Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Cardiovascular Drugs and Therapy
Published in: Cardiovascular Drugs and Therapy 1/2014

01-02-2014 | ORIGINAL ARTICLE

Remote Cardioprotection by Transfer of Coronary Effluent from Ischemic Preconditioned Rabbit Heart Preserves Mitochondrial Integrity and Function via Adenosine Receptor Activation

Authors: Chung Ho Leung, Lixing Wang, Jan M. Nielsen, Michael B. Tropak, Yana Y. Fu, Hideyuki Kato, John Callahan, Andrew N. Redington, Christopher A. Caldarone

Published in: Cardiovascular Drugs and Therapy | Issue 1/2014

Login to get access

Abstract

Background

Coronary effluent from an isolated perfused heart undergoing ischemic preconditioning can be transferred to precondition another naïve isolated heart. We investigated the effects of this effluent on mitochondrial integrity and function following a global infarct model of ischemia/reperfusion and the role of adenosine in this model of remote preconditioning.

Methods and Results

Coronary effluent from isolated perfused rabbit hearts was collected prior to (control effluent) and during three cycles of 5-min ischemia and 10-min reperfusion (IPC effluent). Adenosine concentration was significantly increased in IPC effluent (2.6 ± 1.1 μM) versus control effluent (0.21 ± 0.06 μM, P < 0.01). Infarct size (% necrotic LV mass) after 30-min global ischemia and 90-min reperfusion was significantly reduced in hearts preconditioned with IPC effluent (IPCeff, 23 ± 7 %) and control effluent supplemented with 2.5 μM exogenous adenosine (Ceff + 2.5 μM ADO, 25 ± 10 %) when compared to control effluent perfused hearts (Ceff, 41 ± 8 %, P < 0.05). Compared to Ceff mitochondria, IPCeff mitochondria had preserved complex I/State3 and complex IV/State 3 respiration and outer membrane integrity, and reduced cytochrome c release. In contrast, Ceff + 2.5 μM ADO mitochondria had improved state 2 respiration and coupling to oxidative phosphorylation, reduced reactive oxygen species production and preserved outer membrane integrity. Administration of adenosine receptor blocker 8-(p-sulfophenyl)theophylline abolished the infarct limiting effect (46 ± 7 %) and the mitochondrial integrity and function preservation of IPC effluent.

