise. Old mice were highly susceptible to oxidative stress following high endurance exercise stress (EES), but demonstrated increased adaptive redox homeostasis after moderate exercise training (MET; 10m/min, for 45 min/day) for ~6 weeks. Following EES, transcription and protein levels for most of the ARE-antioxidants were increased in young mice but their induction was blunted in aging mice. In contrast, 6-weeks of chronic MET promoted nuclear levels of Nrf2 along with its target antioxidants in the aging heart to near normal levels as seen in young mice. These observations suggest that enhancing Nrf2 function and endogenous cytoprotective mechanisms by MET, may combat age-induced ROS/RNS and protect the myocardium from oxidative stress diseases.
References
[1]
Gurwitz JH, Goldberg RJ, Gore JM (1991) Coronary thrombolysis for the elderly? Jama 265: 1720–1723.
[2]
Capell BC, Collins FS, Nabel EG (2007) Mechanisms of cardiovascular disease in accelerated aging syndromes. Circ Res 101: 13–26.
[3]
Collins AR, Lyon CJ, Xia X, Liu JZ, Tangirala RK, et al. (2009) Age-accelerated atherosclerosis correlates with failure to upregulate antioxidant genes. Circ Res 104: e42–54.
[4]
Ungvari Z, Kaley G, de Cabo R, Sonntag WE, Csiszar A (2010) Mechanisms of vascular aging: new perspectives. J Gerontol A Biol Sci Med Sci 65: 1028–1041.
[5]
Hazzard WR, Ettinger WH Jr (1995) Aging and Atherosclerosis: Changing Considerations in Cardiovascular Disease Prevention as the Barrier to Immortality is Approached in Old Age. Am J Geriatr Cardiol 4: 16–36.
[6]
Jennings JR, Kamarck T, Manuck S, Everson SA, Kaplan G, et al. (1997) Aging or disease? Cardiovascular reactivity in Finnish men over the middle years. Psychol Aging 12: 225–238.
[7]
Weinsaft JW, Edelberg JM (2001) Aging-associated changes in vascular activity: a potential link to geriatric cardiovascular disease. Am J Geriatr Cardiol 10: 348–354.
[8]
Junn E, Mouradian MM (2001) Apoptotic signaling in dopamine-induced cell death: the role of oxidative stress, p38 mitogen-activated protein kinase, cytochrome c and caspases. J Neurochem 78: 374–383.
[9]
Naumann P, Fortunato F, Zentgraf H, Buchler MW, Herr I, et al. (2011) Autophagy and cell death signaling following dietary sulforaphane act independently of each other and require oxidative stress in pancreatic cancer. Int J Oncol 39: 101–109.
[10]
Kovacic P, Somanathan R (2011) Cell signaling and receptors in toxicity of advanced glycation end products (AGEs): alpha-dicarbonyls, radicals, oxidative stress and antioxidants. J Recept Signal Transduct Res 31: 332–339.
Mitchell C, Joyce AR, Piper JT, McKallip RJ, Fariss MW (2010) Role of oxidative stress and MAPK signaling in reference moist smokeless tobacco-induced HOK-16B cell death. Toxicol Lett 195: 23–30.
[13]
Pi J, Zhang Q, Fu J, Woods CG, Hou Y, et al. (2010) ROS signaling, oxidative stress and Nrf2 in pancreatic beta-cell function. Toxicol Appl Pharmacol 244: 77–83.
[14]
Ungvari Z, Bailey-Downs L, Gautam T, Sosnowska D, Wang M, et al. (2011) Age-associated vascular oxidative stress, Nrf2 dysfunction, and NF-{kappa}B activation in the nonhuman primate Macaca mulatta. J Gerontol A Biol Sci Med Sci 66: 866–875.
[15]
Wissler RW, Robert L (1996) Aging and cardiovascular disease: a summary of the Eighth Munster International Arteriosclerosis Symposium. Circulation 93: 1608–1612.
