Korean J Physiol Pharmacol.  2018 Sep;22(5):467-479. 10.4196/kjpp.2018.22.5.467.

Conditioning-induced cardioprotection: Aging as a confounding factor

• Randhawa P
• Bali A
• Virdi JK
• Jaggi AS

• KMID: 2418997
• DOI: http://doi.org/10.4196/kjpp.2018.22.5.467

Abstract

The aging process induces a plethora of changes in the body including alterations in hormonal regulation and metabolism in various organs including the heart. Aging is associated with marked increase in the vulnerability of the heart to ischemia-reperfusion injury. Furthermore, it significantly hampers the development of adaptive response to various forms of conditioning stimuli (pre/post/remote conditioning). Aging significantly impairs the activation of signaling pathways that mediate preconditioning-induced cardioprotection. It possibly impairs the uptake and release of adenosine, decreases the number of adenosine transporter sites and down-regulates the transcription of adenosine receptors in the myocardium to attenuate adenosine-mediated cardioprotection. Furthermore, aging decreases the expression of peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1α) and subsequent transcription of catalase enzyme which subsequently increases the oxidative stress and decreases the responsiveness to preconditioning stimuli in the senescent diabetic hearts. In addition, in the aged rat hearts, the conditioning stimulus fails to phosphorylate Akt kinase that is required for mediating cardioprotective signaling in the heart. Moreover, aging increases the concentration of Na⁺ and K⁺, connexin expression and caveolin abundance in the myocardium and increases the susceptibility to ischemia-reperfusion injury. In addition, aging also reduces the responsiveness to conditioning stimuli possibly due to reduced kinase signaling and reduced STAT-3 phosphorylation. However, aging is associated with an increase in MKP-1 phosphorylation, which dephosphorylates (deactivates) mitogen activated protein kinase that is involved in cardioprotective signaling. The present review describes aging as one of the major confounding factors in attenuating remote ischemic preconditioning-induced cardioprotection along with the possible mechanisms.

Keyword

Adenosine; Aging; Conditioning; Oxidative stress

MeSH Terms

Adenosine
Aging*
Animals
Catalase
Heart
Metabolism
Myocardium
Negotiating
Oxidative Stress
Phosphorylation
Phosphotransferases
PPAR gamma
Protein Kinases
Rats
Receptors, Purinergic P1
Reperfusion Injury
Adenosine
Catalase
PPAR gamma
Phosphotransferases
Protein Kinases
Receptors, Purinergic P1

Figure

• 

  Fig. 1 Aging attenuates conditioning-induced cardioprotection and decreases the responsiveness to the conditioning stimuli due to impairment in the cellular signaling. Aging reduces the uptake and release of adenosine, decreases the number of transporter sites and the transcription of adenosine receptors in the heart to ultimately reduce adenosine functioning. Furthermore, aging reduces the expression of PGC-1α and reduces catalase activity, which subsequently increases the oxidative stress in the heart. Aging also tends to reduce ERK and AKT phosphorylation which indicates decreased kinase signaling and reduced cardioprotection. Aging also leads to cardiac imbalance which attenuates conditioning-induced protective effects.

Reference

1. Randhawa PK, Bali A, Jaggi AS. RIPC for multiorgan salvage in clinical settings: evolution of concept, evidences and mechanisms. Eur J Pharmacol. 2015; 746:317–332.

2. Randhawa PK, Jaggi AS. Unraveling the role of adenosine in remote ischemic preconditioning-induced cardioprotection. Life Sci. 2016; 155:140–146.

3. Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986; 74:1124–1136.

4. Vinten-Johansen J, Shi W. Perconditioning and postconditioning: current knowledge, knowledge gaps, barriers to adoption, and future directions. J Cardiovasc Pharmacol Ther. 2011; 16:260–266.

5. Randhawa PK, Jaggi AS. Gadolinium and ruthenium red attenuate remote hind limb preconditioning-induced cardioprotection: possible role of TRP and especially TRPV channels. Naunyn Schmiedebergs Arch Pharmacol. 2016; 389:887–896.

6. 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. 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. 2013; 6:1055–1063.

7. Minou AF, Dzyadzko AM, Shcherba AE, Rummo OO. The influence of pharmacological preconditioning with sevoflurane on incidence of early allograft dysfunction in liver transplant recipients. Anesthesiol Res Pract. 2012; DOI: 10.1155/2012/930487.

