Effect of trimetazidine against ovarian ischemia/reperfusion injury in rat model: A new pathway: JAK2/STAT3

Document Type : Original Article


1 Department of Pharmacology, Faculty of Medicine, Tekirdag Namık Kemal University, Tekirdag, Türki̇ye

2 Department of Pharmacology, Faculty of Medicine, Ataturk University, Erzurum, Türki̇ye

3 Clinical Research, Development and Design Application and Research Center, Ataturk University, Erzurum, Türki̇ye

4 Department of Histology and Embryology, Faculty of Medicine, Kafkas University, Kars, Türki̇ye

5 Department of Pharmacology, Faculty of Pharmacy, Van Yuzuncu Yıl University, Van, Türki̇ye


Objective(s): Ovarian ischemia/reperfusion (I/R) is an extremely complex pathological problem that begins with oxygen deprivation, progresses to excessive free radical production, and intensifies inflammation. The JAK2/STAT3 signaling pathway is a multipurpose signaling transcript channel that plays a role in several biological functions. Trimetazidine (TMZ) is a cellular anti-ischemic agent. This study aims to investigate the effects of TMZ on ovarian I/R injury in rats.
Materials and Methods: sixty four rats were divided into 8 groups at random: healthy(group1); healthy+TMZ20(group2); ischemia (I) (group 3); I+TMZ10(group4); I+ TMZ20(group5); I/R(group6); I/R+TMZ10(group7); I/R+TMZ20(group8). Vascular clamps were placed just beneath the ovaries and over the uterine horns for 3 hr to induce ischemia. The clamps were removed for the reperfusion groups, and the rats were reperfused with care to ensure that the blood flowed into the ovaries, subjecting them to reperfusion for 3 hr. TMZ was administered orally by gavage 6 and 1 hr before operations. At the end of the experiment, ovarian tissues were removed for biochemical, molecular, and histopathological investigation.
Results: TMZ administration ameliorated ischemia/reperfusion-induced disturbances in GSH and MDA levels. TMZ treatment inhibited I/R-induced JAK2/STAT3 signaling pathway activation in ovarian tissues. TMZ administration also improved the increase in the mRNA expressions of IL-1β, TNF-α, and NF-κB caused by ischemia/reperfusion injury. Moreover, TMZ treatment improved histopathologic injury in ovarian tissues caused by ischemia/reperfusion.
Conclusion: TMZ treatment protected rats against ovarian ischemia/reperfusion injury by alleviating oxidative stress and inflammatory cascades. These findings may provide a mechanistic basis for using TMZ to treat ovarian ischemia-reperfusion injury.


Main Subjects

1. Demir M, Yilmaz B, Kalyoncu S, Tuncer M, Bozdag Z, Ince O, et al. Metformin reduces ovarian ischemia reperfusion injury in rats by improving oxidative/nitrosative stress. Taiwan J Obstet Gynecol 2021; 60:45-50.
2. Soares ROS, Losada DM, Jordani MC, Evora P, Castro ESO. Ischemia/reperfusion injury revisited: An overview of the latest pharmacological strategies. Int J Mol Sci 2019; 20:5034-5078.
3. Candar T, Uzunlar O, Kiseli M, Ozcan S. The effect of folate on ischemia/reperfusion injury in a rat adnexal torsion model. Arch Gynecol Obstet 2021; 303:1495-1500.
4. Eser A, Hizli D, Haltas H, Namuslu M, Kosus A, Kosus N, et al. Effects of curcumin on ovarian ischemia-reperfusion injury in a rat model. Biomed Rep 2015; 3:807-813.
5. Ozler A, Turgut A, Goruk NY, Alabalik U, Basarali MK, Akdemir F. Evaluation of the protective effects of CoQ(1)(0) on ovarian I/R injury: an experimental study. Gynecol Obstet Invest 2013; 76:100-106.
6. Kultz D. Molecular and evolutionary basis of the cellular stress response. Annu Rev Physiol 2005; 67:225-257.
7. Lagana AS, Sofo V, Salmeri FM, Palmara VI, Triolo O, Terzic MM, et al. Oxidative stress during ovarian torsion in pediatric and adolescent patients: Changing the perspective of the disease. Int J Fertil Steril 2016; 9:416-423.