Conclusion

Remote cardioprotection by IPC effluent preserves mitochondrial integrity and function in an adenosine receptor dependent mechanism, and although infarct size reduction can be mimicked by adenosine, IPC effluent contains additional factor(s) contributing to modulation of the mitochondrial response to ischemia/reperfusion injury.
Appendix
Available only for authorised users
Literature
1.
Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986;74(5):1124–36.PubMedCrossRef
2.
Oxman T, Arad M, Klein R, Avazov N, Rabinowitz B. Limb ischemia preconditions the heart against reperfusion tachyarrhythmia. Am J Physiol. 1997;273(4 Pt 2):H1707–12.PubMed
3.
Pell TJ, Baxter GF, Yellon DM, Drew GM. Renal ischemia preconditions myocardium: role of adenosine receptors and ATP-sensitive potassium channels. Am J Physiol. 1998;275(5 Pt 2):H1542–7.PubMed
4.
Konstantinov IE, Li J, Cheung MM, Shimizu M, Stokoe J, Kharbanda RK, et al. Remote ischemic preconditioning of the recipient reduces myocardial ischemia-reperfusion injury of the denervated donor heart via a Katp channel-dependent mechanism. Transplantation. 2005;79(12):1691–5.PubMedCrossRef
5.
6.
Shimizu M, Tropak M, Diaz RJ, Suto F, Surendra H, Kuzmin E, et al. Transient limb ischaemia remotely preconditions through a humoral mechanism acting directly on the myocardium: evidence suggesting cross-species protection. Clin Sci (Lond). 2009;117(5):191–200.CrossRef
7.
Wang L, Oka N, Tropak M, Callahan J, Lee J, Wilson G, et al. Remote ischemic preconditioning elaborates a transferable blood-borne effector that protects mitochondrial structure and function and preserves myocardial performance after neonatal cardioplegic arrest. J Thorac Cardiovasc Surg. 2008;136(2):335–42.PubMedCrossRef
8.
Dickson EW, Lorbar M, Porcaro WA, Fenton RA, Reinhardt CP, Gysembergh A, et al. Rabbit heart can be “preconditioned” via transfer of coronary effluent. Am J Physiol. 1999;277(6 Pt 2):H2451–7.PubMed
9.
Serejo FC, Rodrigues Jr LF, da Silva Tavares KC, de Carvalho AC, Nascimento JH. Cardioprotective properties of humoral factors released from rat hearts subject to ischemic preconditioning. J Cardiovasc Pharmacol. 2007;49(4):214–20.PubMedCrossRef
10.
Breivik L, Helgeland E, Aarnes EK, Mrdalj J, Jonassen AK. Remote postconditioning by humoral factors in effluent from ischemic preconditioned rat hearts is mediated via PI3K/Akt-dependent cell-survival signaling at reperfusion. Basic Res Cardiol. 2010;106(1):135–45.PubMedCentralPubMedCrossRef
11.
Chen Q, Moghaddas S, Hoppel CL, Lesnefsky EJ. Ischemic defects in the electron transport chain increase the production of reactive oxygen species from isolated rat heart mitochondria. Am J Physiol Cell Physiol. 2008;294(2):C460–6.PubMedCrossRef
12.
Chen Q, Vazquez EJ, Moghaddas S, Hoppel CL, Lesnefsky EJ. Production of reactive oxygen species by mitochondria: central role of complex III. J Biol Chem. 2003;278(38):36027–31.PubMedCrossRef
13.
Borutaite V, Jekabsone A, Morkuniene R, Brown GC. Inhibition of mitochondrial permeability transition prevents mitochondrial dysfunction, cytochrome c release and apoptosis induced by heart ischemia. J Mol Cell Cardiol. 2003;35(4):357–66.PubMedCrossRef
14.
Lesnefsky EJ, Tandler B, Ye J, Slabe TJ, Turkaly J, Hoppel CL. Myocardial ischemia decreases oxidative phosphorylation through cytochrome oxidase in subsarcolemmal mitochondria. Am J Physiol. 1997;273(3 Pt 2):H1544–54.PubMed
15.
16.
Crestanello JA, Lingle DM, Kamelgard J, Millili J, Whitman GJ. Ischemic preconditioning decreases oxidative stress during reperfusion: a chemiluminescence study. J Surg Res. 1996;65(1):53–8.PubMedCrossRef
17.
Javadov SA, Clarke S, Das M, Griffiths EJ, Lim KH, Halestrap AP. Ischaemic preconditioning inhibits opening of mitochondrial permeability transition pores in the reperfused rat heart. J Physiol. 2003;549(Pt 2):513–24.PubMedCrossRef
18.
Lundberg KC, Szweda LI. Preconditioning prevents loss in mitochondrial function and release of cytochrome c during prolonged cardiac ischemia/reperfusion. Arch Biochem Biophys. 2006;453(1):130–4.PubMedCrossRef
19.
