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Abstract
Hypoxia significantly alters cardiomyocyte metabolism, contributing to myocardial injury during ischemic events. In this study, cardiomyocytes cultured under hypoxic conditions were compared to cardiac tissues from rats subjected to experimental myocardial infarction. Both models demonstrated a metabolic shift from oxidative phosphorylation to anaerobic glycolysis, upregulation of hypoxia-inducible factor 1-alpha (HIF-1α), and increased lactate production. The in vivo model also revealed structural changes and fibrosis. Understanding these metabolic adaptations is crucial for developing therapeutic strategies aimed at preserving cardiac function during ischemia and reperfusion.
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Copyright (c) 2025 Zaman S. Hamza, Ruqaya Munther Jalil Ewadh, Raad Habeeb Al-Asadi (Author)

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References
- Su Z, Liu Y, Zhang H. Adaptive cardiac metabolism under chronic hypoxia: mechanism and clinical implications. Front Cell Dev Biol. 2021;9:625524. https://doi.org/10.3389/fcell.2021.625524.
- Ye L, Qiu L, Zhang H, Chen H, Jiang C, Hong H, Liu J. Cardiomyocytes in young infants with congenital heart disease: a three-month window of proliferation. Sci Rep. 2016;6:23188. https://doi.org/10.1038/srep23188.
- Canseco DC, Kimura W, Garg S, Mukherjee S, Bhattacharya S, Abdisalaam S, Das S, Asaithamby A, Mammen PP, Sadek HA. Human ventricular unloading induces cardiomyocyte proliferation. J Am Coll Cardiol. 2015;65:892–900. https://doi.org/10.1016/j.jacc.2014.12.027.
- Su Z, Liu Y, Zhang H. Adaptive cardiac metabolism under chronic hypoxia: mechanism and clinical implications. Front Cell Dev Biol. 2021;9:625524. https://doi.org/10.3389/fcell.2021.625524.
- Williams AM, Levine BD, Stembridge M. A change of heart: mechanisms of cardiac adaptation to acute and chronic hypoxia. J Physiol. 2022;600:4089–4104. https://doi.org/10.1113/JP281724.
- Maufrais C, Rupp T, Bouzat P, Doucende G, Verges S, Nottin S, Walther G. Heart mechanics at high altitude: 6 days on the top of Europe. Eur Heart J Cardiovasc Imaging. 2017;18:1369–1377. https://doi.org/10.1093/ehjci/jew286.
- Sutanto H, Lyon A, Lumens J, Schotten U, Dobrev D, Heijman J. Cardiomyocyte calcium handling in health and disease: insights from in vitro and in silico studies. Prog Biophys Mol Biol. 2020;157:54–75. https://doi.org/10.1016/j.pbiomolbio.2020.02.008.
- Mitsis A, Gragnano F. Myocardial infarction with and without ST-segment elevation: a contemporary reappraisal of similarities and differences. Curr Cardiol Rev. 2021;17(4):e230421189013. https://doi.org/10.2174/1573403X1699920121019570
- Boyette LC, Manna B. Physiology, Myocardial Oxygen Demand. StatPearls Publishing LLC; 2018.
- Piquereau J, Ventura-Clapier R. Maturation of cardiac energy metabolism during perinatal development. Front Physiol. 2018;9:959. https://doi.org/10.3389/fphys.2018.00959.
- Heusch G. Myocardial ischaemia–reperfusion injury and cardioprotection in perspective. Nat Rev Cardiol. 2020;17:773–789. https://doi.org/10.1038/s41569-020-0403-y.
- Prabhakar NR, Semenza GL. Adaptive and maladaptive cardiorespiratory responses to continuous and intermittent hypoxia mediated by hypoxia-inducible factors 1 and 2. Physiol Rev. 2012;92:967–1003. https://doi.org/10.1152/physrev.00030.2011.