8. Akhigbe R, Ajayi A. The impact of reactive oxygen species in the development of cardiometabolic disorders: A review. Lipids Health Dis 2021; 20:23-40.
9. Sengul O, Ferah I, Polat B, Halici Z, Bayir Y, Yilmaz M, et al. Blockade of endothelin receptors with bosentan limits ischaemia/reperfusion-induced injury in rat ovaries. Eur J Obstet Gynecol Reprod Biol 2013; 170:458-463.
10. Aslan M, Erkanli Senturk G, Akkaya H, Sahin S, Yilmaz B. The effect of oxytocin and Kisspeptin-10 in ovary and uterus of ischemia-reperfusion injured rats. Taiwan J Obstet Gynecol 2017; 56:456-462.
11. Nayki C, Nayki U, Keskin Cimen F, Kulhan M, Yapca OE, Kurt N, et al. The effect of rutin on ovarian ischemia-reperfusion injury in a rat model. Gynecol Endocrinol 2018; 34:809-814.
12. Villarino AV, Gadina M, O’Shea JJ, Kanno Y. SnapShot: Jak-STAT Signaling II. Cell 2020; 181:1696-1696 e1691.
13. Goodman MD, Koch SE, Fuller-Bicer GA, Butler KL. Regulating risk: A role for JAK-STAT signaling in postconditioning? Am J Physiol Heart Circ Physiol 2008; 295:H1649-1656.
14. Zhao X, Zhang E, Ren X, Bai X, Wang D, Bai L, et al. Edaravone alleviates cell apoptosis and mitochondrial injury in ischemia-reperfusion-induced kidney injury via the JAK/STAT pathway. Biol Res 2020; 53:28-39.
15. Mercantepe F, Tumkaya L, Mercantepe T, Akyildiz K, Ciftel S, Yilmaz A. The effects of dexmedetomidine on abdominal aortic occlusion-induced ovarian injury via oxidative stress and apoptosis. Cells Tissues Organs 2023.
16. Allam EA, Abdel Moniem RA, Soliman GY. Functional and structural assessment of the possible protective effect of platelet-rich plasma against ischemia/reperfusion-induced ovarian injury in adult rats. Chin J Physiol 2022; 65:64-71.
17. Peng S, Zhao M, Wan J, Fang Q, Fang D, Li K. The efficacy of trimetazidine on stable angina pectoris: a meta-analysis of randomized clinical trials. Int J Cardiol 2014; 177:780-785.
18. Dezsi CA. Trimetazidine in practice: Review of the clinical and experimental evidence. Am J Ther 2016; 23:e871-879.
19. Kim JS, Kim CH, Chun KJ, Kim JH, Park YH, Kim J, et al. Effects of trimetazidine in patients with acute myocardial infarction: data from the Korean Acute Myocardial Infarction Registry. Clin Res Cardiol 2013; 102:915-922.
20. Zheng S, Du Y, Peng Q, Fan X, Li J, Chen M. Trimetazidine protects against atherosclerosis by changing energy charge and oxidative stress. Med Sci Monit 2018; 24:8459-8468.
21. Lu S, Yu L, Liu H. Trimetazidine alleviates hypoxia/reoxygenation-induced apoptosis in neonatal mice cardiomyocytes via up-regulating HMGB1 expression to promote autophagy. J Recept Signal Transduct Res 2021; 41:170-179.
22. Engin S, Barut EN, Yasar YK, Soysal AC, Arici T, Kerimoglu G, et al. Trimetazidine attenuates cyclophosphamide-induced cystitis by inhibiting TLR4-mediated NFkappaB signaling in mice. Life Sci 2022; 301:120590.
23. Park JH, Jun JH, Shim JK, Shin EJ, Shin E, Kwak YL. Effects of post ischemia-reperfusion treatment with trimetazidine on renal injury in rats: Insights on delayed renal fibrosis progression. Oxid Med Cell Longev 2018; 2018:1072805.
24. Da Silveira M, Yoshida WB. Trimetazidine and N-acetylcysteine in attenuating hind-limb ischemia and reperfusion injuries: experimental study in rats. International Angiology 2009; 28:412-417.
25. Dhote V, Mandloi AS, Singour PK, Kawadkar M, Ganeshpurkar A, Jadhav MP. Neuroprotective effects of combined trimetazidine and progesterone on cerebral reperfusion injury. Curr Res Pharmacol Drug Discov 2022; 3:100108.
26. Chen XD, Lin S, Dai SS, Han JB, Shan PR, Wang WQ, et al. Trimetazidine affects pyroptosis by targeting GSDMD in myocardial ischemia/reperfusion injury. Inflamm Res 2022; 71:227-241.
27. Ozturk A, Topcu A, Deniz E, Ozturk SD, Arpa M, Yilmaz EK. The protective effects of trimetazidine against ovary ischemia-reperfusion injury via the TLR4/Nf-kB signal pathway. J Biochem Mol Toxicol 2022; 36:e23114.
28. Dirican AO, Doganay M, Inal HA, Yurtcu E, Togrul C, Bektas G, et al. The role of trimetazidine in ischemia/reperfusion damage treatment in an ovary torsion model experimentally induced in rats. J Obstet Gynaecol 2022; 42:2170-2177.
29. He C, Cao S, Tong Z, Wang W, Zhang Y, Guo C. Trimetazidine ameliorates myocardial ischemia-reperfusion injury. Pak J Pharm Sci 2018; 31:1691-1696.
30. Toktay E, Tastan TB, Gurbuz MA, Erbas E, Demir O, Ugan RA, et al. Potential protective effect of astaxanthin on ovary ischemia-reperfusion injury. Iran J Basic Med Sci 2022; 25:173-178.
31. Bayir Y, Cadirci E, Polat B, Kilic Baygutalp N, Albayrak A, Karakus E, et al. Aliskiren - a promising strategy for ovarian ischemia/reperfusion injury protection in rats via RAAS. Gynecol Endocrinol 2016; 32:675-683.
32. Sedlak J, Lindsay RH. Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman’s reagent. Anal Biochem 1968; 25:192-205.
33. Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 1979; 95:351-358.
34. Bayir Y, Un H, Cadirci E, Akpinar E, Diyarbakir B, Calik I, et al. Effects of Aliskiren, an RAAS inhibitor, on a carrageenan-induced pleurisy model of rats. An Acad Bras Cienc 2019; 91:e20180106.
35. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem 1951; 193:265-275.
36. Kose D, Kose A, Halici Z, Cadirci E, Tavaci T, Gurbuz MA, et al. Bosentan, a drug used in the treatment of pulmonary hypertension, can prevent development of osteoporosis. Iran J Basic Med Sci 2021; 24:922-927.
37. Cadirci E, Ugan RA, Dincer B, Gundogdu B, Cinar I, Akpinar E, et al. Urotensin receptors as a new target for CLP induced septic lung injury in mice. Naunyn Schmiedebergs Arch Pharmacol 2019; 392:135-145.
38. Sipahi H, Orak D, Reis R, Yalman K, Senol O, Palabiyik-Yucelik SS, et al. A comprehensive study to evaluate the wound healing potential of okra (Abelmoschus esculentus) fruit. J Ethnopharmacol 2022; 287:114843.
39. Kose D, Yuksel TN, Halici Z, Cadirci E, Gurbuz MA. The effects of agomelatine treatment on lipopolysaccharide-induced septic lung injuries in rats. Eurasian J Med 2021; 53:127-131.
40. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001; 25:402-408.
41. Yüksel TN, Yayla M, Duygu K, Uğan RA, Toktay E, Kiliçle PA, et al. Investigation of the protective effects of pomegranate (Punica granatum L.) Peel extract on lipopolysaccharide-induced uveitis in rats. TUJNS 2023; 24: 11-20.
42. Demir Caltekin M, Ozkut MM, Caltekin I, Kaymak E, Cakir M, Kara M, et al. The protective effect of JZL184 on ovarian ischemia reperfusion injury and ovarian reserve in rats. J Obstet Gynaecol Res 2021; 47:2692-2704.
43. Eken MK, Ersoy GS, Kaygusuz EI, Devranoglu B, Takir M, Cilingir OT, et al. Etanercept protects ovarian reserve against ischemia/reperfusion injury in a rat model. Arch Med Sci 2019; 15:1104-1112.
44. Nayki UA, Nayki C, Cetin N, Cimen FK, Coban A, Mammadov R, et al. Effect of Kineret(R) on ovarian ischemia reperfusion injury in a rat model. J Obstet Gynaecol Res 2016; 42:1525-1533.
45. Chang ZP, Deng GF, Shao YY, Xu D, Zhao YN, Sun YF, et al. Shaoyao-gancao decoction ameliorates the inflammation state in polycystic ovary syndrome rats via remodeling gut microbiota and suppressing the TLR4/NF-kappaB pathway. Front Pharmacol 2021; 12:670054.
46. Koc K, Erol HS, Colak S, Cerig S, Yildirim S, Geyikoglu F. The protective effect of propolis on rat ovary against ischemia-reperfusion injury: Immunohistochemical, biochemical and histopathological evaluations. Biomed Pharmacother 2019; 111:631-637.
47. Bostanci MS, Bakacak M, Inanc F, Yaylali A, Serin S, Attar R, et al. The protective effect of G-CSF on experimental ischemia/reperfusion injury in rat ovary. Arch Gynecol Obstet 2016; 293:789-795.
48. Agarwal A, Gupta S, Sharma RK. Role of oxidative stress in female reproduction. Reprod Biol Endocrinol 2005; 3:28-48.
49. Agarwal A, Aponte-Mellado A, Premkumar BJ, Shaman A, Gupta S. The effects of oxidative stress on female reproduction: A review. Reprod Biol Endocrinol 2012; 10:49.
50. Shoorei H, Khaki A, Ainehchi N, Hassanzadeh Taheri MM, Tahmasebi M, Seyedghiasi G, et al. Effects of matricaria chamomilla extract on growth and maturation of isolated mouse ovarian follicles in a three-dimensional culture system. Chin Med J (Engl) 2018; 131:218-225.
51. Unlubilgin E, Suleyman B, Balci G, Atakan Al R, Cankaya M, Arslan Nayki U, et al. Prevention of infertility induced by ovarian ischemia reperfusion injury by benidipine in rats: Biochemical, gene expression, histopathological and immunohistochemical evaluation. J Gynecol Obstet Hum Reprod 2017; 46:267-273.
52. Dincer B, Cinar I, Yayla M, Toktay E. Evaluation of the protective effects of gossypin for ischemia/reperfusion injury in ovary tissue. J Obstet Gynaecol Res 2022; 48:748-756.
53. Colak S, Gurlek B, Topcu A, Tumkaya L, Mercantepe T, Yilmaz A. Protective effects of nebivolol on ovarian ischemia-reperfusion injury in rat. J Obstet Gynaecol Res 2020; 46:2407-2416.
54. Barghi B, Shokoohi M, Khaki AA, Khaki A, Moghimian M, Soltani M. Eugenol improves tissue damage and oxidative stress in adult female rats after ovarian torsion/detorsion. J Obstet Gynaecol 2021; 41:933-938.
55. Hazelhoff MH, Bulacio RP, Torres AM. Trimetazidine protects from mercury-induced kidney injury. Pharmacology 2021; 106:332-340.
56. Unal D, Karatas OF, Savas M, Yeni E, Keser BS, Verit A, et al. Protective effects of trimetazidine on testicular ischemia-reperfusion injury in rats. Urol Int 2007; 78:356-362.
57. Nasser AH, Gendy AM, El-Yamany MF, El-Tanbouly DM. Upregulation of neuronal progranulin mediates the antinociceptive effect of trimetazidine in paclitaxel-induced peripheral neuropathy: Role of ERK1/2 signaling. Toxicol Appl Pharmacol 2022; 448:116096.
58. Kiu H, Nicholson SE. Biology and significance of the JAK/STAT signalling pathways. Growth Factors 2012; 30:88-106.
59. Ni Y, Low JT, Silke J, O’Reilly LA. Digesting the Role of JAK-STAT and Cytokine Signaling in Oral and Gastric Cancers. Front Immunol 2022; 13:835997.
60. Li B, Yu J, Liu P, Zeng T, Zeng X. Astragaloside IV protects cardiomyocytes against hypoxia injury via HIF-1alpha and the JAK2/STAT3 pathway. Ann Transl Med 2021; 9:1435-1449.
61. Shao F, Pang X, Baeg GH. Targeting the JAK/STAT Signaling Pathway for Breast Cancer. Curr Med Chem 2021; 28:5137-5151.
