Oxygen Radicals Released During Ischemic Preconditioning Contribute to Cardioprotection in the Rabbit Myocardium
Abstract
Previous studies have proposed that oxygen radicals may play a role in the triggering of ischemic preconditioning. However, studies evaluating the effects of radical scavengers have yielded conflicting results, possibly because of differences in the number of preconditioning episodes used. The present study tested whether N-2-mercaptopropionylglycine (MPG) could block protection of both single and multiple episodes of preconditioning in in situ and in vitro rabbit hearts. All hearts were subjected to 30 min of regional ischemia followed by reperfusion for 2 (in vitro) or 3 (in situ) h. Infarct size was measured by tetrazolium. Infarction in control in situ hearts was 37.5+/-3.5% of the risk zone. A single cycle of preconditioning (PC1), with 5 min ischemia/10 min reperfusion, reduced infarct size to 12.3+/-2.0% (P<0.05). Four cycles of preconditioning (PC4) were equally protective. MPG (1 mg/kg/min i.v.) alone had no effect on infarction but abolished protection afforded by PC1 (35.4+/-3.9%). However, MPG failed to block protection in the PC4 group. In isolated control hearts, infarct size was 31.1+/-1.8% and was reduced to 10.2+/-2.2% (P<0.05) by preconditioning. MPG (300 microM) aborted protection. Infusion of hypoxanthine or xanthine oxidase separately in lieu of preconditioning had no effect on infarct size, but induced protection when combined (14.1+/-2.2%; P<0.05). Polymyxin B, an inhibitor of protein kinase C (PKC), abolished this protection (53.1+/-4.1%). In conclusion, oxygen radicals contribute to ischemic preconditioning in the rabbit and appear to do so via activation of PKC. The fact that MPG could not block protection by PC4 suggests that oxygen radicals act in concert with other triggers of preconditioning such as adenosine and bradykinin.
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Although constitutively expressed, the HIF-1α subunit has a very short half-life in normoxic conditions because of its rapid hydroxylation by prolyl-4 hydroxylases (PH1-3).
“Although constitutively expressed, the HIF-1α subunit has a very short half-life in normoxic conditions because of its rapid hydroxylation by prolyl-4 hydroxylases (PH1–3) (12, 36).”
From Mitochondrial reactive oxygen species production in excitable cells: Modulators of mitochondrial and cell function (2009) · cites this paper as [12]
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“Depending on the concentration, oxidants play a dual role in stimulating or inactivating PKC. IPC is a phenomenon whereby a brief transient ischemic insult causes the heart to become resistant to infarction from a subsequent extended period of ischemia.”
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BackgroundReactive Oxygen Species as Mediators of Signal Transduction in Ischemic Preconditioning
Otani, H. (2004) · Antioxidants and Redox Signaling · doi:10.1089/152308604322899521 · Cited by 141 · see citing works
“Several independent investigators have indeed suggested the involvement of ROS or redox modulation in activating cardio-protective signal transduction pathways in IPC (13, 44, 259, 293, 295).”
cGMP signalling in pre- and post-conditioning: the role of mitochondria
Costa, A. D. T., Pierre, S. V., Cohen, M. V., Downey, J. M., & Garlid, K. (2007) · Cardiovascular Research · doi:10.1093/cvr/cvm050 · Cited by 141 · see citing works
“We believe that ROS produced by mitochondria act as second messengers to activate PKC through redox signalling.(17,18) ROS production is deficient in mice genetically engineered to lack connexin 43, a protein on the inner mitochondrial membrane that forms gap junctions, and this may account for the loss of IPC’s prote…”
BackgroundSelf-citationWeinbrenner, C. (2003) · Cardiovascular Research · doi:10.1016/j.cardiores.2003.10.008 · Cited by 138 · see citing works
“The dose of MPG was selected to 20 mg/kg body weight since other groups have demonstrated that this dose does inhibit the protection by one classical preconditioning stimulus [24, 27,28].”
