Abstract
Diabetes mellitus significantly hampers the development of cardioprotective response to remote pre/post/perconditioning stimuli by impairing the activation of cardioprotective signaling pathways. Among the different pathways, the impairment in O-linked β-N-acetylglucosamine (O-GlcNAc) signaling and release of cardioprotective humoral factor may contribute in attenuating remote preconditioning-induced cardioprotection. Moreover, the failure to phosphorylate extracellular signal related kinase (ERK), phosphoinositide-3-kinase (PI3K), and AKT along with up-regulation of mechanistic target of rapamycin (mTOR) and decrease in autophagy may also attenuate remote preconditioning-induced cardioprotection. Remote perconditioning stimulus also fails to phosphorylate AKT kinase in diabetic heart. In addition, diabetes may increase the oxidative stress, reactive oxygen species (ROS) production, decrease the beclin expression, and inhibit autophagy to attenuate remote perconditioning-induced cardioprotection. Moreover, diabetes-induced increase in the Rho-associated kinase (ROCK) activity, decrease in the arginase activity, and reduction in nitric oxide (NO) bioavailability may also contribute in decreasing remote perconditioning-induced cardioprotection. Diabetes may reduce the phosphorylation of adenosine 5′-monophosphate activated protein kinase (AMPKα) and increase the phosphorylation of mTOR to attenuate cardioprotection of remote postconditioning. The present review describes the role of diabetes in attenuating remote ischemic conditioning-induced cardioprotection along with the possible mechanisms.
Similar content being viewed by others
References
Ansley DM, Wang B (2013 Jan) Oxidative stress and myocardial injury in the diabetic heart. J Pathol 229(2):232–241
Aulakh AS, Randhawa PK, Singh N, Jaggi AS (2017 Mar) Neurogenic pathways in remote ischemic preconditioning induced cardioprotection: evidences and possible mechanisms. Korean J Physiol Pharmacol 21(2):145–152
Bao W, Hu E, Tao L, Boyce R, Mirabile R, Thudium DT, Ma XL, Willette RN, Yue TL (2004) Inhibition of rho-kinase protects the heart against ischemia/reperfusion injury. Cardiovasc Res 61(3):548–558
Baranyai T, Nagy CT, Koncsos G, Onódi Z, Károlyi-Szabó M, Makkos A, Varga ZV, Ferdinandy P, Giricz Z (2015) Acute hyperglycemia abolishes cardioprotection by remote ischemic perconditioning. Cardiovasc Diabetol 14:151
Birnbaum Y, Hale SL, Kloner RA (1997) Ischemic preconditioning at a distance: reduction of myocardial infarct size by partial reduction of blood supply combined with rapid stimulation of the gastrocnemius muscle in the rabbit. Circulation 96(5):1641–1646
Bøtker HE, Kharbanda R, Schmidt MR, Bøttcher 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, Sørensen 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(9716):727–734
Cheung MM, Kharbanda RK, Konstantinov IE, Shimizu M, Frndova H, Li J, Holtby HM, Cox PN, Smallhorn JF, Van Arsdell GS, Redington AN (2006) Randomized controlled trial of the effects of remote ischemic preconditioning on children undergoing cardiac surgery: first clinical application in humans. J Am Coll Cardiol 47(11):2277–2282
Cleveland JC Jr, Meldrum DR, Cain BS, Banerjee A, Harken AH (1997) Oral sulfonylurea hypoglycemic agents prevent ischemic preconditioning in human myocardium. Two paradoxes revisited. Circulation 96(1):29–32
Corcoran D, Young R, Cialdella P, McCartney P, Bajrangee A, Hennigan B, Collison D, Carrick D, Shaukat A, Good R, Watkins S, McEntegart M, Watt J, Welsh P, Sattar N, McConnachie A, Oldroyd KG, Berry C (2018) The effects of remote ischaemic preconditioning on coronary artery function in patients with stable coronary artery disease. Int J Cardiol 252:24–30
