Open Access
Review
Unraveling the Roles of HIF-1, HO-1, GLUT-1 and GLUT-4 in Myocardial Protection
Lionel Chong
, Nicholas Dushaj
, Ani Rakoubian
, Johnathan Yarbro
, Satoru Kobayashi
, Qiangrong Liang*
Author Information
Submitted: 23 Apr 2024 | Revised: 31 May 2024 | Accepted: 3 Jun 2024 | Published: 27 Aug 2024
Abstract
Cardiomyocytes are highly dependent on oxygen for optimal function. Disruption of oxygen availability, as in the case of ischemic heart disease, can significantly impair heart function. Moreover, comorbidities like diabetes, hyperlipidemia, and hypertension can exacerbate ischemic cardiac injury. However, cardiomyocytes possess inherent protective mechanisms that can be activated to enhance myocardial survival under such conditions. Understanding the functions and regulatory mechanisms of these cardioprotective genes is crucial for advancing our knowledge of cardiovascular health and for developing therapeutic strategies. This review examines the intricate mechanisms of cardioprotection, with a focus on key genes and proteins, including hypoxia-inducible factor-1 (HIF-1), heme oxygenase-1 (HO-1), glucose transporter 1 (GLUT-1), and GLUT-4. In addition, the review explores the roles and regulation of these factors in the heart under ischemic stress, shedding light on their relevance in conditions like diabetes, hypertension, and hyperlipidemia/atherosclerosis. Moreover, it highlights the complex interplay among their mechanisms and suggests opportunities for developing targeted therapiesfor the treatment of ischemic heart disease, hypertension, and hyperlipidemia.
Keywords
References
1.
Sowter, H.M.; Raval, R.R.; Moore, J.W.; et al. Predominant role of hypoxia-inducible transcription factor (Hif)-1alpha versus Hif-2alpha in regulation of the transcriptional response to hypoxia. Cancer Res. 2003, 63, 6130–6134.
2.
Tekin, D.; Dursun, A.D.; Xi L. Hypoxia inducible factor 1 (HIF-1) and cardioprotection. Acta Pharmacol. Sin. 2010, 31, 1085–1094.
3.
Masson, N.; Ratcliffe, P.J. HIF prolyl and asparaginyl hydroxylases in the biological response to intracellular O(2) levels. J. Cell Sci. 2003, 116, 3041–3049.
4.
Semenza, G.L. Hypoxia-inducible factor 1 and cardiovascular disease. Annu. Rev. Physiol. 2014, 76, 39–56.
5.
Ockaili, R.; Natarajan, R.; Salloum, F.; et al. HIF-1 activation attenuates postischemic myocardial injury: Role for heme oxygenase-1 in modulating microvascular chemokine generation. Am. J. Physiol. Heart Circ. Physiol. 2005, 289, H542–H548.
6.
Cai, Z.; Manalo, D.J.; Wei, G.; et al. Hearts from rodents exposed to intermittent hypoxia or erythropoietin are protected against ischemia-reperfusion injury. Circulation 2003, 108, 79–85.
7.
Natarajan, R.; Salloum, F.N.; Fisher, B.J.; et al. Hypoxia inducible factor-1 activation by prolyl 4-hydroxylase-2 gene silencing attenuates myocardial ischemia reperfusion injury. Circ. Res. 2006, 98, 133–140.
8.
Eckle, T.; Kohler, D.; Lehmann, R.; et al. Hypoxia-inducible factor-1 is central to cardioprotection: A new paradigm for ischemic preconditioning. Circulation 2008, 118, 166–175.
9.
Sarkar, K.; Cai, Z.; Gupta, R.; et al. Hypoxia-inducible factor 1 transcriptional activity in endothelial cells is required for acute phase cardioprotection induced by ischemic preconditioning. Proc. Natl. Acad. Sci. USA 2012, 109, 10504–10509.
10.
Iyer, N.V.; Kotch, L.E.; Agani, F.; et al. Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. Genes Dev. 1998, 12, 149–162.
11.
Lee, S.H.; Wolf, P.L.; Escudero, R.; et al. Early expression of angiogenesis factors in acute myocardial ischemia and infarction. N. Engl. J. Med. 2000, 342, 626–633.
12.
Cerychova, R.; Pavlinkova, G. HIF-1, Metabolism, and Diabetes in the Embryonic and Adult Heart. Front. Endocrinol. 2018, 9, 460.