Liu GS, Thornton J, Van Winkle DM, Stanley AW, Olsson RA, Downey JM. Protection against infarction afforded by preconditioning is mediated by A1 adenosine receptors in rabbit heart. Circulation. 1991;84(1):350–6.PubMedCrossRef
20.
Takaoka A, Nakae I, Mitsunami K, Yabe T, Morikawa S, Inubushi T, et al. Renal ischemia/reperfusion remotely improves myocardial energy metabolism during myocardial ischemia via adenosine receptors in rabbits: effects of “remote preconditioning”. J Am Coll Cardiol. 1999;33(2):556–64.PubMedCrossRef
21.
Goto M, Cohen MV, van Wylen DG, Downey JM. Attenuated purine production during subsequent ischemia in preconditioned rabbit myocardium is unrelated to the mechanism of protection. J Mol Cell Cardiol. 1996;28(3):447–54.PubMedCrossRef
22.
Chen Q, Camara AK, Stowe DF, Hoppel CL, Lesnefsky EJ. Modulation of electron transport protects cardiac mitochondria and decreases myocardial injury during ischemia and reperfusion. Am J Physiol Cell Physiol. 2007;292(1):C137–47.PubMedCrossRef
23.
Palmer JW, Tandler B, Hoppel CL. Biochemical properties of subsarcolemmal and interfibrillar mitochondria isolated from rat cardiac muscle. J Biol Chem. 1977;252(23):8731–9.PubMed
24.
Ricci JE, Gottlieb RA, Green DR. Caspase-mediated loss of mitochondrial function and generation of reactive oxygen species during apoptosis. J Cell Biol. 2003;160(1):65–75.PubMedCrossRef
25.
Lee AC, Zizi M, Colombini M. Beta-NADH decreases the permeability of the mitochondrial outer membrane to ADP by a factor of 6. J Biol Chem. 1994;269(49):30974–80.PubMed
26.
Mootha VK, Wei MC, Buttle KF, Scorrano L, Panoutsakopoulou V, Mannella CA, et al. A reversible component of mitochondrial respiratory dysfunction in apoptosis can be rescued by exogenous cytochrome c. EMBO J. 2001;20(4):661–71.PubMedCrossRef
27.
William JN. A method for the simultaneous quantitative estimation of cytochrome a, b, c1 and and c in mitochondrial. Arch Biochem Biophys. 1964;107:537–43.CrossRef
28.
Leung CH, Wang L, Fu YY, Yuen W, Caldarone CA. Transient mitochondrial permeability transition pore opening after neonatal cardioplegic arrest. J Thorac Cardiovasc Surg. 2011;141(4):975–82.PubMedCrossRef
29.
Dickson EW, Blehar DJ, Carraway RE, Heard SO, Steinberg G, Przyklenk K. Naloxone blocks transferred preconditioning in isolated rabbit hearts. J Mol Cell Cardiol. 2001;33(9):1751–6.PubMedCrossRef
30.
Schrader J, Haddy FJ, Gerlach E. Release of adenosine, inosine and hypoxanthine from the isolated guinea pig heart during hypoxia, flow-autoregulation and reactive hyperemia. Pflugers Arch. 1977;369(1):1–6.PubMedCrossRef
31.
Peart JN, Gross GJ. Adenosine and opioid receptor-mediated cardioprotection in the rat: evidence for cross-talk between receptors. Am J Physiol Heart Circ Physiol. 2003;285(1):H81–9.PubMed
32.
Surendra H, Diaz RJ, Harvey K, Tropak M, Callahan J, Hinek A, et al. Interaction of delta and kappa opioid receptors with adenosine A1 receptors mediates cardioprotection by remote ischemic preconditioning. J Mol Cell Cardiol. 2013;60:142–50.PubMedCrossRef
33.
Halestrap AP, Clarke SJ, Javadov SA. Mitochondrial permeability transition pore opening during myocardial reperfusion–a target for cardioprotection. Cardiovasc Res. 2004;61(3):372–85.PubMedCrossRef
34.
Brand MD, Pakay JL, Ocloo A, Kokoszka J, Wallace DC, Brookes PS, et al. The basal proton conductance of mitochondria depends on adenine nucleotide translocase content. Biochem J. 2005;392(Pt 2):353–62.PubMed
35.
Yang Z, Sun W, Hu K. Molecular mechanism underlying adenosine receptor-mediated mitochondrial targeting of protein kinase C. Biochim Biophys Acta. 2012;1823(4):950–8.PubMedCrossRef
36.
Baines CP, Song CX, Zheng YT, Wang GW, Zhang J, Wang OL, et al. Protein kinase Cepsilon interacts with and inhibits the permeability transition pore in cardiac mitochondria. Circ Res. 2003;92(8):873–80.PubMedCentralPubMedCrossRef
37.
Scorrano L, Petronilli V, Bernardi P. On the voltage dependence of the mitochondrial permeability transition pore. A critical appraisal. J Biol Chem. 1997;272(19):12295–9.PubMedCrossRef
38.
Dana A, Jonassen AK, Yamashita N, Yellon DM. Adenosine A(1) receptor activation induces delayed preconditioning in rats mediated by manganese superoxide dismutase. Circulation. 2000;101(24):2841–8.PubMedCrossRef
39.