BackgroundInfluentialXia, Z., Huang, Z., & Ansley, D. M. (2006) · Anesthesia & Analgesia · doi:10.1213/01.ane.0000230612.29452.a6 · Cited by 136 · see citing works
Tang, X., Feng, J., Chen, J., Chen, P., Zhi, J., Cui, Y., Guo, R., & Yu, H. (2005) · Brain Research · doi:10.1016/j.brainres.2005.07.072 · Cited by 136 · see citing works
Miki, T., Cohen, M. V., & Downey, J. M. (1998) · Molecular and Cellular Biochemistry · doi:10.1023/a:1006856124501 · Cited by 131 · see citing works
“Many substances are released by the myocardium during ischemia, and several of them, including adenosine [3, 4], bradykinin [5, 6] and free radicals [7, 8], act to trigger preconditioning.”
InfluentialSelf-citationRavati, A., Ahlemeyer, B., Becker, A., Klumpp, S., & Krieglstein, J. (2001) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2001.00463.x · Cited by 130 · see citing works
Pasdois, P., Parker, J. E., Griffiths, E. J., & Halestrap, A. P. (2011) · Biochemical Journal · doi:10.1042/bj20101957 · Cited by 127 · see citing works
COHEN, M., YANG, X., & Downey, J. M. (2005) · Cardiovascular Research · doi:10.1016/j.cardiores.2005.10.021 · Cited by 128 · see citing works
“Thus interference with ROS production after triggering of preconditioning with ischemia can abort cardioprotection while controlled production of ROS in lieu of another preconditioning stimulus can decrease infarction [24,25].”
BackgroundSelf-citationThe paradigm of postconditioning to protect the heart
Penna, C. R. R., Mancardi, D., Raimondo, S., Geuna, S., & Pagliaro, P. (2007) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2007.00210.x · Cited by 122 · see citing works
“Thus the main idea was that ROS play an essential, though double-edged, role in cardioprotection: they may participate in reperfusion injury or may play a role as signalling elements of protection in pre-ischaemic phase [10, 48, 57–59, 64–68, 76, 125, 136, 138, 139, 144–147].”
BackgroundYamashita, N., Hoshida, S., Taniguchi, N., et al. (1998) · Circulation · doi:10.1161/01.cir.98.14.1414 · Cited by 124 · see citing works
Mitochondrial dysfunction as the cause of the failure to precondition the diabetic human myocardium
HASSOUNA, A., Loubani, M., Matata, B. M., FOWLER, A., Standen, N. B., & Galiñanes, M. (2005) · Cardiovascular Research · doi:10.1016/j.cardiores.2005.11.004 · Cited by 123 · see citing works
“Release of superoxide by coinfusion of hypoxanthine and xanthine oxidase elicits cardioprotection in the rabbit heart [22] while the superoxide scavenger MnTBAP abrogates ischemic protection in the guinea pig [56].”
BackgroundJoo, J. D., Kim, M., D’Agati, V. D., & Lee, H. T. (2006) · Journal of the American Society of Nephrology · doi:10.1681/asn.2006050424 · Cited by 121 · see citing works
Carroll, R. (2001) · Cardiovascular Research · doi:10.1016/s0008-6363(01)00330-3 · Cited by 122 · see citing works
Hypoxia-inducible factor as a therapeutic target for cardioprotection
Ong, S., & Hausenloy, D. J. (2012) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2012.07.005 · Cited by 111 · see citing works
“(1988) first demonstrated that antioxidants could abolish the protective effect elicited by IPC, implicating for the first time a role for ROS as a critical mediator of IPC, a finding which was later supported by several experimental studies (Tanaka et al., 1994; Chen et al., 1995; Baines et al., 1997).”
BackgroundResultInfluentialComplex Regulation of Mitochondrial Function During Cardiac Development
Zhao, Q., Sun, Q., Zhou, L., Liu, K., & Jiao, K. (2019) · Journal of the American Heart Association · doi:10.1161/jaha.119.012731 · Cited by 112 · see citing works
Xenon and Sevoflurane Protect against Brain Injury in a Neonatal Asphyxia Model
Luo, Y., Ma, D., Ieong, E., et al. (2008) · Anesthesiology · doi:10.1097/aln.0b013e3181895f88 · Cited by 110 · see citing works
“Protein kinase C is thought to be activated possibly by reactive oxygen spices, which are generated by preconditioning.(35) Experimental studies have implied that PKC activation is an important step in preconditioning by ischemia, xenon, and sevoflurane.”