8. Gallagher D, Allen A, Wang Z, Heymsfield SB, Krasnow N. Smaller organ tissue mass in the elderly fails to explain lower resting metabolic rate. Ann N Y Acad Sci. 2000; 904:449–455.

9. See Hoe LE, May LT, Headrick JP, Peart JN. Sarcolemmal dependence of cardiac protection and stress-resistance: roles in aged or diseased hearts. Br J Pharmacol. 2016; 173:2966–2991.

10. Roth GA, Forouzanfar MH, Moran AE, Barber R, Nguyen G, Feigin VL, Naghavi M, Mensah GA, Murray CJ. Demographic and epidemiologic drivers of global cardiovascular mortality. N Engl J Med. 2015; 372:1333–1341.

11. Ashton KJ, Nilsson U, Willems L, Holmgren K, Headrick JP. Effects of aging and ischemia on adenosine receptor transcription in mouse myocardium. Biochem Biophys Res Commun. 2003; 312:367–372.

12. Juhaszova M, Rabuel C, Zorov DB, Lakatta EG, Sollott SJ. Protection in the aged heart: preventing the heart-break of old age? Cardiovasc Res. 2005; 66:233–244.

13. O'Brien JD, Ferguson JH, Howlett SE. Effects of ischemia and reperfusion on isolated ventricular myocytes from young adult and aged Fischer 344 rat hearts. Am J Physiol Heart Circ Physiol. 2008; 294:H2174–H2183.

14. O'Brien JD, Howlett SE. Simulated ischemia-induced preconditioning of isolated ventricular myocytes from young adult and aged Fischer-344 rat hearts. Am J Physiol Heart Circ Physiol. 2008; 295:H768–H777.

15. Whittington HJ, Harding I, Stephenson CI, Bell R, Hausenloy DJ, Mocanu MM, Yellon DM. Cardioprotection in the aging, diabetic heart: the loss of protective Akt signalling. Cardiovasc Res. 2013; 99:694–704.

16. Przyklenk K, Maynard M, Darling CE, Whittaker P. Aging mouse hearts are refractory to infarct size reduction with post-conditioning. J Am Coll Cardiol. 2008; 51:1393–1398.

17. Behmenburg F, Heinen A, Bruch LV, Hollmann MW, Huhn R. Cardioprotection by remote ischemic preconditioning is blocked in the aged rat heart in vivo. J Cardiothorac Vasc Anesth. 2017; 31:1223–1226.

18. Tofler GH, Muller JE, Stone PH, Willich SN, Davis VG, Poole WK, Braunwald E. Factors leading to shorter survival after acute myocardial infarction in patients ages 65 to 75 years compared with younger patients. Am J Cardiol. 1988; 62:860–867.

19. Abete P, Cioppa A, Calabrese C, Pascucci I, Cacciatore F, Napoli C, Carnovale V, Ferrara N, Rengo F. Ischemic threshold and myocardial stunning in the aging heart. Exp Gerontol. 1999; 34:875–884.

20. Boengler K, Schulz R, Heusch G. Loss of cardioprotection with ageing. Cardiovasc Res. 2009; 83:247–261.

21. Lesnefsky EJ, Gallo DS, Ye J, Whittingham TS, Lust WD. Aging increases ischemia-reperfusion injury in the isolated, buffer-perfused heart. J Lab Clin Med. 1994; 124:843–851.

22. Tani M, Suganuma Y, Hasegawa H, Shinmura K, Ebihara Y, Hayashi Y, Guo X, Takayama M. Decrease in ischemic tolerance with aging in isolated perfused Fischer 344 rat hearts: relation to increases in intracellular Na+ after ischemia. J Mol Cell Cardiol. 1997; 29:3081–3089.

23. Azhar G, Gao W, Liu L, Wei JY. Ischemia-reperfusion in the adult mouse heart influence of age. Exp Gerontol. 1999; 34:699–714.

24. Willems L, Zatta A, Holmgren K, Ashton KJ, Headrick JP. Age-related changes in ischemic tolerance in male and female mouse hearts. J Mol Cell Cardiol. 2005; 38:245–256.

