Top

Published in:

01-03-2011 | Original Contribution

Mitochondrial complex I and NAD(P)H oxidase are major sources of exacerbated oxidative stress in pressure-overloaded ischemic-reperfused hearts

Authors: Mahmood S. Mozaffari, Babak Baban, Jun Yao Liu, Worku Abebe, Jennifer C. Sullivan, Ahmed El-Marakby

Published in: Basic Research in Cardiology | Issue 2/2011

Abstract

We tested the hypothesis that pressure overload exacerbates oxidative stress associated with augmented mitochondrial permeability transition (MPT) pore opening and cell death in ischemic-reperfused hearts. Pressure overload decreased the level of reduced glutathione but increased nitrotyrosine and 8-hydroxydeoxyguanosine levels in ischemic-reperfused hearts. The activity of catalase, but not superoxide dismutase (SOD), was lower in ischemic-reperfused hearts perfused at higher pressure. Mitochondria from ischemic-reperfused hearts subjected to higher perfusion pressure displayed significantly greater [³H]-2-deoxyglucose-6-P entrapment suggestive of greater MPT pore opening and consistent with greater necrosis and apoptosis. Tempol (SOD mimetic) reduced infarct size in both groups but it remained greater in the higher pressure group. By contrast, uric acid (peroxynitrite scavenger) markedly reduced infarct size at higher pressure, effectively eliminating the differential between the two groups. Inhibition of xanthine oxidase, with allopurinol, reduced infarct size but did not eliminate the differential between the two groups. However, amobarbital (inhibitor of mitochondrial complex I) or apocynin [inhibitor of NAD(P)H oxidase] reduced infarct size at both pressures and also abrogated the differential between the two groups. Consistent with the effect of apocynin, pressure-overloaded hearts displayed significantly higher NAD(P)H oxidase activity. Furthermore, pressure-overloaded hearts displayed increased nitric oxide synthase activity which, along with increased propensity to superoxide generation, may underlie uric acid-induced cardioprotection. In conclusion, increased oxidative and nitrosative stress, coupled with lack of augmented SOD and catalase activities, contributes importantly to the exacerbating impact of pressure overload on MPT pore opening and cell death in ischemic-reperfused hearts.

Ambrosio G, Zweier JL, Duilio C, Kuppusamy P, Santoro G, Elia PP, Tritto I, Cirillo P, Condorelli M, Chiariello M, Flaherty JT (1993) Evidence that mitochondrial respiration is a source of potentially toxic oxygen free radicals in intact rabbit hearts subjected to ischemia and reflow. J Biol Chem 268: 18532-18541. Available at http://www.jbc.org/

Ananthakrishnan R, Kaneko M, Hwang YC, Quadri N, Gomez T, Li Q, Caspersen C, Ramasamy R (2009) Aldose reductase mediates myocardial ischemia-reperfusion injury in part by opening mitochondrial permeability transition pore. Am J Physiol Heart Circ Physiol 296:H333–H341. doi:10.1152/ajpheart.01012.2008 CrossRefPubMed

Baban B, Chandler PR, Sharma MD, Pihkala J, Koni PA, Munn DH, Mellor AL (2009) IDO activates regulatory T cells and blocks their conversion into Th17-like T cells. J Immunol 183:2475–2483. doi:10.4049/jimmunol.0900986 CrossRefPubMed

Baines CP (2009) The mitochondrial permeability transition pore and ischemia-reperfusion injury. Basic Res Cardiol 104:181–188. doi:10.1007/s00395-009-0004-8 CrossRefPubMed

Boengler K, Stahlhofen S, van de Sand A, Gres P, Ruiz-Meana M, Garcia-Dorado D, Heusch G, Schulz R (2009) Presence of connexin 43 in subsarcolemmal, but not in interfibrillar cardiomyocyte mitochondria. Basic Res Cardiol 104:141–147. doi:10.1007/s00395-009-0007-5 CrossRefPubMed