Crimi G, Pica S, Raineri C, Bramucci E, De Ferrari GM, Klersy C, Ferlini M, Marinoni B, Repetto A, Romeo M, Rosti V, Massa M, Raisaro A, Leonardi S, Rubartelli P, Oltrona Visconti L, Ferrario M (2013) Remote ischemic post-conditioning of the lower limb during primary percutaneous coronary intervention safely reduces enzymatic infarct size in anterior myocardial infarction: a randomized controlled trial. JACC Cardiovasc Interv 6(10):1055–1063
Das A, Durrant D, Koka S, Salloum FN, Xi L, Kukreja RC (2014) Mammalian target of rapamycin (mTOR) inhibition with rapamycin improves cardiac function in type 2 diabetic mice: potential role of attenuated oxidative stress and altered contractile protein expression. J Biol Chem 289(7):4145–4160
Diwan V, Kant R, Jaggi AS, Singh N, Singh D (2008) Signal mechanism activated by erythropoietin preconditioning and remote renal preconditioning-induced cardioprotection. Mol Cell Biochem 315(1–2):195–201
Ferdinandy P, Hausenloy DJ, Heusch G, Baxter GF, Schulz R (2014) Interaction of risk factors, comorbidities, and comedications with ischemia/reperfusion injury and cardioprotection by preconditioning, postconditioning, and remote conditioning. Pharmacol Rev 66(4):1142–1174
Fraenkel M, Ketzinel-Gilad M, Ariav Y, Pappo O, Karaca M, Castel J, Berthault MF, Magnan C, Cerasi E, Kaiser N, Leibowitz G (2008) mTOR inhibition by rapamycin prevents beta-cell adaptation to hyperglycemia and exacerbates the metabolic state in type 2 diabetes. Diabetes 57(4):945–957
Gho BC, Schoemaker RG, van den Doel MA, Duncker DJ, Verdouw PD (1996) Myocardial protection by brief ischemia in noncardiac tissue. Circulation 94(9):2193–2200
Han Z, Cao J, Song D, Tian L, Chen K, Wang Y, Gao L, Yin Z, Fan Y, Wang C (2014) Autophagy is involved in the cardioprotection effect of remote limb ischemic postconditioning on myocardial ischemia/reperfusion injury in normal mice, but not diabetic mice. PLoS One 9(1):e86838
Hao M, Zhu S, Hu L, Zhu H, Wu X, Li Q (2017) Myocardial ischemic postconditioning promotes autophagy against ischemia reperfusion injury via the activation of the nNOS/AMPK/mTOR pathway. Int J Mol Sci 18(3):614
Hausenloy DJ, Yellon DM (2004) New directions for protecting the heart against ischaemia–reperfusion injury: targeting the reperfusion injury salvage kinase (RISK)-pathway. Cardiovasc Res 61(3):448–460
Hausenloy DJ, Candilio L, Evans R, Ariti C, Jenkins DP, Kolvekar S, Knight R, Kunst G, Laing C, Nicholas J, Pepper J, Robertson S, Xenou M, Clayton T, Yellon DM (2015) Remote ischemic preconditioning and outcomes of cardiac surgery. N Engl J Med 373:1408–1417
Heung Yong J, Baek HS, Park TS (2015) Morphologic changes in autonomic nerves in diabetic autonomic neuropathy. Diabetes Metab J 39(6):461–467
Hu Z, Chen M, Zhang P, Liu J, Abbott GW (2017) Remote ischemic preconditioning differentially attenuates post-ischemic cardiac arrhythmia in streptozotocin-induced diabetic versus nondiabetic rats. Cardiovasc Diabetol 16(1):57
Iliodromitis EK, Cohen MV, Dagres N, Andreadou I, Kremastinos DT, Downey JM (2015) What is wrong with cardiac conditioning? We may be shooting at moving targets. J Cardiovasc Pharmacol Ther 20(4):357–369
Jensen RV, Støttrup NB, Kristiansen SB, Bøtker HE (2012) Release of a humoral circulating cardioprotective factor by remote ischemic preconditioning is dependent on preserved neural pathways in diabetic patients. Basic Res Cardiol 107(5):285