25. Mariani J, Ou R, Bailey M, Rowland M, Nagley P, Rosenfeldt F, Pepe S. Tolerance to ischemia and hypoxia is reduced in aged human myocardium. J Thorac Cardiovasc Surg. 2000; 120:660–667.

26. Fenton RA, Dickson EW, Meyer TE, Dobson JG Jr. Aging reduces the cardioprotective effect of ischemic preconditioning in the rat heart. J Mol Cell Cardiol. 2000; 32:1371–1375.

27. Schulman D, Latchman DS, Yellon DM. Effect of aging on the ability of preconditioning to protect rat hearts from ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol. 2001; 281:H1630–H1636.

28. Tani M, Honma Y, Takayama M, Hasegawa H, Shinmura K, Ebihara Y, Tamaki K. Loss of protection by hypoxic preconditioning in aging Fischer 344 rat hearts related to myocardial glycogen content and Na+ imbalance. Cardiovasc Res. 1999; 41:594–602.

29. Boengler K, Konietzka I, Buechert A, Heinen Y, Garcia-Dorado D, Heusch G, Schulz R. Loss of ischemic preconditioning's cardioprotection in aged mouse hearts is associated with reduced gap junctional and mitochondrial levels of connexin 43. Am J Physiol Heart Circ Physiol. 2007; 292:H1764–H1769.

30. McCully JD, Uematsu M, Parker RA, Levitsky S. Adenosine-enhanced ischemic preconditioning provides enhanced postischemic recovery and limitation of infarct size in the rabbit heart. J Thorac Cardiovasc Surg. 1998; 116:154–162.

31. McCully JD, Uematsu M, Parker RA, Levitsky S. Adenosine-enhanced ischemic preconditioning provides enhanced cardioprotection in the aged heart. Ann Thorac Surg. 1998; 66:2037–2043.

32. Hata K, Whittaker P, Kloner RA, Przyklenk K. Brief antecedent ischemia attenuates platelet-mediated thrombosis in damaged and stenotic canine coronary arteries: role of adenosine. Circulation. 1998; 97:692–702.

33. Przyklenk K, Whittaker P. In vitro platelet responsiveness to adenosine-mediated “preconditioning” is age-dependent. J Thromb Thrombolysis. 2005; 19:5–10.

34. Abete P, Ferrara N, Cacciatore F, Madrid A, Bianco S, Calabrese C, Napoli C, Scognamiglio P, Bollella O, Cioppa A, Longobardi G, Rengo F. Angina-induced protection against myocardial infarction in adult and elderly patients: a loss of preconditioning mechanism in the aging heart? J Am Coll Cardiol. 1997; 30:947–954.

35. Wu ZK, Pehkonen E, Laurikka J, Kaukinen L, Honkonen EL, Kaukinen S, Laippala P, Tarkka MR. The protective effects of preconditioning decline in aged patients undergoing coronary artery bypass grafting. J Thorac Cardiovasc Surg. 2001; 122:972–978.

36. Bartling B, Friedrich I, Silber RE, Simm A. Ischemic preconditioning is not cardioprotective in senescent human myocardium. Ann Thorac Surg. 2003; 76:105–111.

37. van den Munckhof I, Riksen N, Seeger JP, Schreuder TH, Borm GF, Eijsvogels TM, Hopman MT, Rongen GA, Thijssen DH. Aging attenuates the protective effect of ischemic preconditioning against endothelial ischemia-reperfusion injury in humans. Am J Physiol Heart Circ Physiol. 2013; 304:H1727–H1732.

38. Loubani M, Ghosh S, Galiñanes M. The aging human myocardium: tolerance to ischemia and responsiveness to ischemic preconditioning. J Thorac Cardiovasc Surg. 2003; 126:143–147.

39. 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. ERICCA Trial Investigators. Remote ischemic preconditioning and outcomes of cardiac surgery. N Engl J Med. 2015; 373:1408–1417.

40. Sniecinski R, Liu H. Reduced efficacy of volatile anesthetic preconditioning with advanced age in isolated rat myocardium. Anesthesiology. 2004; 100:589–597.

41. Peart JN, Gross GJ. Chronic exposure to morphine produces a marked cardioprotective phenotype in aged mouse hearts. Exp Gerontol. 2004; 39:1021–1026.