- Nanduri J, Semenza GL, Prabhakar NR. Epigenetic changes by DNA methylation in chronic and intermittent hypoxia. Am J Physiol Lung Cell Mol Physiol. 2017;313:L1096–L1100. https://doi.org/10.1152/ajplung.00147.2017.
- Dirscherl K, Schlapfer M, Z'graggen BR, et al. Hypoxia sensing by hepatic stellate cells leads to VEGF-dependent angiogenesis and may contribute to accelerated liver regeneration. Sci Rep. 2020;10:4392. https://doi.org/10.1038/s41598-020-61122-9.
- Su Z, Liu Y, Zhang H. Adaptive cardiac metabolism under chronic hypoxia: Mechanism and clinical implications. Front Cell Dev Biol. 2021;9:625524. https://doi.org/.3389/fcell.2021.625524
- Williams AM, Levine BD, Stembridge M. A change of heart: Mechanisms of cardiac adaptation to acute and chronic hypoxia. J Physiol. 2022;600:4089–4104. https://doi.org/10.1113/JP282672
- Piquereau J, Ventura-Clapier R. Maturation of cardiac energy metabolism during perinatal development. Front Physiol. 2018;9:959. https://doi.org/10.3389/fphys.2018.00959
- Maufrais C, Rupp T, Bouzat P, Doucende G, Verges S, Nottin S, Walther G. Heart mechanics at high altitude: 6 days on the top of Europe. Eur Heart J Cardiovasc Imaging. 2017;18:1369–1377. https://doi.org/10.1093/ehjci/jex102
- Hauton D, Al-Shammari A, Gaffney EA, Egginton S. Maternal Hypoxia Decreases Capillary Supply and Increases Metabolic Inefficiency Leading to Divergence in Myocardial Oxygen Supply and Demand. Front Physiol. 2015;6:231. https://doi.org/10.3389/fphys.2015.00231
- Williams AM, Levine BD, Stembridge M. A change of heart: Mechanisms of cardiac adaptation to acute and chronic hypoxia. J Physiol. 2022;600:4089–4104. https://doi.org/10.1113/JP282672
- Nakada Y, Canseco DC, Thet S, et al. Hypoxia induces heart regeneration in adult mice. Nature. 2017;541:222–227. https://doi.org/10.1038/nature20173.
- Norman JT, Clark IM, Garcia PL. Hypoxia promotes fibrogenesis in human renal fibroblasts. Kidney Int. 2000;58:2351–2366. https://doi.org/10.1046/j.1523-1755.2000.00323.x.
- Jiang M, Fan X, Wang Y, Sun X. Effects of hypoxia in cardiac metabolic remodeling and heart failure. Exp Cell Res. 2023;432(1):113763. https://doi.org/10.1016/j.yexcr.2023.113763
- Podkalicka P, Stępniewski J, Mucha O, Kachamakova-Trojanowska N, Dulak J, Łoboda A. Hypoxia as a driving force of pluripotent stem cell reprogramming and differentiation to endothelial cells. Biomolecules. 2020;10(12):1614. https://doi.org/10.3390/biom10121614
- Hu D, Linders A, Abir A, et al. Metabolic maturation of human pluripotent stem cell-derived cardiomyocytes by inhibition of HIF1α and LDHA. Circ Res. 2018;123(7):e30–e45.https://doi.org/10.1161/CIRCRESAHA.118.313249
- Hauton D, Al-Shammari A, Gaffney EA, Egginton S. Maternal hypoxia decreases capillary supply and increases metabolic inefficiency leading to divergence in myocardial oxygen supply and demand. PLoS One. 2015;10(6):e0127424. https://doi.org/10.1371/journal.pone.0127424
- Semenza GL, Nejfelt MK, Chi SM, et al. Hypoxia-inducible nuclear factors bind to an enhancer element located 3′ to the human erythropoietin gene. Proc Natl Acad Sci USA. 1991;88:5680–5684. https://doi.org/10.1073/pnas.88.13.5680.