[16]
Rhoades DA, Welty TK, Wang W, Yeh F, Devereux RB, et al. (2007) Aging and the prevalence of cardiovascular disease risk factors in older American Indians: the Strong Heart Study. J Am Geriatr Soc 55: 87–94.
[17]
Lakatta E (1994) Aging Effects on the Vasculature in Health: Risk Factors for Cardiovascular Disease. Am J Geriatr Cardiol 3: 11–17.
[18]
Seddon M, Looi YH, Shah AM (2007) Oxidative stress and redox signalling in cardiac hypertrophy and heart failure. Heart 93: 903–907.
[19]
Sugamura K, Keaney JF Jr (2011) Reactive oxygen species in cardiovascular disease. Free Radic Biol Med 51: 978–992.
[20]
Jialal I, Devaraj S (2003) Antioxidants and atherosclerosis: don’t throw out the baby with the bath water. Circulation 107: 926–928.
[21]
Madamanchi NR, Hakim ZS, Runge MS (2005) Oxidative stress in atherogenesis and arterial thrombosis: the disconnect between cellular studies and clinical outcomes. J Thromb Haemost 3: 254–267.
[22]
Madamanchi NR, Vendrov A, Runge MS (2005) Oxidative stress and vascular disease. Arterioscler Thromb Vasc Biol 25: 29–38.
[23]
Gutierrez J, Ballinger SW, Darley-Usmar VM, Landar A (2006) Free radicals, mitochondria, and oxidized lipids: the emerging role in signal transduction in vascular cells. Circ Res 99: 924–932.
[24]
Guzik TJ, Harrison DG (2006) Vascular NADPH oxidases as drug targets for novel antioxidant strategies. Drug Discov Today 11: 524–533.
[25]
Dreger H, Westphal K, Weller A, Baumann G, Stangl V, et al. (2009) Nrf2-dependent upregulation of antioxidative enzymes: a novel pathway for proteasome inhibitor-mediated cardioprotection. Cardiovasc Res 83: 354–361.
[26]
Lee JM, Li J, Johnson DA, Stein TD, Kraft AD, et al. (2005) Nrf2, a multi-organ protector? Faseb J 19: 1061–1066.
[27]
Niture SK, Kaspar JW, Shen J, Jaiswal AK (2010) Nrf2 signaling and cell survival. Toxicol Appl Pharmacol 244: 37–42.
[28]
Rangasamy T, Cho CY, Thimmulappa RK, Zhen L, Srisuma SS, et al. (2004) Genetic ablation of Nrf2 enhances susceptibility to cigarette smoke-induced emphysema in mice. J Clin Invest 114: 1248–1259.
[29]
Rajasekaran NS, Varadharaj S, Khanderao GD, Davidson CJ, Kannan S, et al. (2011) Sustained activation of nuclear erythroid 2-related factor 2/antioxidant response element signaling promotes reductive stress in the human mutant protein aggregation cardiomyopathy in mice. Antioxid Redox Signal 14: 957–971.
[30]
Muthusamy VR, Kannan S, Sadhaasivam K, Gounder SS, Davidson CJ, et al.. (2012) Acute exercise stress activates Nrf2/ARE signaling and promotes antioxidant mechanisms in the myocardium. Free Radic Biol Med.
[31]
Asghar M, George L, Lokhandwala MF (2007) Exercise decreases oxidative stress and inflammation and restores renal dopamine D1 receptor function in old rats. Am J Physiol Renal Physiol 293: F914–919.
[32]
George L, Lokhandwala MF, Asghar M (2009) Exercise activates redox-sensitive transcription factors and restores renal D1 receptor function in old rats. Am J Physiol Renal Physiol 297: F1174–1180.
[33]
Safdar A, deBeer J, Tarnopolsky MA (2011) Dysfunctional Nrf2-Keap1 redox signaling in skeletal muscle of the sedentary old. Free Radic Biol Med 49: 1487–1493.