Jensen RV, Zachara NE, Nielsen PH, Kimose HH, Kristiansen SB, Bøtker HE (2013) Impact of O-GlcNAc on cardioprotection by remote ischaemic preconditioning in non-diabetic and diabetic patients. Cardiovasc Res 97(2):369–378
Kannel WB, McGee DL (1979) Diabetes and cardiovascular disease. The Framingham study. JAMA 241(19):2035–2038
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(23):2881–2883
Kiss A, Tratsiakovich Y, Gonon AT, Fedotovskaya O, Lanner J, Andersson DC, Yang J, Pernow J (2014a) The role of arginase and rho kinase in cardioprotection from remote ischemic perconditioning in non-diabetic and diabetic rat in vivo. PLoS One 9(8):e104731
Kiss A, Tratsiakovich Y, Gonon AT, Fedotovskaya O, Lanner JT, Andersson DC, Yang J, Pernow J (2014b) The role of arginase and rho kinase in cardioprotection from remote ischemic perconditioning in non-diabetic and diabetic rat in vivo. PLoS One 9(8):e104731
Kobayashi S, Xu X, Chen K, Liang Q (2012) Suppression of autophagy is protective in high glucose-induced cardiomyocyte injury. Autophagy 8(4):577–592
Kottenberg E, Musiolik J, Thielmann M, Jakob H, Peters J, Heusch G (2014) Interference of propofol with signal transducer and activator of transcription 5 activation and cardioprotection by remote ischemic preconditioning during coronary artery bypass grafting. J Thorac Cardiovasc Surg 147(1):376–382
Lambert JP, Nicholson CK, Amin H, Amin S, Calvert JW (2014) Hydrogen sulfide provides cardioprotection against myocardial/ischemia reperfusion injury in the diabetic state through the activation of the RISK pathway. Med Gas Res 4(1):20
Lambert EA, Thomas CJ, Hemmes R, Eikelis N, Pathak A, Schlaich MP, Lambert GW (2016) Sympathetic nervous response to ischemia–reperfusion injury in humans is altered with remote ischemic preconditioning. Am J Physiol Heart Circ Physiol 311:H364–H370
Lee TM, Su SF, Chou TF, Lee YT, Tsai CH (2002) Loss of preconditioning by attenuated activation of myocardial ATP-sensitive potassium channels in elderly patients undergoing coronary angioplasty. Circulation 105(3):334–340
Lewis P, Stefanovic N, Pete J, Calkin AC, Giunti S, Thallas-Bonke V, Jandeleit-Dahm KA, Allen TJ, Kola I, Cooper ME, de Haan JB (2007) Lack of the antioxidant enzyme glutathione peroxidase-1 accelerates atherosclerosis in diabetic apolipoprotein E-deficient mice. Circulation 115(16):2178–2187
Lim SY, Yellon DM, Hausenloy DJ (2010) The neural and humoral pathways in remote limb ischemic preconditioning. Basic Res Cardiol 105(5):651–655
Lindholm CR, Ertel RL, Bauwens JD, Schmuck EG, Mulligan JD, Saupe KW (2013) A high-fat diet decreases AMPK activity in multiple tissues in the absence of hyperglycemia or systemic inflammation in rats. J Physiol Biochem 69(2):165–175
Loubani M, Fowler A, Standen NB, Galiñanes M (2005) The effect of gliclazide and glibenclamide on preconditioning of the human myocardium. Eur J Pharmacol 515(1–3):142–149
Mapanga RF, Joseph D, Symington B, Garson KL, Kimar C, Kelly-Laubscher R, Essop MF (2014) Detrimental effects of acute hyperglycaemia on the rat heart. Acta Physiol (Oxf) 210(3):546–564
McCafferty K, Forbes S, Thiemermann C, Yaqoob MM (2014) The challenge of translating ischemic conditioning from animal models to humans: the role of comorbidities. Dis Model Mech 7(12):1321–1333
Meybohm P, Bein B, Brosteanu O, Cremer J, Gruenewald M, Stoppe C, Coburn M, Schaelte G, Boning A, Niemann B, Roesner J, Kletzin F, Strouhal U, Reyher C, Laufenberg-Feldmann R, Ferner M, Brandes IF, Bauer M, Stehr SN, Kortgen A, Wittmann M, Baumgarten G, Meyer-Treschan T, Kienbaum P, Heringlake M, Schon J, Sander M, Treskatsch S, Smul T, Wolwender E, Schilling T, Fuernau G, Hasenclever D, Zacharowski K (2015) A multicenter trial of remote ischemic preconditioning for heart surgery. N Engl J Med 373:1397–1407
