References
1. Sachs HG, Colgan JA, Lazarus ML. Ultrastructure of the aging myocardium: A morphometric approach. Am J Anat . 1977;150(1):63-71. doi:10.1002/aja.1001500105
2. Lemieux H, Vazquez EJ, Fujioka H, Hoppel CL. Decrease in mitochondrial function in rat cardiac permeabilized fibers correlates with the aging phenotype. Journals Gerontol - Ser A Biol Sci Med Sci . 2010;65 A(11):1157-1164. doi:10.1093/gerona/glq141
3. Ma X, Liu H, Foyil SR, et al. Impaired Autophagosome Clearance Contributes to Cardiomyocyte Death in Ischemia-Reperfusion Injury.Circulation . 2012;125(25):3170-3181. doi:10.1161/CIRCULATIONAHA.110.956839
4. Marek-Iannucci S, Thomas A, Hou J, et al. Myocardial hypothermia increases autophagic flux, mitochondrial mass and myocardial function after ischemia-reperfusion injury. Sci Rep . 2019;9(1):1-17. doi:10.1038/s41598-019-46452-w
5. Huang C, Yitzhaki S, Perry CN, et al. Autophagy induced by ischemic preconditioning is essential for cardioprotection. J Cardiovasc Transl Res . 2010;3(4):365-373. doi:10.1007/s12265-010-9189-3
6. Kanamori H, Takemura G, Goto K, et al. Autophagy limits acute myocardial infarction induced by permanent coronary artery occlusion.Am J Physiol - Hear Circ Physiol . 2011;300(6):2261-2271. doi:10.1152/ajpheart.01056.2010
7. Matsui Y, Takagi H, Qu X, et al. Distinct roles of autophagy in the heart during ischemia and reperfusion: Roles of AMP-activated protein kinase and beclin 1 in mediating autophagy. Circ Res . 2007;100(6):914-922. doi:10.1161/01.RES.0000261924.76669.36
8. Ravikumar B, Berger Z, Vacher C, O’Kane CJ, Rubinsztein DC. Rapamycin pre-treatment protects against apoptosis. Hum Mol Genet . 2006;15(7):1209-1216. doi:10.1093/hmg/ddl036
9. Loos B, Genade S, Ellis B, Lochner A, Engelbrecht AM. At the core of survival: Autophagy delays the onset of both apoptotic and necrotic cell death in a model of ischemic cell injury. Exp Cell Res . 2011;317(10):1437-1453. doi:10.1016/j.yexcr.2011.03.011
10. Leidal AM, Levine B, Debnath J. Autophagy and the cell biology of age-related disease. Nat Cell Biol . 2018;20(12):1338-1348. doi:10.1038/s41556-018-0235-8
11. Taneike M, Yamaguchi O, Nakai A, et al. Inhibition of autophagy in the heart induces age-related cardiomyopathy. Autophagy . 2010;6(5):600-606. doi:10.4161/auto.6.5.11947
12. Nakai A, Yamaguchi O, Takeda T, et al. The role of autophagy in cardiomyocytes in the basal state and in response to hemodynamic stress.Nat Med . 2007;13(5):619-624. doi:10.1038/nm1574
13. Fernández ÁF, Sebti S, Wei Y, et al. Disruption of the beclin 1/Bcl-2 autophagy regulatory complex promotes longevity in mice.Nature . 2018;558(7708):136-140. doi:10.1038/s41586-018-0162-7.Disruption
14. Clements RT, Sodha NR, Feng J, et al. Phosphorylation and translocation of heat shock protein 27 and αB-crystallin in human myocardium after cardioplegia and cardiopulmonary bypass. J Thorac Cardiovasc Surg . 2007;134(6). doi:10.1016/j.jtcvs.2007.06.026
15. Singh KK, Yanagawa B, Quan A, et al. Autophagy gene fingerprint in human ischemia and reperfusion. J Thorac Cardiovasc Surg . 2014;147(3):1065-1072.e1. doi:10.1016/j.jtcvs.2013.04.042
16. Kleinbongard P, Gedik N, Kirca M, et al. Mitochondrial and contractile function of human right atrial tissue in response to remote ischemic conditioning. J Am Heart Assoc . 2018;7(15):1-17. doi:10.1161/JAHA.118.009540
17. Storti S, Vittorini S, Iascone M, et al. Analysis of the variation in the hsp70 and hsp90alpha mRNA expression in human myocardial tissue that has undergone surgical stress. Cell Stress Chaperones . 2003;8(1):18-25.