Borutaite V, Morkuniene R, Brown GC (1999) Release of cytochrome c from heart mitochondria is induced by high Ca2+ and peroxynitrite and is responsible for Ca(2+)-induced inhibition of substrate oxidation. Biochim Biophys Acta 1453(1):41–48. doi:10.1016/S0925-4439(98)00082-9 PubMed

Brandes RP (2005) Triggering mitochondrial radical release: a new function for NADPH oxidases. Hypertension 45:847–848. doi:10.1161/01.HYP.0000165019.32059.b2 CrossRefPubMed

Chen Q, Moghaddas S, Hoppel CL, Lesnefsky EJ (2006) Reversible blockade of electron transport during ischemia protects mitochondria and decreases myocardial injury following reperfusion. J Pharmacol Exp Ther 319:1405–1412. doi:10.1124/jpet.106.110262 CrossRefPubMed

De Giusti VC, Correa MV, Villa-Abrille MC, Beltrano C, Yeves AM, Chiappe de Cingolani GE, Cingolani HE, Aiello EA (2008) The positive inotropic effect of endothelin-1 is mediated by mitochondrial reactive oxygen species. Life Sci 83:264–271. doi:10.1016/j.lfs.2008.06.008 CrossRefPubMed

10.

Di Lisa F, Klaudercic N, Carpi A, Menabo R, Giorgio M (2009) Mitochondrial pathways for ROS formation and myocardial injury: the relevance of p66(Shc) and monoamine oxidase. Basic Res Cardiol 104:131–139. doi:10.1007/s00395-009-0008-4 CrossRefPubMed

11.

Guarnieri C, Flamigni F, Caldarera CM (1980) Role of oxygen in the cellular damage induced by reoxygenation of hypoxic hearts. J Mol Cell Cardiol 12:797–808. doi:10.1016/0022-2828(80)90081-4 CrossRefPubMed

12.

Gustafsson AB, Gottlieb RA (2008) Heart mitochondria: gates of life and death. Cardiovasc Res 77:334–343. doi:10.1093/cvr/cvm005 CrossRefPubMed

13.

Hadzimichalis NM, Baliga SS, Golfetti R, Jaques KM, Firestein BL, Merrill GF (2007) Acetaminophen-mediated cardioprotection via inhibition of the mitochondrial permeability transition pore-induced apoptotic pathway. Am J Physiol Heart Circ Physiol 293:H3348–H3355. doi:10.1152/ajpheart.00947.2007 CrossRefPubMed

14.

Heusch G, Boengler K, Schulz R (2010) Inhibition of mitochondrial permeability transition pore opening: the holy grail of cardioprotection. Basic Res Cardiol 105:151–154. doi:10.1007/s00395-009-0080-9 CrossRefPubMed

15.

Javadov SA, Clarke S, Das M, Griffiths EJ, Lim KH, Halestrap AP (2003) Ischaemic preconditioning inhibits opening of mitochondrial permeability transition pores in the reperfused rat heart. J Physiol 549:513–524. doi:10.1113/jphysiol.2003.034231 CrossRefPubMed

16.

Javadov S, Karmazyn M (2007) Mitochondrial permeability transition pore opening as an endpoint to initiate cell death and as a putative target for cardioprotection. Cell Physiol Biochem 20:11–22. doi:10.1159/000103747 CrossRef

17.

Kutala VK, Khan M, Mandal R, Potaraju V, Colantuono G, Kumbala D, Kuppuamy P (2006) Prevention of postischemic myocardial reperfusion injury by the combined treatment of NCX-4016 and tempol. J Cardiovasc Pharmacol 48:79–87. doi:10.1097/01.fjc.0000242050.16790.65 CrossRefPubMed

18.

Lesnefsky E, Chen Q, Moghaddas S, Hassan MO, Tandler B, Hoppel CL (2004) Blockade of electron transport during ischemia protects cardiac mitochondria. J Biol Chem 279:47961–47967. doi:10.1074/jbc.M409720200 CrossRefPubMed

19.