BackgroundChen, H., Chien, C., Yu, S., Lee, Y., & Chen, W. (2002) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0704908 · Cited by 108 · see citing works
“Mitochondria produce and are a ected by ROS, which have been shown to paradoxically initiate both apoptosis and cardioprotection (Baines et al., 1997; Cai & Jones, 1998).”
BackgroundCohen, M. V., & Downey, J. M. (2014) · British Journal of Pharmacology · doi:10.1111/bph.12903 · Cited by 108 · see citing works
“Ytrehus et al. (1994) reported that PKC seemed to play a major role in IPC and it was found that protection triggered by any of the three receptors could be blocked by PKC inhibitors (Goto et al., 1995; Sakamoto et al., 1995; Baines et al., 1997; Miki et al., 1998a).”
BackgroundSelf-citationChurchill, E., Disatnik, M., & Mochly-Rosen, D. (2008) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2008.09.713 · Cited by 108 · see citing works
“Additionally, there are several mitochondrial targets of εPKC which protect the heart from I/ R injury through mechanisms including ROS generation [59,60], opening of the mitochondrial permeability transition pore (MPTP) [61,62], regulation of the mitochondrial kATP channels (reviewed in [63,64]) and activation of mit…”
BackgroundImmunity, Inflammation, and Oxidative Stress in Heart Failure: Emerging Molecular Targets
Ayoub, K. F., Pothineni, N. V. K., Rutland, J. J., Ding, Z., & Mehta, J. L. (2017) · Cardiovascular Drugs and Therapy · doi:10.1007/s10557-017-6752-z · Cited by 107 · see citing works
“preconditions the heart against subsequent episodes of severe ischemia, and antioxidant therapies may decrease this beneficial effect of preconditioning [99].”
BackgroundSánchez, G., Escobar, M., Pedrozo, Z., Macho, P., DOMENECH, R. J., Härtel, S., Hidalgo, C., & Donoso, P. (2007) · Cardiovascular Research · doi:10.1093/cvr/cvm011 · Cited by 105 · see citing works
Oldenburg, O. (2002) · Cardiovascular Research · doi:10.1016/s0008-6363(02)00332-2 · Cited by 105 · see citing works
- Authors
- Baines, C. P., Goto, M., & Downey, J. M.
- Affiliations
- University of South Alabama (US)
- Venue
- Journal of Molecular and Cellular Cardiology
- Publisher
- Elsevier BV
- Published
- 1997-01
- Volume
- 29
- Issue
- 1
- Pages
- 207-216
- ISSN
- 0022-2828 (ISSN-L)
- OpenAlex
- W2122501550
- Cited by
- 484
- References
- 0
- Citations by year
- 2025: 1 · 2023: 1 · 2022: 5 · 2021: 4 · 2020: 7 · 2019: 8 · 2018: 8 · 2017: 11 · 2016: 12 · 2015: 12 · 2014: 16 · 2013: 21 · 2012: 18
- FWCI
- 13.61
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Molecular and Cellular Cardiology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Cardiac Ischemia and Reperfusion
- Health Sciences › Medicine › Surgery › Organ Transplantation Techniques and Outcomes
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Keywords
- ischemic preconditioning, oxygen free radicals, cardioprotection, protein kinase C, infarct size, myocardial ischemia-reperfusion injury, xanthine oxidase, hypoxanthine, adenosine, bradykinin, radical scavengers
- MeSH terms
- Analysis of Variance, Animals, Enzyme Activation, Female, Free Radicals, Hemodynamics, Male, Tiopronin, Myocardial Infarction, Protein Kinase C, Rabbits, Free Radical Scavengers, Reactive Oxygen Species, Ischemic Preconditioning, Myocardial, In Vitro Techniques
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