[34]
Rajasekaran NS, Connell P, Christians ES, Yan LJ, Taylor RP, et al. (2007) Human alpha B-crystallin mutation causes oxido-reductive stress and protein aggregation cardiomyopathy in mice. Cell 130: 427–439.
[35]
Rajasekaran NS, Sathyanarayanan S, Devaraj NS, Devaraj H (2005) Chronic depletion of glutathione (GSH) and minimal modification of LDL in vivo: its prevention by glutathione mono ester (GME) therapy. Biochim Biophys Acta 1741: 103–112.
[36]
Hirayama A, Yoh K, Nagase S, Ueda A, Itoh K, et al. (2003) EPR imaging of reducing activity in Nrf2 transcriptional factor-deficient mice. Free Radic Biol Med 34: 1236–1242.
[37]
Varadharaj S, Watkins T, Cardounel AJ, Garcia JG, Zweier JL, et al. (2005) Vitamin C-induced loss of redox-dependent viability in lung microvascular endothelial cells. Antioxid Redox Signal 7: 287–300.
[38]
Kensler TW, Wakabayashi N, Biswal S (2007) Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu Rev Pharmacol Toxicol 47: 89–116.
[39]
Kobayashi M, Yamamoto M (2006) Nrf2-Keap1 regulation of cellular defense mechanisms against electrophiles and reactive oxygen species. Adv Enzyme Regul 46: 113–140.
[40]
Rangasamy T, Guo J, Mitzner WA, Roman J, Singh A, et al. (2005) Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice. J Exp Med 202: 47–59.
[41]
Zhu H, Itoh K, Yamamoto M, Zweier JL, Li Y (2005) Role of Nrf2 signaling in regulation of antioxidants and phase 2 enzymes in cardiac fibroblasts: protection against reactive oxygen and nitrogen species-induced cell injury. FEBS Lett 579: 3029–3036.
[42]
Bean JF, Vora A, Frontera WR (2004) Benefits of exercise for community-dwelling older adults. Arch Phys Med Rehabil 85: S31–42; quiz S43–34.
[43]
Navarro A, Gomez C, Lopez-Cepero JM, Boveris A (2004) Beneficial effects of moderate exercise on mice aging: survival, behavior, oxidative stress, and mitochondrial electron transfer. Am J Physiol Regul Integr Comp Physiol 286: R505–511.
[44]
Kobayashi A, Ohta T, Yamamoto M (2004) Unique function of the Nrf2-Keap1 pathway in the inducible expression of antioxidant and detoxifying enzymes. Methods Enzymol 378: 273–286.
[45]
He X, Kan H, Cai L, Ma Q (2009) Nrf2 is critical in defense against high glucose-induced oxidative damage in cardiomyocytes. J Mol Cell Cardiol 46: 47–58.
[46]
Jyrkkanen HK, Kansanen E, Inkala M, Kivela AM, Hurttila H, et al. (2008) Nrf2 regulates antioxidant gene expression evoked by oxidized phospholipids in endothelial cells and murine arteries in vivo. Circ Res 103: e1–9.
[47]
Li J, Ichikawa T, Villacorta L, Janicki JS, Brower GL, et al. (2009) Nrf2 protects against maladaptive cardiac responses to hemodynamic stress. Arterioscler Thromb Vasc Biol 29: 1843–1850.
[48]
Suh JH, Shenvi SV, Dixon BM, Liu H, Jaiswal AK, et al. (2004) Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid. Proc Natl Acad Sci U S A 101: 3381–3386.
[49]
Ungvari Z, Bailey-Downs L, Sosnowska D, Gautam T, Koncz P, et al. (2011) Vascular oxidative stress in aging: a homeostatic failure due to dysregulation of NRF2-mediated antioxidant response. Am J Physiol Heart Circ Physiol 301: H363–372.
[50]
Hochmuth CE, Biteau B, Bohmann D, Jasper H (2011) Redox regulation by Keap1 and Nrf2 controls intestinal stem cell proliferation in Drosophila. Cell Stem Cell 8: 188–199.