Lin KM, Lin B, Lian IY, Mestril R, Scheffler IE, Dillmann WH (2001) Combined and individual mitochondrial HSP60 and HSP10 expression in cardiac myocytes protects mitochondrial function and prevents apoptotic cell death induced by simulated ischemia-reoxygenation. Circulation 103:1787–1792. Available at http://circ.ahajournals.org/

20.

Loomis ED, Sullivan JC, Osmond DA, Pollock DM, Pollock JS (2005) Endothelin mediates superoxide production and vasoconstriction through activation of NADPH oxidase and uncoupled nitric-oxide synthase in the rat aorta. J Pharmacol Exp Ther 315:1058–1064. doi:10.1124/jpet.105.091728 CrossRefPubMed

21.

Matsushima S, Kinugawa S, Yokota T, Inoue N, Ohta Y, Hamaguchi S, Tsutsui H (2009) Increased myocardial NAD(P)H oxidase-derived superoxide causes the exacerbation of postinfarct heart failure in type 2 diabetes. Am J Physiol Heart Circ Physiol 297:H409–H416. doi:10.1152/ajpheart.01332.2008 CrossRefPubMed

22.

McDonald MC, Zacharowski K, Bowes J, Cuzzocrea S, Thiemermann C (1999) Tempol reduces infarct size in rodent models of regional myocardial ischemia and reperfusion. Free Radic Biol Med 27:493–503. doi:10.1016/S0891-5849(99)00100-8 CrossRefPubMed

23.

Mozaffari MS, Abdelsayed R, Liu JY, Wimborne H, El-Remessy A, El-Marakby A (2009) Effects of chromium picolinate on glycemic control and kidney of the obese Zucker rat. Nutr Metab (Lond) 6:51. doi:10.1186/1743-7075-6-51 CrossRef

24.

Mozaffari MS, Liu JY, Schaffer SW (2010) Effect of pressure overload on cardioprotection via PI3K-Akt: comparison of postconditioning, insulin, and pressure unloading. Am J Hypertens 23:668–674. doi:10.1038/ajh.2010.43 CrossRefPubMed

25.

Mozaffari MS, Patel C, Schaffer SW (2006) Mechanisms underlying afterload-induced exacerbation of myocardial infarct size: role of T-type Ca2+ channel. Hypertension 47:912–919. doi:10.1161/01.HYP.0000209940.65941.46 CrossRefPubMed

26.

Mozaffari MS, Schaffer SW (2008) Effect of pressure overload on cardioprotection of mitochondrial K_ATP channels and GSK-3beta: interaction with the MPT pore. Am J Hypertens 21:570–575. doi:10.1038/ajh.2008.25 CrossRefPubMed

27.

Murphy E, Steenbergen C (2008) Mechanisms underlying acute protection from cardiac ischemia-reperfusion injury. Physiol Rev 88:581–609. doi:10.1152/physrev.00024.2007 CrossRefPubMed

28.

Paravicini TM, Touyz RM (2008) NADPH oxidases, reactive oxygen species, and hypertension: clinical implications and therapeutic possibilities. Diabetes Care 31:S170–S180. doi:10.2337/dc08-s247 CrossRefPubMed

29.

Pimentel DR, Amin JK, Xiao L, Miller T, Vierek J, Oliver-Krasinski J, Baliga R, Wang J, Siwik DA, Singh K, Pagano P, Colucci WS, Sawyer DB (2001) Reactive oxygen species mediate amplitude-dependent hypertrophic and apoptotic responses to mechanical stretch in cardiac myocytes. Circ Res 89:453–460. doi:10.1161/hh1701.096615 CrossRefPubMed

30.

Shiva S, Gladwin MT (2009) Nitrite mediates cytoprotection after ischemia/reperfusion by modulating mitochondrial function. Basic Res Cardiol 104:113–119. doi:10.1007/s00395-009-0009-3 CrossRefPubMed

31.

Sorescu D, Griendling KK (2002) Reactive oxygen species, mitochondria, and NAD(P)H oxidases in the development and progression of heart failure. Congest Heart Fail 8:132–140. doi:10.1111/j.1527-5299.2002.00717.x CrossRefPubMed

32.