42. Nguyen LT, Rebecchi MJ, Moore LC, Glass PS, Brink PR, Liu L. Attenuation of isoflurane-induced preconditioning and reactive oxygen species production in the senescent rat heart. Anesth Analg. 2008; 107:776–782.

43. Li H, Zhou C, Chen D, Fang N, Yao Y, Li L. Failure to protect against myocardial ischemia-reperfusion injury with sevoflurane postconditioning in old rats in vivo. Acta Anaesthesiol Scand. 2013; 57:1024–1031.

44. Jiang JJ, Li C, Li H, Zhang L, Lin ZH, Fu BJ, Zeng YM. Sevoflurane postconditioning affects post-ischaemic myocardial mitochondrial ATP-sensitive potassium channel function and apoptosis in ageing rats. Clin Exp Pharmacol Physiol. 2016; 43:552–561.

45. Boengler K, Buechert A, Heinen Y, Roeskes C, Hilfiker-Kleiner D, Heusch G, Schulz R. Cardioprotection by ischemic postconditioning is lost in aged and STAT3-deficient mice. Circ Res. 2008; 102:131–135.

46. Zhai P, Eurell TE, Cotthaus R, Jeffery EH, Bahr JM, Gross DR. Effect of estrogen on global myocardial ischemia-reperfusion injury in female rats. Am J Physiol Heart Circ Physiol. 2000; 279:H2766–H2775.

47. Korzick DH, Lancaster TS. Age-related differences in cardiac ischemia-reperfusion injury: effects of estrogen deficiency. Pflugers Arch. 2013; 465:669–685.

48. Xu Y, Armstrong SJ, Arenas IA, Pehowich DJ, Davidge ST. Cardioprotection by chronic estrogen or superoxide dismutase mimetic treatment in the aged female rat. Am J Physiol Heart Circ Physiol. 2004; 287:H165–H171.

49. Murphy E, Steenbergen C. Gender-based differences in mechanisms of protection in myocardial ischemia-reperfusion injury. Cardiovasc Res. 2007; 75:478–486.

50. Novotny JL, Simpson AM, Tomicek NJ, Lancaster TS, Korzick DH. Rapid estrogen receptor-alpha activation improves ischemic tolerance in aged female rats through a novel protein kinase C epsilon-dependent mechanism. Endocrinology. 2009; 150:889–896.

51. Node K, Kitakaze M, Kosaka H, Minamino T, Funaya H, Hori M. Amelioration of ischemia- and reperfusion-induced myocardial injury by 17beta-estradiol: role of nitric oxide and calcium-activated potassium channels. Circulation. 1997; 96:1953–1963.

52. Ostadal B, Ostadal P. Sex-based differences in cardiac ischaemic injury and protection: therapeutic implications. Br J Pharmacol. 2014; 171:541–554.

53. Schierbeck LL, Rejnmark L, Tofteng CL, Stilgren L, Eiken P, Mosekilde L, Køber L, Jensen JE. Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial. BMJ. 2012; 345:e6409.

54. Morkuniene R, Arandarcikaite O, Borutaite V. Estradiol prevents release of cytochrome c from mitochondria and inhibits ischemia-induced apoptosis in perfused heart. Exp Gerontol. 2006; 41:704–708.

55. Kam KW, Qi JS, Chen M, Wong TM. Estrogen reduces cardiac injury and expression of beta1-adrenoceptor upon ischemic insult in the rat heart. J Pharmacol Exp Ther. 2004; 309:8–15.

56. Negoro S, Kunisada K, Tone E, Funamoto M, Oh H, Kishimoto T, Yamauchi-Takihara K. Activation of JAK/STAT pathway transduces cytoprotective signal in rat acute myocardial infarction. Cardiovasc Res. 2000; 47:797–805.

57. Osugi T, Oshima Y, Fujio Y, Funamoto M, Yamashita A, Negoro S, Kunisada K, Izumi M, Nakaoka Y, Hirota H, Okabe M, Yamauchi-Takihara K, Kawase I, Kishimoto T. Cardiac-specific activation of signal transducer and activator of transcription 3 promotes vascular formation in the heart. J Biol Chem. 2002; 277:6676–6681.

58. Ferdinandy P, Schulz R, Baxter GF. Interaction of cardiovascular risk factors with myocardial ischemia/reperfusion injury, preconditioning, and postconditioning. Pharmacol Rev. 2007; 59:418–458.

59. Hilfiker-Kleiner D, Hilfiker A, Fuchs M, Kaminski K, Schaefer A, Schieffer B, Hillmer A, Schmiedl A, Ding Z, Podewski E, Podewski E, Poli V, Schneider MD, Schulz R, Park JK, Wollert KC, Drexler H. Signal transducer and activator of transcription 3 is required for myocardial capillary growth, control of interstitial matrix deposition, and heart protection from ischemic injury. Circ Res. 2004; 95:187–195.

60. Oshima Y, Fujio Y, Nakanishi T, Itoh N, Yamamoto Y, Negoro S, Tanaka K, Kishimoto T, Kawase I, Azuma J. STAT3 mediates cardioprotection against ischemia/reperfusion injury through metallothionein induction in the heart. Cardiovasc Res. 2005; 65:428–435.

61. Wohlgemuth SE, Calvani R, Marzetti E. The interplay between autophagy and mitochondrial dysfunction in oxidative stress-induced cardiac aging and pathology. J Mol Cell Cardiol. 2014; 71:62–70.

62. Taneike M, Yamaguchi O, Nakai A, Hikoso S, Takeda T, Mizote I, Oka T, Tamai T, Oyabu J, Murakawa T, Nishida K, Shimizu T, Hori M, Komuro I, Takuji Shirasawa TS, Mizushima N, Otsu K. Inhibition of autophagy in the heart induces age-related cardiomyopathy. Autophagy. 2010; 6:600–606.

63. Biala AK, Dhingra R, Kirshenbaum LA. Mitochondrial dynamics: Orchestrating the journey to advanced age. J Mol Cell Cardiol. 2015; 83:37–43.

64. Dutta D, Calvani R, Bernabei R, Leeuwenburgh C, Marzetti E. Contribution of impaired mitochondrial autophagy to cardiac aging: mechanisms and therapeutic opportunities. Circ Res. 2012; 110:1125–1138.

65. Fernandez-Sanz C, Ruiz-Meana M, Castellano J, Miro-Casas E, Nuñez E, Inserte J, Vázquez J, Garcia-Dorado D. Altered FoF1 ATP synthase and susceptibility to mitochondrial permeability transition pore during ischaemia and reperfusion in aging cardiomyocytes. Thromb Haemost. 2015; 113:441–451.

66. Duicu OM, Mirica SN, Gheorgheosu DE, Privistirescu AI, Fira-Mladinescu O, Muntean DM. Ageing-induced decrease in cardiac mitochondrial function in healthy rats. Can J Physiol Pharmacol. 2013; 91:593–600.

67. Rahman S, Li J, Bopassa JC, Umar S, Iorga A, Partownavid P, Eghbali M. Phosphorylation of GSK-3β mediates intralipid-induced cardioprotection against ischemia/reperfusion injury. Anesthesiology. 2011; 115:242–253.

68. Gao HK, Yin Z, Zhou N, Feng XY, Gao F, Wang HC. Glycogen synthase kinase 3 inhibition protects the heart from acute ischemia-reperfusion injury via inhibition of inflammation and apoptosis. J Cardiovasc Pharmacol. 2008; 52:286–292.

69. Peart JN, Pepe S, Reichelt ME, Beckett N, See Hoe L, Ozberk V, Niesman IR, Patel HH, Headrick JP. Dysfunctional survival-signaling and stress-intolerance in aged murine and human myocardium. Exp Gerontol. 2014; 50:72–81.

70. Zhu J, Rebecchi MJ, Glass PS, Brink PR, Liu L. Cardioprotection of the aged rat heart by GSK-3beta inhibitor is attenuated: age-related changes in mitochondrial permeability transition pore modulation. Am J Physiol Heart Circ Physiol. 2011; 300:H922–H930.

71. Hunter JC, Kostyak JC, Novotny JL, Simpson AM, Korzick DH. Estrogen deficiency decreases ischemic tolerance in the aged rat heart: Roles of PKCdelta, PKCepsilon, Akt, and GSK3beta. Am J Physiol Regul Integr Comp Physiol. 2007; 292:R800–R809.

72. Yoshioka J, Lee RT. Thioredoxin-interacting protein and myocardial mitochondrial function in ischemia-reperfusion injury. Trends Cardiovasc Med. 2014; 24:75–80.