- Tanaka S, Tanaka T, Nangaku M. CALL FOR PAPERS Renal Hypoxia. Hypoxia is a key player in the AKI-to-CKD transition. Am J Physiol Renal Physiol. 2014;307:F1187–F1195. https://doi.org/10.1152/ajprenal.00157.2014.
- Taylor CT, Doherty G, Fallon PG, et al. Hypoxia-dependent regulation of inflammatory pathways in immune cells. J Clin Invest. 2016;126:3716–3724. https://doi.org/10.1172/JCI86143.
- Tuder RM, Yun JH, Bhunia A, et al. Hypoxia and chronic lung disease. J Mol Med. 2007;85:1317–1324. https://doi.org/10.1007/s00109-007-0238-9.
- Niu R, et al. MicroRNA-582-5p targeting Creb1 modulates apoptosis in cardiomyocytes, hypoxia/reperfusion-induced injury. Immunity Inflamm Dis. 2022;10:e708. https://doi.org/10.1002/iid3.708.
- Ali SS, Noordin L, Bakar RA, Zainalabidin S, Jubri Z, Wan Ahmad WAN. Current updates on potential role of flavonoids in hypoxia/reoxygenation cardiac injury model. Cardiovasc Toxicol. 2021;21:605–618. https://doi.org/10.1007/s12012-021-09666-x.
- Wu JW, Hu H, Hua J, Ma LK. ATPase inhibitory factor 1 protects the heart from acute myocardial ischemia/reperfusion injury through activating the AMPK signaling pathway. Int J Biol Sci. 2022;18:731–741. https://doi.org/10.7150/ijbs.64956.
- Majmundar AJ, Wong WJ, Simon MC. Hypoxia-inducible factors and the response to hypoxic stress. Mol Cell. 2010;40:294–309. doi: https://doi.org/10.1016/j.molcel.2010.09.022.
- Hoda SA, Cheng E. Robbins Basic Pathology. Oxford University Press; 2017.
- Ojha N, Dhamoon AS, Chapagain R. Myocardial Infarction (Nursing). StatPearls Publishing; 2021.
- Laflamme MA, Murry CE. Regenerating the heart. Nat Biotechnol. 2005;23:845–855. doi: https://doi.org/10.1038/nbt1117.
- Yan GX, Lankipalli RS, Burke JF, Musco S, Kowey PR. Ventricular repolarization components on the electrocardiogram: cellular basis and clinical significance. J Am Coll Cardiol. 2003;42:401–409. https://doi.org/10.1016/S0735-1097(03)00607-7.
- Stroobandt RX, Barold SS, Sinnaeve AF. ECG from Basics to Essentials: Step by Step. John Wiley & Sons; 2016.
- Jennings RB. Historical perspective on the pathology of myocardial ischemia/reperfusion injury. Circ Res. 2013;113:428–438. https://doi.org/10.1161/CIRCRESAHA.113.300187.
- Avner BS, Shioura KM, Scruggs SB, Grachoff M, Geenen DL, Helseth DL, Farjah M, Goldspink PH, Solaro RJ. Myocardial infarction in mice alters sarcomeric function via post-translational protein modification. Mol Cell Biochem. 2012;363:203–215. https://doi.org/10.1007/s11010-011-1126-6.
- Wheaton WW, Chandel NS. Hypoxia. 2. Hypoxia regulates cellular metabolism. Am J Physiol Cell Physiol. 2011;300:C385–C393. https://doi.org/10.1152/ajpcell.00305.2010.
- Hong SJ, Gokulrangan G, Schöneich C. Proteomic analysis of age-dependent nitration of rat cardiac proteins by solution isoelectric focusing coupled to nanoHPLC tandem mass spectrometry. Exp Gerontol. 2007;42:639–651. https://doi.org/10.1016/j.exger.2006.12.004.
- Frangogiannis NG. Pathophysiology of myocardial infarction. Compr Physiol. 2015;5:1841–1875. https://doi.org/10.1002/cphy.c140047.