62. Fasouli ES, Katsantoni E. JAK-STAT in Early Hematopoiesis and Leukemia. Front Cell Dev Biol 2021; 9:669363.
63. Malemud CJ. The role of the JAK/STAT signal pathway in rheumatoid arthritis. Ther Adv Musculoskelet Dis 2018; 10:117-127.
64. Zhao X, Zhao B, Zhao Y, Zhang Y, Qian M. Protective effect of anisodamine on bleomycin-induced acute lung injury in immature rats via modulating oxidative stress, inflammation, and cell apoptosis by inhibiting the JAK2/STAT3 pathway. Ann Transl Med 2021; 9:859-871.
65. Tang Y, Tong X, Li Y, Jiang G, Yu M, Chen Y, et al. JAK2/STAT3 pathway is involved in the protective effects of epidermal growth factor receptor activation against cerebral ischemia/reperfusion injury in rats. Neurosci Lett 2018; 662:219-226.
66. Li CD, Zhao JY, Chen JL, Lu JH, Zhang MB, Huang Q, et al. Mechanism of the JAK2/STAT3-CAV-1-NR2B signaling pathway in painful diabetic neuropathy. Endocrine 2019; 64:55-66.
67. Zhong Y, Yin B, Ye Y, Dekhel O, Xiong X, Jian Z, et al. The bidirectional role of the JAK2/STAT3 signaling pathway and related mechanisms in cerebral ischemia-reperfusion injury. Exp Neurol 2021; 341:113690.
68. Roskoski R, Jr. Janus kinase (JAK) inhibitors in the treatment of inflammatory and neoplastic diseases. Pharmacol Res 2016; 111:784-803.
69. Liu C, Zhao Q, Zhong L, Li Q, Li R, Li S, et al. Tibetan medicine Ershiwuwei Lvxue Pill attenuates collagen-induced arthritis via inhibition of JAK2/STAT3 signaling pathway. J Ethnopharmacol 2021; 270:113820.
70. Du W, Wang N, Li F, Jia K, An J, Liu Y, et al. STAT3 phosphorylation mediates high glucose-impaired cell autophagy in an HDAC1-dependent and -independent manner in Schwann cells of diabetic peripheral neuropathy. FASEB J 2019; 33:8008-8021.
71. Satriotomo I, Bowen KK, Vemuganti R. JAK2 and STAT3 activation contributes to neuronal damage following transient focal cerebral ischemia. J Neurochem 2006; 98:1353-1368.
72. Xie HF, Xu RX, Wei JP, Jiang XD, Liu ZH. [P-JAK2 and P-STAT3 protein expression and cell apoptosis following focal cerebral ischemia-reperfusion injury in rats]. Nan Fang Yi Ke Da Xue Xue Bao 2007; 27:208-211, 218.
73. Liu H, Yao YM, Yu Y, Dong N, Yin HN, Sheng ZY. Role of Janus kinase/signal transducer and activator of transcription pathway in regulation of expression and inflammation-promoting activity of high mobility group box protein 1 in rat peritoneal macrophages. Shock 2007; 27:55-60.
74. Dong Y, Hu C, Huang C, Gao J, Niu W, Wang D, et al. Interleukin-22 plays a protective role by regulating the JAK2-STAT3 pathway to improve inflammation, oxidative stress, and neuronal apoptosis following cerebral ischemia-reperfusion injury. Mediators Inflamm 2021; 2021:6621296.
75. El-Mokadem BM, El-Abhar HS, Abdallah DM, Awad AS, Soubh AA. Epac-1/Rap-1 signaling pathway orchestrates the reno-therapeutic effect of ticagrelor against renal ischemia/reperfusion model. Biomed Pharmacother 2021; 139:111488.
76. Kong DH, Kim YK, Kim MR, Jang JH, Lee S. Emerging roles of vascular cell adhesion molecule-1 (VCAM-1) in immunological disorders and cancer. Int J Mol Sci 2018; 19.:1057-1072.
77. Akhigbe R, Ajayi A. Testicular toxicity following chronic codeine administration is via oxidative DNA damage and up-regulation of NO/TNF-alpha and caspase 3 activities. PLoS One 2020; 15:e0224052.