73. Zhang H, Tao L, Jiao X, Gao E, Lopez BL, Christopher TA, Koch W, Ma XL. Nitrative thioredoxin inactivation as a cause of enhanced myocardial ischemia/reperfusion injury in the aging heart. Free Radic Biol Med. 2007; 43:39–47.

74. Meldrum DR, Cleveland JC Jr, Sheridan BC, Rowland RT, Banerjee A, Harken AH. Differential effects of adenosine preconditioning on the postischemic rat myocardium. J Surg Res. 1996; 65:159–164.

75. Liem DA, Verdouw PD, Ploeg H, Kazim S, Duncker DJ. Sites of action of adenosine in interorgan preconditioning of the heart. Am J Physiol Heart Circ Physiol. 2002; 283:H29–H37.

76. Centelles JJ, Cascante M, Canela EI, Franco R. A model for adenosine transport and metabolism. Biochem J. 1992; 287(Pt 2):461–472.

77. Lorbar M, Fenton RA, Duffy AJ, Graybill CA, Dobson JG Jr. Effect of aging on myocardial adenosine production, adenosine uptake and adenosine kinase activity in rats. J Mol Cell Cardiol. 1999; 31:401–412.

78. Dobson JG Jr, Fenton RA. Adenosine inhibition of beta-adrenergic induced responses in aged hearts. Am J Physiol. 1993; 265(2 Pt 2):H494–H503.

79. Fenton RA, Dobson JG Jr. Reduced adenosine release from the aged mammalian heart. J Cell Physiol. 2012; 227:3709–3714.

80. Jenner TL, Mellick AS, Harrison GJ, Griffiths LR, Rose'Meyer RB. Age-related changes in cardiac adenosine receptor expression. Mech Ageing Dev. 2004; 125:211–217.

81. Cai G, Wang HY, Gao E, Horwitz J, Snyder DL, Pelleg A, Roberts J, Friedman E. Reduced adenosine A1 receptor and G alpha protein coupling in rat ventricular myocardium during aging. Circ Res. 1997; 81:1065–1071.

82. Headrick JP, Willems L, Ashton KJ, Holmgren K, Peart J, Matherne GP. Ischaemic tolerance in aged mouse myocardium: the role of adenosine and effects of A1 adenosine receptor overexpression. J Physiol. 2003; 549(Pt 3):823–833.

83. Narayan P, Mentzer RM Jr, Lasley RD. Adenosine A1 receptor activation reduces reactive oxygen species and attenuates stunning in ventricular myocytes. J Mol Cell Cardiol. 2001; 33:121–129.

84. Bejma J, Ramires P, Ji LL. Free radical generation and oxidative stress with ageing and exercise: differential effects in the myocardium and liver. Acta Physiol Scand. 2000; 169:343–351.

85. Olmos Y, Valle I, Borniquel S, Tierrez A, Soria E, Lamas S, Monsalve M. Mutual dependence of Foxo3a and PGC-1alpha in the induction of oxidative stress genes. J Biol Chem. 2009; 284:14476–14484.

86. Lucas DT, Szweda LI. Cardiac reperfusion injury: aging, lipid peroxidation, and mitochondrial dysfunction. Proc Natl Acad Sci U S A. 1998; 95:510–514.

87. Lesnefsky EJ, Minkler P, Hoppel CL. Enhanced modification of cardiolipin during ischemia in the aged heart. J Mol Cell Cardiol. 2009; 46:1008–1015.

88. Boengler K, Dodoni G, Rodriguez-Sinovas A, Cabestrero A, Ruiz-Meana M, Gres P, Konietzka I, Lopez-Iglesias C, Garcia-Dorado D, Di Lisa F, Heusch G, Schulz R. Connexin 43 in cardiomyocyte mitochondria and its increase by ischemic preconditioning. Cardiovasc Res. 2005; 67:234–244.

89. Schwanke U, Konietzka I, Duschin A, Li X, Schulz R, Heusch G. No ischemic preconditioning in heterozygous connexin43-deficient mice. Am J Physiol Heart Circ Physiol. 2002; 283:H1740–H1742.

90. Heinzel FR, Luo Y, Li X, Boengler K, Buechert A, García-Dorado D, Di Lisa F, Schulz R, Heusch G. Impairment of diazoxide-induced formation of reactive oxygen species and loss of cardioprotection in connexin 43 deficient mice. Circ Res. 2005; 97:583–586.