Clarke SJ, Khaliulin I, Das M, Parker JE, Heesom KJ, Halestrap AP. Inhibition of mitochondrial permeability transition pore opening by ischemic preconditioning is probably mediated by reduction of oxidative stress rather than mitochondrial protein phosphorylation. Circ Res. 2008;102(9):1082–90.PubMedCentralPubMedCrossRef
40.
Kerr PM, Suleiman MS, Halestrap AP. Reversal of permeability transition during recovery of hearts from ischemia and its enhancement by pyruvate. Am J Physiol. 1999;276(2 Pt 2):H496–502.PubMed
41.
Kristiansen SB, Henning O, Kharbanda RK, Nielsen-Kudsk JE, Schmidt MR, Redington AN, et al. Remote preconditioning reduces ischemic injury in the explanted heart by a KATP channel-dependent mechanism. Am J Physiol Heart Circ Physiol. 2005;288(3):H1252–6.PubMedCrossRef
42.
Wang L, Cherednichenko G, Hernandez L, Halow J, Camacho SA, Figueredo V, et al. Preconditioning limits mitochondrial Ca(2+) during ischemia in rat hearts: role of K(ATP) channels. Am J Physiol Heart Circ Physiol. 2001;280(5):H2321–8.PubMed
43.
Murata M, Akao M, O’Rourke B, Marban E. Mitochondrial ATP-sensitive potassium channels attenuate matrix Ca(2+) overload during simulated ischemia and reperfusion: possible mechanism of cardioprotection. Circ Res. 2001;89(10):891–8.PubMedCrossRef
44.
Fryer RM, Eells JT, Hsu AK, Henry MM, Gross GJ. Ischemic preconditioning in rats: role of mitochondrial K(ATP) channel in preservation of mitochondrial function. Am J Physiol Heart Circ Physiol. 2000;278(1):H305–12.PubMed
45.
Koomen JM, Wilson CR, Guthrie P, Androlewicz MJ, Kobayashi R, Taegtmeyer H. Proteome analysis of isolated perfused organ effluent as a novel model for protein biomarker discovery. J Proteome Res. 2006;5(1):177–82.PubMedCrossRef
46.
Naydenova Z, Rose JB, Coe IR. Inosine and equilibrative nucleoside transporter 2 contribute to hypoxic preconditioning in the murine cardiomyocyte HL-1 cell line. Am J Physiol Heart Circ Physiol. 2008;294(6):H2687–92.PubMedCrossRef
47.
Jin X, Shepherd RK, Duling BR, Linden J. Inosine binds to A3 adenosine receptors and stimulates mast cell degranulation. J Clin Invest. 1997;100(11):2849–57.PubMedCentralPubMedCrossRef
48.
Peart J, Matherne GP, Cerniway RJ, Headrick JP. Cardioprotection with adenosine metabolism inhibitors in ischemic-reperfused mouse heart. Cardiovasc Res. 2001;52(1):120–9.PubMedCrossRef
49.
Steensrud T, Li J, Dai X, Manlhiot C, Kharbanda RK, Tropak M, et al. Pretreatment with the nitric oxide donor SNAP or nerve transection blocks humoral preconditioning by remote limb ischemia or intra-arterial adenosine. Am J Physiol Heart Circ Physiol. 2010;299(5):H1598–603.PubMedCrossRef
Metadata
Title
Remote Cardioprotection by Transfer of Coronary Effluent from Ischemic Preconditioned Rabbit Heart Preserves Mitochondrial Integrity and Function via Adenosine Receptor Activation
Authors
Chung Ho Leung
Lixing Wang
Jan M. Nielsen
Michael B. Tropak
Yana Y. Fu
Hideyuki Kato
John Callahan
Andrew N. Redington
Christopher A. Caldarone
Publication date
01-02-2014
Publisher
Springer US
Published in
Cardiovascular Drugs and Therapy / Issue 1/2014
Print ISSN: 0920-3206
Electronic ISSN: 1573-7241
DOI
https://doi.org/10.1007/s10557-013-6489-2

Other articles of this Issue 1/2014

Cardiovascular Drugs and Therapy 1/2014 Go to the issue

REVIEW ARTICLE

Can Antihypertensive Medication Interfere with the Vicious Cycle Between Hypertension and Vascular Calcification?

ORIGINAL ARTICLE

Rationale and Design of the EPISTEME Trial: Efficacy of Post-Stroke Intensive Rosuvastatin Treatment for Aortogenic Embolic Stroke

ORIGINAL ARTICLE

Clinical Effectiveness of Tolvaptan in Patients with Acute Decompensated Heart Failure and Renal Failure: Design and Rationale of the AQUAMARINE Study

EDITORIAL

The NLRP3 Inflammasome and Diabetic Cardiomyopathy

ORIGINAL ARTICLE

Cost–Effectiveness of Different Strategies for Stroke Prevention in Patients with Atrial Fibrillation in a Health Resource-Limited Setting

EDITORIAL

Transferring Protection: Adenosine as the Lone Ranger?

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

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

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits