Abstract
Efficacy of ischemic preconditioning is decreased in animal models of type 2 diabetes mellitus while the responses in humans with diabetes are contradictory. It is unknown whether attenuation is related to decreased release of a mediating humoral cardioprotective factor or reduced ability to respond in the target tissue. The aim of the present study was to investigate the release and effect of a circulating cardioprotective factor in type 2 diabetes mellitus patients. Blood samples were drawn from nine non-diabetic subjects, eight diabetic patients without peripheral neuropathy, and eight diabetic patients with peripheral neuropathy before (control) and after a remote ischemic preconditioning (rIPC) stimulus. Blood samples were dialyzed against Krebs–Henseleit buffer and the cardioprotective effects of the dialysates were tested in rabbit hearts mounted on a Langendorff model and subjected to 30-min global ischemia and 120-min reperfusion. rIPC dialysate from non-diabetic and diabetic subjects without peripheral neuropathy reduced infarct size and improved hemodynamic recovery compared to control dialysate from non-diabetic and diabetic subjects. However, in the subgroup of diabetic patients with neuropathy the cardioprotective effect was attenuated. These findings indicate that the release mechanism involves neural pathways.
Similar content being viewed by others
References
Botker HE, Kharbanda R, Schmidt MR, Bottcher M, Kaltoft AK, Terkelsen CJ, Munk K, Andersen NH, Hansen TM, Trautner S, Lassen JF, Christiansen EH, Krusell LR, Kristensen SD, Thuesen L, Nielsen SS, Rehling M, Sorensen HT, Redington AN, Nielsen TT (2010) Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial. Lancet 375:727–734. doi:10.1016/S0140-6736(09)62001-8
Breivik L, Helgeland E, Aarnes EK, Mrdalj J, Jonassen AK (2011) Remote postconditioning by humoral factors in effluent from ischemic preconditioned rat hearts is mediated via PI3 K/Akt-dependent cell-survival signaling at reperfusion. Basic Res Cardiol 106:135–145. doi:10.1007/s00395-010-0133-0
Dickson EW, Reinhardt CP, Renzi FP, Becker RC, Porcaro WA, Heard SO (1999) Ischemic preconditioning may be transferable via whole blood transfusion: preliminary evidence. J Thromb Thrombolysis 8:123–129
Domenech R, Macho P, Schwarze H, Sanchez G (2002) Exercise induces early and late myocardial preconditioning in dogs. Cardiovasc Res 55:561–566
Finegan BA, Lopaschuk GD, Gandhi M, Clanachan AS (1995) Ischemic preconditioning inhibits glycolysis and proton production in isolated working rat hearts. Am J Physiol 269:H1767–H1775
Galagudza MM, Nekrasova MK, Syrenskii AV, Nifontov EM (2007) Resistance of the myocardium to ischemia and the efficacy of ischemic preconditioning in experimental diabetes mellitus. Neurosci Behav Physiol 37:489–493. doi:10.1007/s11055-007-0040-5
Hausenloy DJ, Baxter G, Bell R, Botker HE, Davidson SM, Downey J, Heusch G, Kitakaze M, Lecour S, Mentzer R, Mocanu MM, Ovize M, Schulz R, Shannon R, Walker M, Walkinshaw G, Yellon DM (2010) Translating novel strategies for cardioprotection: the Hatter Workshop Recommendations. Basic Res Cardiol 105:677–686. doi:10.1007/s00395-010-0121-4
Jonassen AK, Sack MN, Mjos OD, Yellon DM (2001) Myocardial protection by insulin at reperfusion requires early administration and is mediated via Akt and p70s6 kinase cell-survival signaling. Circ Res 89:1191–1198