91. Li X, Heinzel FR, Boengler K, Schulz R, Heusch G. Role of connexin 43 in ischemic preconditioning does not involve intercellular communication through gap junctions. J Mol Cell Cardiol. 2004; 36:161–163.

92. Yang C, Talukder MA, Varadharaj S, Velayutham M, Zweier JL. Early ischaemic preconditioning requires Akt- and PKA-mediated activation of eNOS via serine1176 phosphorylation. Cardiovasc Res. 2013; 97:33–43.

93. Hausenloy DJ, Tsang A, Mocanu MM, Yellon DM. Ischemic preconditioning protects by activating prosurvival kinases at reperfusion. Am J Physiol Heart Circ Physiol. 2005; 288:H971–H976.

94. Tsang A, Hausenloy DJ, Mocanu MM, Carr RD, Yellon DM. Preconditioning the diabetic heart: the importance of Akt phosphorylation. Diabetes. 2005; 54:2360–2364.

95. Ledvenyiova V, Pancza D, Matejiková J, Ferko M, Bernatova I, Ravingerova T. Impact of age and sex on response to ischemic preconditioning in the rat heart: differential role of the PI3K-AKT pathway. Can J Physiol Pharmacol. 2013; 91:640–647.

96. Tani M, Honma Y, Hasegawa H, Tamaki K. Direct activation of mitochondrial K(ATP) channels mimics preconditioning but protein kinase C activation is less effective in middle-aged rat hearts. Cardiovasc Res. 2001; 49:56–68.

97. Barry SP, Townsend PA, Latchman DS, Stephanou A. Role of the JAK-STAT pathway in myocardial injury. Trends Mol Med. 2007; 13:82–89.

98. Hattori R, Maulik N, Otani H, Zhu L, Cordis G, Engelman RM, Siddiqui MA, Das DK. Role of STAT3 in ischemic preconditioning. J Mol Cell Cardiol. 2001; 33:1929–1936.

99. Smith RM, Suleman N, Lacerda L, Opie LH, Akira S, Chien KR, Sack MN. Genetic depletion of cardiac myocyte STAT-3 abolishes classical preconditioning. Cardiovasc Res. 2004; 63:611–616.

100. Signore S, Sorrentino A, Borghetti G, Cannata A, Meo M, Zhou Y, Kannappan R, Pasqualini F, O'Malley H, Sundman M, Tsigkas N, Zhang E, Arranto C, Mangiaracina C, Isobe K, Sena BF, Kim J, Goichberg P, Nahrendorf M, Isom LL, Leri A, Anversa P, Rota M. Late Na+ current and protracted electrical recovery are critical determinants of the aging myopathy. Nat Commun. 2015; 6:8803.

101. Schilling JM, Roth DM, Patel HH. Caveolins in cardioprotection - translatability and mechanisms. Br J Pharmacol. 2015; 172:2114–2125.

102. Sun J, Nguyen T, Kohr MJ, Murphy E. Cardioprotective role of caveolae in ischemia-reperfusion injury. Transl Med (Sunnyvale). 2013; 3:1000114. DOI: 10.4172/2161-1025.1000114.

103. Ajmani P, Yadav HN, Singh M, Sharma PL. Possible involvement of caveolin in attenuation of cardioprotective effect of ischemic preconditioning in diabetic rat heart. BMC Cardiovasc Disord. 2011; 11:43.

104. Goyal A, Semwal BC, Yadav HN. Abrogated cardioprotective effect of ischemic preconditioning in ovariectomized rat heart. Hum Exp Toxicol. 2016; 35:644–653.

105. Ratajczak P, Damy T, Heymes C, Oliviéro P, Marotte F, Robidel E, Sercombe R, Boczkowski J, Rappaport L, Samuel JL. Caveolin-1 and -3 dissociations from caveolae to cytosol in the heart during aging and after myocardial infarction in rat. Cardiovasc Res. 2003; 57:358–369.

106. Fenton RA, Dickson EW, Dobson JG Jr. Inhibition of phosphatase activity enhances preconditioning and limits cell death in the ischemic/reperfused aged rat heart. Life Sci. 2005; 77:3375–3388.