Motta GL, Souza PC, EBdos S, Bona SR, Schaefer PG, Lima CAT, Marroni NAP, Corso CO (2018) Effects of remote ischemic preconditioning and topical hypothermia in renal ischemia–reperfusion injury in rats. Acta Cir Bras 33(5):396–407
Przyklenk K (2011) Efficacy of cardioprotective ‘conditioning’ strategies in aging and diabetic cohorts the co-morbidity conundrum. Drugs Aging 28(5):331–343
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(3):893–899
Qian J, Ren X, Wang X, Zhang P, Jones WK, Molkentin JD, Fan G, Kranias EG (2009) Blockade of Hsp20 phosphorylation exacerbates cardiac ischemia/reperfusion injury by suppressed autophagy and increased cell death. Circ Res 105:1223–1231
Ramakrishna V, Jailkhani R (2008) Oxidative stress in non-insulin-dependent diabetes mellitus (NIDDM) patients. Acta Diabetol 45(1):41–46
Randhawa PK, Jaggi AS (2016) Gadolinium and ruthenium red attenuate remote hind limb preconditioning-induced cardioprotection: possible role of TRP and especially TRPV channels. Arch Pharmacol 389(8):887–896
Randhawa PK, Jaggi AS (2017a) Investigating the involvement of glycogen synthase kinase-3β and gap junction signaling in TRPV1 and remote hind preconditioning-induced cardioprotection. Eur J Pharmacol 814:9–17
Randhawa PK, Jaggi AS (2017b) Investigating the involvement of TRPV1 ion channels in remote hind limb preconditioning-induced cardioprotection in rats. Naunyn Schmiedeberg's Arch Pharmacol 390(2):117–126
Randhawa PK, Jaggi AS (2017c) Opioids in remote ischemic preconditioning-induced cardioprotection. J Cardiovasc Pharmacol Ther 22(2):112–121
Randhawa PK, Bali A, Jaggi AS (2015) RIPC for multiorgan salvage in clinical settings: evolution of concept, evidences and mechanisms. Eur J Pharmacol 746:317–332
Randhawa PK, Bali A, Virdi JK, Jaggi AS (2018) Conditioning-induced cardioprotection: aging as a confounding factor. Korean J Physiol Pharmacol. 22(5):467–479
Rohailla S, Clarizia N, Sourour M, Sourour W, Gelber N, Wei C, Li J, Redington AN (2014) Acute, delayed and chronic remote ischemic conditioning is associated with downregulation of mTOR and enhanced autophagy signaling. PLoS One 9(10):e111291
Rossello X, Yellon DM (2017) The RISK pathway and beyond. Basic Res Cardiol 113(1):2
Saxena P, Newman MA, Shehatha JS, Redington AN, Konstantinov IE (2010) Remote ischemic conditioning: evolution of the concept, mechanisms, and clinical application. J Card Surg 25(1):127–134
Schmidt MR, Smerup M, Konstantinov IE, Shimizu M, Li J, Cheung M, White PA, Kristiansen SB, Sorensen K, Dzavik V, Redington AN, Kharbanda RK (2007) Intermittent peripheral tissue ischemia during coronary ischemia reduces myocardial infarction through a KATP-dependent mechanism: first demonstration of remote ischemic perconditioning. Am J Physiol Heart Circ Physiol 292(4):H1883–H1890
Schmidt MR, Rasmussen ME, Bøtker HE (2017) Remote ischemic conditioning for patients with STEMI. J Cardiovasc Pharmacol Ther 22(4):302–309
Singh H, Kumar M, Singh N, Jaggi AS (2018) Late phases of cardioprotection during remote ischemic preconditioning and adenosine preconditioning involves activation of neurogenic pathway. J Cardiovasc Pharmacol. https://doi.org/10.1097/FJC.0000000000000634
Su H, Ji L, Xing W, Zhang W, Zhou H, Qian X, Wang X, Gao F, Sun X, Zhang H (2013) Acute hyperglycaemia enhances oxidative stress and aggravates myocardial ischaemia/reperfusion injury: role of thioredoxin-interacting protein. J Cell Mol Med 17(1):181–191