18. Wilson PWF, Castelli WP, Kannel WB. Coronary risk prediction in adults (The Framingham Heart Study). Am J Cardiol . 1987;59(14). doi:10.1016/0002-9149(87)90165-2
19. Kiffin R, Kaushik S, Zeng M, et al. Altered dynamics of the lysosomal receptor for chaperone-mediated autophagy with age. J Cell Sci . 2007;120(5):782-791. doi:10.1242/jcs.001073
20. Barbosa MC, Grosso RA, Fader CM. Hallmarks of aging: An autophagic perspective. Front Endocrinol (Lausanne) . 2019;10(JAN):1-13. doi:10.3389/fendo.2018.00790
21. Pyo JO, Yoo SM, Ahn HH, et al. Overexpression of Atg5 in mice activates autophagy and extends lifespan. Nat Commun . 2013;4:1-9. doi:10.1038/ncomms3300
22. Jahania SM, Sengstock D, Vaitkevicius P, et al. Activation of the homeostatic intracellular repair response during cardiac surgery.J Am Coll Surg . 2013;216(4):719-726. doi:10.1016/j.jamcollsurg.2012.12.034
23. Yan Y, Finkel T. Autophagy as a regulator of cardiovascular redox homeostasis. Free Radic Biol Med . 2017;109(November 2016):108-113. doi:10.1016/j.freeradbiomed.2016.12.003
24. Huang C, Andres AM, Ratliff EP, Hernandez G, Lee P, Gottlieb RA. Preconditioning involves selective mitophagy mediated by parkin and p62/SQSTM1. PLoS One . 2011;6(6). doi:10.1371/journal.pone.0020975
25. Andres AM, Hernandez G, Lee P, et al. Mitophagy is required for acute cardioprotection by simvastatin. Antioxidants Redox Signal . 2014;21(14):1960-1973. doi:10.1089/ars.2013.5416
26. Lesnefsky EJ, Chen Q, Hoppel CL. Mitochondrial Metabolism in Aging Heart Edward. Circ Res . 2016;118(10):1593-1611. doi:10.1016/j.physbeh.2017.03.040
27. Örlander J, Kiessling K-H, Larsson L, Karlsson J, Aniansson A. Skeletal muscle metabolism and ultrastructure in relation to age in sedentary men. Acta Physiol Scand . 1978;104(3):249-261. doi:10.1111/j.1748-1716.1978.tb06277.x
28. Höhn A, König J, Grune T. Protein oxidation in aging and the removal of oxidized proteins. J Proteomics . 2013. doi:10.1016/j.jprot.2013.01.004
29. Cuervo AM, Bergamini E, Bunk ET, Droge W, Ffrench M, Terman A. Autophagy and Aging: The Importance of Maintaining “Clean” Cells.Autophagy . 2005;1(3):131-140. doi:10.4161/auto.1.3.2017
30. 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(8):1125-1138. doi:10.1161/CIRCRESAHA.111.246108.Contribution
31. Parousis A, Carter HN, Tran C, et al. Contractile activity attenuates autophagy suppression and reverses mitochondrial defects in skeletal muscle cells. Autophagy . 2018;14(11):1886-1897. doi:10.1080/15548627.2018.1491488
32. Andres AM, Tucker KC, Thomas A, et al. Mitophagy and mitochondrial biogenesis in atrial tissue of patients undergoing heart surgery with cardiopulmonary bypass. JCI Insight . 2017;2(4). doi:10.1172/jci.insight.89303
33. Heusch G, Gersh BJ. The pathophysiology of acute myocardial infarction and strategies of protection beyond reperfusion: A continual challenge. Eur Heart J . 2017;38(11):774-784. doi:10.1093/eurheartj/ehw224
34. Baines CP. How and when do myocytes die during ischemia and reperfusion: The late phase. J Cardiovasc Pharmacol Ther . 2011;16(3-4):239-243. doi:10.1177/1074248411407769
35. Paradies G, Paradies V, Ruggiero FM, Petrosillo G. Mitochondrial bioenergetics and cardiolipin alterations in myocardial ischemia-reperfusion injury: Implications for pharmacological cardioprotection. Am J Physiol - Hear Circ Physiol . 2018;315(5):H1341-H1352. doi:10.1152/ajpheart.00028.2018