Kharbanda RK, Mortensen UM, White PA, Kristiansen SB, Schmidt MR, Hoschtitzky JA, Vogel M, Sorensen K, Redington AN, MacAllister R (2002) Transient limb ischemia induces remote ischemic preconditioning in vivo. Circulation 106:2881–2883
Krenz M, Baines CP, Heusch G, Downey JM, Cohen MV (2001) Acute alcohol-induced protection against infarction in rabbit hearts: differences from and similarities to ischemic preconditioning. J Mol Cell Cardiol 33:2015–2022. doi:10.1006/jmcc.2001.1465
Kristiansen SB, Lofgren B, Stottrup NB, Khatir D, Nielsen-Kudsk JE, Nielsen TT, Botker HE, Flyvbjerg A (2004) Ischaemic preconditioning does not protect the heart in obese and lean animal models of type 2 diabetes. Diabetologia 47:1716–1721. doi:10.1007/s00125-004-1514-4
Lim SY, Yellon DM, Hausenloy DJ (2010) The neural and humoral pathways in remote limb ischemic preconditioning. Basic Res Cardiol 105:651–655. doi:10.1007/s00395-010-0099-y
Loukogeorgakis SP, Panagiotidou AT, Broadhead MW, Donald A, Deanfield JE, MacAllister RJ (2005) Remote ischemic preconditioning provides early and late protection against endothelial ischemia–reperfusion injury in humans: role of the autonomic nervous system. J Am Coll Cardiol 46:450–456. doi:10.1016/j.jacc.2005.04.044
Ludman A, Venugopal V, Yellon DM, Hausenloy DJ (2009) Statins and cardioprotection–more than just lipid lowering? Pharmacol Ther 122:30–43. doi:10.1016/j.pharmthera.2009.01.002
Michelsen MM, Stottrup NB, Schmidt MR, Lofgren B, Jensen RV, Tropak M, St-Michel EJ, Redington AN, Botker HE (2012) Exercise-induced cardioprotection is mediated by a bloodborne, transferable factor. Basic Res Cardiol 107:260. doi:10.1007/s00395-012-0260-x
Murry CE, Jennings RB, Reimer KA (1986) Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74:1124–1136
Murry CE, Richard VJ, Reimer KA, Jennings RB (1990) Ischemic preconditioning slows energy metabolism and delays ultrastructural damage during a sustained ischemic episode. Circ Res 66:913–931
Przyklenk K, Bauer B, Ovize M, Kloner RA, Whittaker P (1993) Regional ischemic ‘preconditioning’ protects remote virgin myocardium from subsequent sustained coronary occlusion. Circulation 87:893–899
Przyklenk K, Maynard M, Greiner DL, Whittaker P (2011) Cardioprotection with postconditioning: loss of efficacy in murine models of type-2 and type-1 diabetes. Antioxid Redox Signal 14:781–790. doi:10.1089/ars.2010.3343
Redington KL, Disenhouse T, Strantzas SC, Gladstone R, Wei C, Tropak MB, Dai X, Manlhiot C, Li J, Redington AN (2012) Remote cardioprotection by direct peripheral nerve stimulation and topical capsaicin is mediated by circulating humoral factors. Basic Res Cardiol 107:241. doi:10.1007/s00395-011-0241-5
Riksen NP, Zhou Z, Oyen WJ, Jaspers R, Ramakers BP, Brouwer RM, Boerman OC, Steinmetz N, Smits P, Rongen GA (2006) Caffeine prevents protection in two human models of ischemic preconditioning. J Am Coll Cardiol 48:700–707. doi:10.1016/j.jacc.2006.04.083
Schwartz LL, Kloner RA, Arai AE, Baines CP, Bolli R, Braunwald E, Downey J, Gibbons RJ, Gottlieb RA, Heusch G, Jennings RB, Lefer DJ, Mentzer RM, Murphy E, Ovize M, Ping P, Przyklenk K, Sack MN, Vander Heide RS, Vinten-Johansen J, Yellon DM (2011) New horizons in cardioprotection: recommendations from the 2010 National Heart, Lung, and Blood Institute Workshop. Circulation 124:1172–1179. doi:10.1161/CIRCULATIONAHA.111.032698