- Milligan LP, McBride BW. Energy costs of ion pumping by animal tissues. J Nutr. 1985 Oct;115(10):1374–82. https://doi.org/10.1093/jn/115.10.1374.
- Wang R, Wang M, He S, Sun G, Sun X. Targeting calcium homeostasis in myocardial ischemia/reperfusion injury: an overview of regulatory mechanisms and therapeutic reagents. Front Pharmacol. 2020;11:872. https://doi.org/10.3389/fphar.2020.00872
References
Su Z, Liu Y, Zhang H. Adaptive cardiac metabolism under chronic hypoxia: mechanism and clinical implications. Front Cell Dev Biol. 2021;9:625524. https://doi.org/10.3389/fcell.2021.625524.
Ye L, Qiu L, Zhang H, Chen H, Jiang C, Hong H, Liu J. Cardiomyocytes in young infants with congenital heart disease: a three-month window of proliferation. Sci Rep. 2016;6:23188. https://doi.org/10.1038/srep23188.
Canseco DC, Kimura W, Garg S, Mukherjee S, Bhattacharya S, Abdisalaam S, Das S, Asaithamby A, Mammen PP, Sadek HA. Human ventricular unloading induces cardiomyocyte proliferation. J Am Coll Cardiol. 2015;65:892–900. https://doi.org/10.1016/j.jacc.2014.12.027.
Su Z, Liu Y, Zhang H. Adaptive cardiac metabolism under chronic hypoxia: mechanism and clinical implications. Front Cell Dev Biol. 2021;9:625524. https://doi.org/10.3389/fcell.2021.625524.
Williams AM, Levine BD, Stembridge M. A change of heart: mechanisms of cardiac adaptation to acute and chronic hypoxia. J Physiol. 2022;600:4089–4104. https://doi.org/10.1113/JP281724.
Maufrais C, Rupp T, Bouzat P, Doucende G, Verges S, Nottin S, Walther G. Heart mechanics at high altitude: 6 days on the top of Europe. Eur Heart J Cardiovasc Imaging. 2017;18:1369–1377. https://doi.org/10.1093/ehjci/jew286.
Sutanto H, Lyon A, Lumens J, Schotten U, Dobrev D, Heijman J. Cardiomyocyte calcium handling in health and disease: insights from in vitro and in silico studies. Prog Biophys Mol Biol. 2020;157:54–75. https://doi.org/10.1016/j.pbiomolbio.2020.02.008.
Mitsis A, Gragnano F. Myocardial infarction with and without ST-segment elevation: a contemporary reappraisal of similarities and differences. Curr Cardiol Rev. 2021;17(4):e230421189013. https://doi.org/10.2174/1573403X1699920121019570
Boyette LC, Manna B. Physiology, Myocardial Oxygen Demand. StatPearls Publishing LLC; 2018.
Piquereau J, Ventura-Clapier R. Maturation of cardiac energy metabolism during perinatal development. Front Physiol. 2018;9:959. https://doi.org/10.3389/fphys.2018.00959.
Heusch G. Myocardial ischaemia–reperfusion injury and cardioprotection in perspective. Nat Rev Cardiol. 2020;17:773–789. https://doi.org/10.1038/s41569-020-0403-y.
Prabhakar NR, Semenza GL. Adaptive and maladaptive cardiorespiratory responses to continuous and intermittent hypoxia mediated by hypoxia-inducible factors 1 and 2. Physiol Rev. 2012;92:967–1003. https://doi.org/10.1152/physrev.00030.2011.
Nanduri J, Semenza GL, Prabhakar NR. Epigenetic changes by DNA methylation in chronic and intermittent hypoxia. Am J Physiol Lung Cell Mol Physiol. 2017;313:L1096–L1100. https://doi.org/10.1152/ajplung.00147.2017.
Dirscherl K, Schlapfer M, Z'graggen BR, et al. Hypoxia sensing by hepatic stellate cells leads to VEGF-dependent angiogenesis and may contribute to accelerated liver regeneration. Sci Rep. 2020;10:4392. https://doi.org/10.1038/s41598-020-61122-9.