Sun Z, Wu X, Li W, Peng H, Shen X, Ma L, Liu H, Li H (2016) RhoA/rock signaling mediates peroxynitrite-induced functional impairment of rat coronary vessels. BMC Cardiovasc Disord 16(1):193
Tan W, Zhang C, Liu J, Li X, Chen Y, Miao Q (2018) Remote ischemic preconditioning has a cardioprotective effect in children in the early postoperative phase: a meta-analysis of randomized controlled trials. Pediatr Cardiol 39(3):617–626
Varga ZV, Giricz Z, Bencsik P, Madonna R, Gyongyosi M, Schulz R, Mayr M, Thum T, Puskas LG, Ferdinandy P (2015) Functional genomics of cardioprotection by ischemic conditioning and the influence of comorbid conditions: implications in target identification. Curr Drug Targets 16(8):904–911
Völkers M, Konstandin MH, Doroudgar S, Toko H, Quijada P, Din S, Joyo A, Ornelas L, Samse K, Thuerauf DJ, Gude N, Glembotski CC, Sussman MA (2013) Mechanistic target of rapamycin complex 2 protects the heart from ischemic damage. Circulation 128(19):2132–2144
Voucharas C, Lazou A, Triposkiadis F, Tsilimingas N (2011 Mar 23) Remote preconditioning in normal and hypertrophic rat hearts. J Cardiothorac Surg 6:34
Wider J, Przyklenk K (2014) Ischemic conditioning: the challenge of protecting the diabetic heart. Cardiovasc Diagn Ther 4(5):383–396
Yamamoto K, Maruyama K, Himori N, Omodaka K, Yokoyama Y, Shiga Y, Morin R, Nakazawa T (2014) The novel rho kinase (ROCK) inhibitor K-115: a new candidate drug for neuroprotective treatment in glaucoma. Invest Ophthalmol Vis Sci 55(11):7126–7136
Zhang J, Liu XB, Cheng C, Xu DL, Lu QH, Ji XP (2014) Rho-kinase inhibition is involved in the activation of PI3-kinase/Akt during ischemic-preconditioning-induced cardiomyocyte apoptosis. Int J Clin Exp Med 7(11):4107–4114 eCollection 2014
Zhang M, Sun D, Li S, Pan X, Zhang X, Zhu D, Li C, Zhang R, Gao E, Wang H (2015) Lin28a protects against cardiac ischaemia/reperfusion injury in diabetic mice through the insulin-PI3K-mTOR pathway. J Cell Mol Med 19(6):1174–1182
Zhou CC, Ge YZ, Yao WT, Wu R, Xin H, Lu TZ, Li MH, Song KW, Wang M, Zhu YP, Zhu M, Geng LG, Gao XF, Zhou LH, Zhang SL, Zhu JG, Jia RP (2017) Limited clinical utility of remote ischemic conditioning in renal transplantation: a meta-analysis of randomized controlled trials. PLoS One 12(1):e0170729
Zhu SB, Liu Y, Zhu Y, Yin GL, Wang RP, Zhang Y, Zhu J, Jiang W (2013) Remote preconditioning, perconditioning, and postconditioning: a comparative study of their cardio-protective properties in rat models. Clinics (Sao Paulo) 68(2):263–268
Acknowledgements
The authors are thankful to the Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, India for supporting the study.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Disclosure of potential conflicts of interest
The authors declare no conflict of interests.
Research involving human participants and/or animals
The study did not involve usage of animals or employment of human participants.
Informed consent
The study did not involve participants of human volunteers.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
S.T. did the literature review and prepared the manuscript
J.K.V. helped in writing the manuscript and revised the manuscript
N.S. helped in literature review and completion of the article
A.S.J. conceived the idea and edited the manuscript
Rights and permissions
About this article
Cite this article
Tyagi, S., Singh, N., Virdi, J.k. et al. Diabetes abolish cardioprotective effects of remote ischemic conditioning: evidences and possible mechanisms. J Physiol Biochem 75, 19–28 (2019). https://doi.org/10.1007/s13105-019-00664-w
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13105-019-00664-w