36. Napolitano G, Ballabio A. TFEB at a glance. J Cell Sci . 2016;129:2475-2481.
37. Xie M, Kong Y, Tan W, et al. HDAC Inhibition Blunts Ischemia/Reperfusion Injury by Inducing Cardiomyocyte Autophagy.Circulation . 2014;129(10):1139-1151. doi:10.1161/CIRCULATIONAHA.113.002416.HDAC
Figure Legends:
Figure 1: Mitochondrial markers following ischemia-reperfusion with age. Representative western blots of mitochondrial markers pre- and post-operative in atrial samples of young and aged patients (A ). Graphical representation of changes in protein content of VDAC (B ), citrate synthase (C ), COX I (D ), COX IV (E ), and UQCRC2 (F ). Correlation between UQCRC2 protein expression and age (G).Ponceau stain was used for normalization of the data. #, effect of ischemia p<0.05; *, effect of age p<0.05; Y, young; A, aged; n=2-8. VDAC, voltage dependent anion channel; COX I, cytochrome oxidase subunit I; COX IV, cytochrome oxidase subunit IV; UQCRC2, ubiquinol-cytochrome c reductase core protein 2.
Figure 2: Autophagy markers following ischemia-reperfusion with age. Representative blots of autophagy markers pre- and post-operative in atrial tissues of young and aged patients (A ). Graphical representation of changes in protein content of the mature form of LC3, LC3-II (B ), ratio of LC3-II to I (C ), p62 (D ), Optineurin (E ), and Beclin-1 (F ). Correlation between age and Optineurin protein content based on western blot data (G ). Ponceau stain was used for normalization of the data. ##, effect of ischemia p<0.01; Y, young; A, aged; n=2-11. LC3, microtubule-associated proteins 1A/1B light chain 3B; p62, sequestosome 1.
Figure 3 : Mitophagy markers following ischemia-reperfusion with age. Representative blots of mitophagy markers pre- and post-operative in atrial tissues of young and aged patients (A ). Graphical representation of observed changes in protein content of Parkin (B ), NIX (C ). Correlation between Parkin protein content and age (G ). Ponceau stain was used for normalization of the data. φ, interaction effect p<0.05; #, effect of ischemia p<0.05; ##, effect of ischemia p<0.01; **, effect of age p<0.01; ***, effect of age p<0.001; Y, young; A, aged; n=2-11.
Figure 4: Lysosomal markers following ischemia-reperfusion with age. Representative blots of lysosomal markers pre- and post-operative in atrial tissues of young and aged patients (A ). Graphical representation of changes in protein content of TFEB (B ), TFE3 (C ), immature Cathepsin D (D ), and v-ATPase (E ). Graph of the relationship between TFEB protein content (F ), TFE3 protein content (G ) and age. Ponceau stain was used for normalization of the data. φ, interaction effect p<0.05; φφ, interaction effect p<0.01; #, effect of ischemia p<0.05; ##, effect of ischemia p<0.01; *, effect of age p<0.05; **, effect of age p<0.01; ***, effect of age p<0.001; Y, young; A, aged; n=2-11. TFEB, transcription factor EB; TFE3, transcription factor E3; v-ATPase, vacuolar-type H+ATPase.
Figure 5: Stress response markers following ischemia-reperfusion with age. Representative blots of stress response markers pre- and post-operative in atrial tissues of young and aged patients (A ). Graphical representation of changes in protein content of HSP70 (B ), Caspase-3 middle band (C ), Caspase-3 top band (D ). Ponceau stain was used for normalization of the data. Y, young; A, aged; n=5-11. HSP70, heat shock protein 70.
Table 1 : Differential responses to IR in young and aged patients. Summary of how proteins respond following IR in human atrial tissues and how age influences the overall stress response. This wide sampling of proteins illustrates a blunted response in the aged patients, which may influence the degree of recovery to IR.