[51]
Sykiotis GP, Bohmann D (2010) Stress-activated cap’n’collar transcription factors in aging and human disease. Sci Signal 3: re3.
[52]
Sykiotis GP, Bohmann D (2008) Keap1/Nrf2 signaling regulates oxidative stress tolerance and lifespan in Drosophila. Dev Cell 14: 76–85.
[53]
Li M, Liu RM, Timblin CR, Meyer SG, Mossman BT, et al. (2006) Age affects ERK1/2 and NRF2 signaling in the regulation of GCLC expression. J Cell Physiol 206: 518–525.
[54]
Newsholme P, Homen De Bittencourt PI, O’Hagan C, De Vito G, Murphy C, et al. (2010) Exercise and possible molecular mechanisms of protection from vascular disease and diabetes: the central role of ROS and nitric oxide. Clin Sci (Lond) 118: 341–349.
[55]
Frasier CR, Moore RL, Brown DA (2011) Exercise-induced cardiac preconditioning: how exercise protects your achy-breaky heart. J Appl Physiol 111: 905–915.
[56]
Zhang KR, Liu HT, Zhang HF, Zhang QJ, Li QX, et al. (2007) Long-term aerobic exercise protects the heart against ischemia/reperfusion injury via PI3 kinase-dependent and Akt-mediated mechanism. Apoptosis 12: 1579–1588.
[57]
Chicco AJ, Schneider CM, Hayward R (2005) Voluntary exercise protects against acute doxorubicin cardiotoxicity in the isolated perfused rat heart. Am J Physiol Regul Integr Comp Physiol 289: R424–R431.
[58]
La Gerche A, Burns AT, Mooney DJ, Inder WJ, Taylor AJ, et al.. (2011) Exercise-induced right ventricular dysfunction and structural remodelling in endurance athletes. Eur Heart J.
[59]
Sharma S, Zaidi A (2011) Exercise-induced arrhythmogenic right ventricular cardiomyopathy: fact or fallacy? Eur Heart J.
[60]
Neilan TG, Januzzi JL, Lee-Lewandrowski E, Ton-Nu TT, Yoerger DM, et al. (2006) Myocardial injury and ventricular dysfunction related to training levels among nonelite participants in the Boston marathon. Circulation 114: 2325–2333.
[61]
Trivax JE, Franklin BA, Goldstein JA, Chinnaiyan KM, Gallagher MJ, et al. (2010) Acute cardiac effects of marathon running. J Appl Physiol 108: 1148–1153.
[62]
Baker JM, De Lisio M, Parise G (2011) Endurance exercise training promotes medullary hematopoiesis. Faseb J 25: 4348–4357.
[63]
Sussan TE, Rangasamy T, Blake DJ, Malhotra D, El-Haddad H, et al. (2009) Targeting Nrf2 with the triterpenoid CDDO-imidazolide attenuates cigarette smoke-induced emphysema and cardiac dysfunction in mice. Proc Natl Acad Sci U S A 106: 250–255.
[64]
Thimmulappa RK, Fuchs RJ, Malhotra D, Scollick C, Traore K, et al. (2007) Preclinical evaluation of targeting the Nrf2 pathway by triterpenoids (CDDO-Im and CDDO-Me) for protection from LPS-induced inflammatory response and reactive oxygen species in human peripheral blood mononuclear cells and neutrophils. Antioxid Redox Signal 9: 1963–1970.
[65]
Ungvari Z, Bagi Z, Feher A, Recchia FA, Sonntag WE, et al. (2010) Resveratrol confers endothelial protection via activation of the antioxidant transcription factor Nrf2. Am J Physiol Heart Circ Physiol 299: H18–24.
[66]
Ren D, Villeneuve NF, Jiang T, Wu T, Lau A, et al. (2011) Brusatol enhances the efficacy of chemotherapy by inhibiting the Nrf2-mediated defense mechanism. Proc Natl Acad Sci U S A 108: 1433–1438.