Su Z, Liu Y, Zhang H. Adaptive cardiac metabolism under chronic hypoxia: Mechanism and clinical implications. Front Cell Dev Biol. 2021;9:625524. https://doi.org/.3389/fcell.2021.625524
Williams AM, Levine BD, Stembridge M. A change of heart: Mechanisms of cardiac adaptation to acute and chronic hypoxia. J Physiol. 2022;600:4089–4104. https://doi.org/10.1113/JP282672
Piquereau J, Ventura-Clapier R. Maturation of cardiac energy metabolism during perinatal development. Front Physiol. 2018;9:959. https://doi.org/10.3389/fphys.2018.00959
Maufrais C, Rupp T, Bouzat P, Doucende G, Verges S, Nottin S, Walther G. Heart mechanics at high altitude: 6 days on the top of Europe. Eur Heart J Cardiovasc Imaging. 2017;18:1369–1377. https://doi.org/10.1093/ehjci/jex102
Hauton D, Al-Shammari A, Gaffney EA, Egginton S. Maternal Hypoxia Decreases Capillary Supply and Increases Metabolic Inefficiency Leading to Divergence in Myocardial Oxygen Supply and Demand. Front Physiol. 2015;6:231. https://doi.org/10.3389/fphys.2015.00231
Williams AM, Levine BD, Stembridge M. A change of heart: Mechanisms of cardiac adaptation to acute and chronic hypoxia. J Physiol. 2022;600:4089–4104. https://doi.org/10.1113/JP282672
Nakada Y, Canseco DC, Thet S, et al. Hypoxia induces heart regeneration in adult mice. Nature. 2017;541:222–227. https://doi.org/10.1038/nature20173.
Norman JT, Clark IM, Garcia PL. Hypoxia promotes fibrogenesis in human renal fibroblasts. Kidney Int. 2000;58:2351–2366. https://doi.org/10.1046/j.1523-1755.2000.00323.x.
Jiang M, Fan X, Wang Y, Sun X. Effects of hypoxia in cardiac metabolic remodeling and heart failure. Exp Cell Res. 2023;432(1):113763. https://doi.org/10.1016/j.yexcr.2023.113763
Podkalicka P, Stępniewski J, Mucha O, Kachamakova-Trojanowska N, Dulak J, Łoboda A. Hypoxia as a driving force of pluripotent stem cell reprogramming and differentiation to endothelial cells. Biomolecules. 2020;10(12):1614. https://doi.org/10.3390/biom10121614
Hu D, Linders A, Abir A, et al. Metabolic maturation of human pluripotent stem cell-derived cardiomyocytes by inhibition of HIF1α and LDHA. Circ Res. 2018;123(7):e30–e45.https://doi.org/10.1161/CIRCRESAHA.118.313249
Hauton D, Al-Shammari A, Gaffney EA, Egginton S. Maternal hypoxia decreases capillary supply and increases metabolic inefficiency leading to divergence in myocardial oxygen supply and demand. PLoS One. 2015;10(6):e0127424. https://doi.org/10.1371/journal.pone.0127424
Semenza GL, Nejfelt MK, Chi SM, et al. Hypoxia-inducible nuclear factors bind to an enhancer element located 3′ to the human erythropoietin gene. Proc Natl Acad Sci USA. 1991;88:5680–5684. https://doi.org/10.1073/pnas.88.13.5680.
Tanaka S, Tanaka T, Nangaku M. CALL FOR PAPERS Renal Hypoxia. Hypoxia is a key player in the AKI-to-CKD transition. Am J Physiol Renal Physiol. 2014;307:F1187–F1195. https://doi.org/10.1152/ajprenal.00157.2014.
Taylor CT, Doherty G, Fallon PG, et al. Hypoxia-dependent regulation of inflammatory pathways in immune cells. J Clin Invest. 2016;126:3716–3724. https://doi.org/10.1172/JCI86143.