Shimizu M, Tropak M, Diaz RJ, Suto F, Surendra H, Kuzmin E, Li J, Gross G, Wilson GJ, Callahan J, Redington AN (2009) Transient limb ischaemia remotely preconditions through a humoral mechanism acting directly on the myocardium: evidence suggesting cross-species protection. Clin Sci (Lond) 117:191–200. doi:10.1042/CS20080523
Sivaraman V, Hausenloy DJ, Wynne AM, Yellon DM (2010) Preconditioning the diabetic human myocardium. J Cell Mol Med 14:1740–1746. doi:10.1111/j.1582-4934.2009.00796.x
Steensrud T, Li J, Dai X, Manlhiot C, Kharbanda RK, Tropak M, Redington A (2010) 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 299:H1598–H1603. doi:10.1152/ajpheart.00396.2010
Stottrup NB, Lofgren B, Birkler RD, Nielsen JM, Wang L, Caldarone CA, Kristiansen SB, Contractor H, Johannsen M, Botker HE, Nielsen TT (2010) Inhibition of the malate-aspartate shuttle by pre-ischaemic aminooxyacetate loading of the heart induces cardioprotection. Cardiovasc Res 88:257–266. doi:10.1093/cvr/cvq205
Tamareille S, Mateus V, Ghaboura N, Jeanneteau J, Croue A, Henrion D, Furber A, Prunier F (2011) RISK and SAFE signaling pathway interactions in remote limb ischemic perconditioning in combination with local ischemic postconditioning. Basic Res Cardiol 106:1329–1339. doi:10.1007/s00395-011-0210-z
Thielmann M, Kottenberg E, Boengler K, Raffelsieper C, Neuhaeuser M, Peters J, Jakob H, Heusch G (2010) Remote ischemic preconditioning reduces myocardial injury after coronary artery bypass surgery with crystalloid cardioplegic arrest. Basic Res Cardiol 105:657–664. doi:10.1007/s00395-010-0104-5
Tomai F, Crea F, Gaspardone A, Versaci F, De PR, de Penta PA, Chiariello L, Gioffre PA (1994) Ischemic preconditioning during coronary angioplasty is prevented by glibenclamide, a selective ATP-sensitive K+ channel blocker. Circulation 90:700–705
Tsang A, Hausenloy DJ, Mocanu MM, Carr RD, Yellon DM (2005) Preconditioning the diabetic heart: the importance of Akt phosphorylation. Diabetes 54:2360–2364
Vladic N, Ge ZD, Leucker T, Brzezinska AK, Du JH, Shi Y, Warltier DC, Pratt PF Jr, Kersten JR (2011) Decreased tetrahydrobiopterin and disrupted association of Hsp90 with eNOS by hyperglycemia impair myocardial ischemic preconditioning. Am J Physiol Heart Circ Physiol 301:H2130–H2139. doi:10.1152/ajpheart.01078.2010
Ye Y, Perez-Polo JR, Aguilar D, Birnbaum Y (2011) The potential effects of anti-diabetic medications on myocardial ischemia-reperfusion injury. Basic Res Cardiol 106:925–952. doi:10.1007/s00395-011-0216-6
Acknowledgments
The study was funded by Leducq (06CVD), The Danish Research Council (11-108354), The Danish Strategic Research Council (11-115818), and Aarhus University Institute of Clinical Medicine. The skillful technical assistance of Eva Sparrewath and Bente Jacobsen is greatly appreciated.
Conflict of interest
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Jensen, R.V., Støttrup, N.B., Kristiansen, S.B. et al. Release of a humoral circulating cardioprotective factor by remote ischemic preconditioning is dependent on preserved neural pathways in diabetic patients. Basic Res Cardiol 107, 285 (2012). https://doi.org/10.1007/s00395-012-0285-1
Received:
Revised:
Accepted:
Published:
DOI: https://doi.org/10.1007/s00395-012-0285-1