Stewart S, Lesnefsky E, Chen Q (2009) Reversible blockade of electron transport with amobarbital at the onset of reperfusion attenuates cardiac injury. Transl Res 153:224–231. doi:10.1016/j.trsl.2009.02.003 CrossRefPubMed

33.

Sullivan JC, Pardieck JL, Hyndman KA, Pollock JS (2010) Renal NOS activity, expression and localization in male and female spontaneously hypertensive rats. Am J Physiol Regul Integr Comp Physiol 298(1):R61–R69. doi:10.1152/ajpregu.00526.2009 PubMed

34.

Wang HC, Zhang HF, Guo WY, Su H, Zhang KR, Li QX, Yan W, Ma XL, Lopez BL, Christopher TA, Gao F (2006) Hypoxic postconditioning enhances the survival and inhibits apoptosis of cardiomyocytes following reoxygenation: role of peroxynitrite formation. Apoptosis 11:1453–1460. doi:10.1007/s10495-006-7786-z CrossRefPubMed

35.

Wojtovich AP, Brookes PS (2009) The complex II inhibitor atpenin A5 protects against cardiac ischemia-reperfusion injury via activation of mitochondrial K_ATP channels. Basic Res Cardiol 104:121–129. doi:10.1007/s00395-009-0001-y CrossRefPubMed

36.

Zhang YH, Dingle L, Hall R, Casadei B (2009) The role of nitric oxide and reactive oxygen species in the positive inotropic response to mechanical stretch in the mammalian myocardium. Biochim Biophys Acta 1787:811–817. doi:10.1016/j.bbabio.2009.03.020 CrossRefPubMed

37.

Zorov DB, Juhaszova M, Sollott SJ (2006) Mitochondrial ROS-induced-ROS release: an update and review. Biochim Biophys Acta 1757:509–517. doi:10.1016/j.bbabio.2006.04.029 CrossRefPubMed

38.

Zou Y, Akazawa H, Qin Y, Sano M, Takano H, Minamino T, Makita N, Iwanaga K, Zhu W, Kudoh S, Toko H, Tamura K, Kihara M, Nagai T, Fukamizu A, Umemura S, Iiri T, Fujita T, Komuro I (2004) Mechanical stress activates angiotensin II type 1 receptor without the involvement of angiotensin II. Nat Cell Biol 6:499–506. doi:10.1038/ncb1137 CrossRefPubMed

39.

Zweier JL, Talukder MA (2006) The role of oxidants and free radicals in reperfusion injury. Cardiovasc Res 70:181–190. doi:10.1016/j.cardiores.2006.02.025 CrossRefPubMed

Title: Mitochondrial complex I and NAD(P)H oxidase are major sources of exacerbated oxidative stress in pressure-overloaded ischemic-reperfused hearts
Authors: Mahmood S. Mozaffari
Babak Baban
Jun Yao Liu
Worku Abebe
Jennifer C. Sullivan
Ahmed El-Marakby
Publication date: 01-03-2011
Publisher: Springer-Verlag
Published in: Basic Research in Cardiology / Issue 2/2011
Print ISSN: 0300-8428
Electronic ISSN: 1435-1803
DOI: https://doi.org/10.1007/s00395-011-0150-7

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Mitochondrial complex I and NAD(P)H oxidase are major sources of exacerbated oxidative stress in pressure-overloaded ischemic-reperfused hearts

Abstract

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 2/2011

Molecular characterization of thyroid hormone-inhibited atrial L-type calcium channel expression: implication for atrial fibrillation in hyperthyroidism

Adipocyte-derived lipids increase angiotensin-converting enzyme (ACE) expression and modulate macrophage phenotype

Central TNF inhibition results in attenuated neurohumoral excitation in heart failure: a role for superoxide and nitric oxide

Exercise-induced modulation of cardiac lipid content in healthy lean young men

Diastolic dysfunction and arrhythmias caused by overexpression of CaMKIIδC can be reversed by inhibition of late Na+ current

Conserved expression and functions of PDE4 in rodent and human heart

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page