Tuder RM, Yun JH, Bhunia A, et al. Hypoxia and chronic lung disease. J Mol Med. 2007;85:1317–1324. https://doi.org/10.1007/s00109-007-0238-9.
Niu R, et al. MicroRNA-582-5p targeting Creb1 modulates apoptosis in cardiomyocytes, hypoxia/reperfusion-induced injury. Immunity Inflamm Dis. 2022;10:e708. https://doi.org/10.1002/iid3.708.
Ali SS, Noordin L, Bakar RA, Zainalabidin S, Jubri Z, Wan Ahmad WAN. Current updates on potential role of flavonoids in hypoxia/reoxygenation cardiac injury model. Cardiovasc Toxicol. 2021;21:605–618. https://doi.org/10.1007/s12012-021-09666-x.
Wu JW, Hu H, Hua J, Ma LK. ATPase inhibitory factor 1 protects the heart from acute myocardial ischemia/reperfusion injury through activating the AMPK signaling pathway. Int J Biol Sci. 2022;18:731–741. https://doi.org/10.7150/ijbs.64956.
Majmundar AJ, Wong WJ, Simon MC. Hypoxia-inducible factors and the response to hypoxic stress. Mol Cell. 2010;40:294–309. doi: https://doi.org/10.1016/j.molcel.2010.09.022.
Hoda SA, Cheng E. Robbins Basic Pathology. Oxford University Press; 2017.
Ojha N, Dhamoon AS, Chapagain R. Myocardial Infarction (Nursing). StatPearls Publishing; 2021.
Laflamme MA, Murry CE. Regenerating the heart. Nat Biotechnol. 2005;23:845–855. doi: https://doi.org/10.1038/nbt1117.
Yan GX, Lankipalli RS, Burke JF, Musco S, Kowey PR. Ventricular repolarization components on the electrocardiogram: cellular basis and clinical significance. J Am Coll Cardiol. 2003;42:401–409. https://doi.org/10.1016/S0735-1097(03)00607-7.
Stroobandt RX, Barold SS, Sinnaeve AF. ECG from Basics to Essentials: Step by Step. John Wiley & Sons; 2016.
Jennings RB. Historical perspective on the pathology of myocardial ischemia/reperfusion injury. Circ Res. 2013;113:428–438. https://doi.org/10.1161/CIRCRESAHA.113.300187.
Avner BS, Shioura KM, Scruggs SB, Grachoff M, Geenen DL, Helseth DL, Farjah M, Goldspink PH, Solaro RJ. Myocardial infarction in mice alters sarcomeric function via post-translational protein modification. Mol Cell Biochem. 2012;363:203–215. https://doi.org/10.1007/s11010-011-1126-6.
Wheaton WW, Chandel NS. Hypoxia. 2. Hypoxia regulates cellular metabolism. Am J Physiol Cell Physiol. 2011;300:C385–C393. https://doi.org/10.1152/ajpcell.00305.2010.
Hong SJ, Gokulrangan G, Schöneich C. Proteomic analysis of age-dependent nitration of rat cardiac proteins by solution isoelectric focusing coupled to nanoHPLC tandem mass spectrometry. Exp Gerontol. 2007;42:639–651. https://doi.org/10.1016/j.exger.2006.12.004.
Frangogiannis NG. Pathophysiology of myocardial infarction. Compr Physiol. 2015;5:1841–1875. https://doi.org/10.1002/cphy.c140047.
Milligan LP, McBride BW. Energy costs of ion pumping by animal tissues. J Nutr. 1985 Oct;115(10):1374–82. https://doi.org/10.1093/jn/115.10.1374.
Wang R, Wang M, He S, Sun G, Sun X. Targeting calcium homeostasis in myocardial ischemia/reperfusion injury: an overview of regulatory mechanisms and therapeutic reagents. Front Pharmacol. 2020;11:872. https://doi.org/10.3389/fphar.2020.00872