78. Hashmi SF, Rathore HA, Sattar MA, Johns EJ, Gan CY, Chia TY, et al. Hydrogen sulphide treatment prevents renal ischemia-reperfusion injury by inhibiting the expression of icam-1 and nf-kb concentration in normotensive and hypertensive rats. Biomolecules 2021; 11: 1549.
79. Prince PD, Rodriguez Lanzi C, Fraga CG, Galleano M. Dietary (-)-epicatechin affects NF-kappaB activation and NADPH oxidases in the kidney cortex of high-fructose-fed rats. Food Funct 2019; 10:26-32.
80. Zhang X, Jin C, Li Y, Guan S, Han F, Zhang S. Catalpol improves cholinergic function and reduces inflammatory cytokines in the senescent mice induced by D-galactose. Food Chem Toxicol 2013; 58:50-55.
81. Aydogan Kirmizi D, Baser E, Kaymak E, Kilic D, Onat T, Ozkut MM. 2-Arachidonoylglycerol activity in over ischemia reperfusion damage: Can endocannabinoids protect ovarian reserve? Cannabis Cannabinoid Res 2023.
82. Refaie MMM, El-Hussieny M, Shehata S. TLR4/NF-kappaB/TNFalpha and cAMP/SIRT1 signaling cascade involved in mediating the dose-dependent effect of cilostazol in ovarian ischemia reperfusion-induced injury. Immunopharmacol Immunotoxicol 2022; 44:338-346.
83. El-Khodary NM, Ghoneim AI, El-Tayaar AA, El-Touny EM. The impact of trimetazidine on cardiac fibrosis, inflammation, and function in ischemic cardiomyopathy patients. Cardiovasc Drugs Ther 2022.
84. Gao Y, Song G, Cao YJ, Yan KP, Li B, Zhu XF, et al. The guizhi gancao decoction attenuates myocardial ischemia-reperfusion injury by suppressing inflammation and cardiomyocyte apoptosis. Evid Based Complement Alternat Med 2019; 2019:1947465.
85. Abdelrahman RS, Abdelsalam RA, Zaghloul MS. Beneficial effect of trimetazidine on folic acid-induced acute kidney injury in mice: Role of HIF-1alpha/HO-1. J Biochem Mol Toxicol 2022; 36:e23011.
86. Tanoglu A, Yamanel L, Inal V, Ocal R, Comert B, Bilgi C. Appreciation of trimetazidine treatment in experimental sepsis rat model. Bratisl Lek Listy 2015; 116:124-127.
87. Kamranian H, Asoudeh H, Sharif RK, Taheri F, Hayes AW, Gholami M, et al. Neuroprotective potential of trimetazidine against tramadol-induced neurotoxicity: Role of pi3k/akt/mtor signaling pathways. Toxicol Mech Methods 2023:1-50.
88. Shokoohi M, Soltani M, Abtahi-Eivary S-H, Niazi V, Poor MJR, Ravaei H, et al. Effect of hydro--alcoholic extract of Olea europaea on apoptosis--related genes and oxidative stress in a rat model of torsion/detorsion--induced ovarian damage. Asian Pac J Reprod 2019; 8:148-156.
89. Sapmaz-Metin M, Topcu-Tarladacalisir Y, Uz YH, Inan M, Omurlu IK, Cerkezkayabekir A, et al. Vitamin E modulates apoptosis and c-jun N-terminal kinase activation in ovarian torsion-detorsion injury. Exp Mol Pathol 2013; 95:213-219.
90. Gharamaleki H, Parivar K, Rad JS, Roushangar L, Shariati M. Effects of extremely low-frequency electromagnetic field exposure during the prenatal period on biomarkers of oxidative stress and pathology of ovarian tissue in F1 generation. Int J Curr Res Rev 2013; 5:23-27.
91. Zhu J, Yao K, Wang Q, Guo J, Shi H, Ma L, et al. Ischemic postconditioning-regulated mir-499 protects the rat heart against ischemia/reperfusion injury by inhibiting apoptosis through PDCD4. Cell Physiol Biochem 2016; 39:2364-2380.
92. Ibanez B, Heusch G, Ovize M, Van de Werf F. Evolving therapies for myocardial ischemia/reperfusion injury. J Am Coll Cardiol 2015; 65:1454-1471.