13.
Zhang, Z.; Yao, L.; Yang, J.; et al. PI3K/Akt and HIF‑1 signaling pathway in hypoxia‑ischemia (Review). Mol. Med. Rep. 2018, 18, 3547–3554.
14.
Masoud, G.N.; Li W. HIF-1alpha pathway: Role, regulation and intervention for cancer therapy. Acta Pharm Sin. B 2015, 5, 378–389.
15.
Catrina, S.B.; Zheng X. Hypoxia and hypoxia-inducible factors in diabetes and its complications. Diabetologia 2021, 64, 709–716.
16.
Dodd, M.S.; Sousa Fialho, M.D.L.; Montes Aparicio, C.N.; et al. Fatty Acids Prevent Hypoxia-Inducible Factor-1alpha Signaling Through Decreased Succinate in Diabetes. JACC. Basic to translational science 2018, 3, 485–498.
17.
Marfella, R.; Esposito, K.; Nappo, F.; et al. Expression of angiogenic factors during acute coronary syndromes in human type 2 diabetes. Diabetes 2004, 53, 2383–2391.
18.
Loor, G.; Schumacker, P.T. Role of hypoxia-inducible factor in cell survival during myocardial ischemia-reperfusion. Cell. Death Differ. 2008, 15, 686–690.
19.
Zhao, X.; Liu, S.; Wang, X.; et al. Diabetic cardiomyopathy: Clinical phenotype and practice. Front. Endocrinol 2022, 13, 1032268.
20.
Sousa Fialho, M.D.L.; Abd Jamil, A.H.; Stannard, G.A.; et al. Hypoxia-inducible factor 1 signalling, metabolism and its therapeutic potential in cardiovascular disease. Biochim. Biophys. Acta Mol. Basis Dis. 2019, 1865, 831–843.
21.
Maxwell, P.H.; Eckardt, K.U. HIF prolyl hydroxylase inhibitors for the treatment of renal anaemia and beyond. Nat. Rev. Nephrol 2016, 12, 157–168.
22.
Sousa Fialho, M.D.L.; Purnama, U.; Dennis, K.; et al. Activation of HIF1alpha Rescues the Hypoxic Response and Reverses Metabolic Dysfunction in the Diabetic Heart. Diabetes 2021, 70, 2518–2531.
23.
Yeh, T.L.; Leissing, T.M.; Abboud, M.I.; et al. Molecular and cellular mechanisms of HIF prolyl hydroxylase inhibitors in clinical trials. Chem. Sci. 2017, 8, 7651–7668.
24.
Lei, L.; Mason, S.; Liu, D.; et al. Hypoxia-inducible factor-dependent degeneration, failure, and malignant transformation of the heart in the absence of the von Hippel-Lindau protein. Mol. Cell. Biol. 2008, 28, 3790–3803.
25.
Loboda, A.; Jazwa, A.; Grochot-Przeczek, A.; et al. Heme oxygenase-1 and the vascular bed: From molecular mechanisms to therapeutic opportunities. Antioxid. Redox Sign. 2008, 10, 1767–1812.
26.
Maines, M.D.; Trakshel, G.M.; Kutty, R.K. Characterization of two constitutive forms of rat liver microsomal heme oxygenase. Only one molecular species of the enzyme is inducible. The J. Biol. Chem. 1986, 261, 411–419.
27.
Iyer, S.; Woo, J.; Cornejo, M.C.; et al. Characterization and biological significance of immunosuppressive peptide D2702.75-84(E→V) binding protein. Isolation of heme oxygenase-1. J. Biol. Chem. 1998, 273, 2692–2697.
28.
Drummond, H.A.; Mitchell, Z.L.; Abraham, N.G.; et al. Targeting Heme Oxygenase-1 in Cardiovascular and Kidney Disease. Antioxidants 2019, 8, 181.
29.
Abraham, N.G.; Kappas A. Pharmacological and clinical aspects of heme oxygenase. Pharmacol. Rev. 2008, 60, 79–127.
30.
Lee, P.J.; Jiang, B.H.; Chin, B.Y.; et al. Hypoxia-inducible factor-1 mediates transcriptional activation of the heme oxygenase-1 gene in response to hypoxia. J. Biol. Chem. 1997, 272, 5375–5381.
31.
Medina, M.V.; Sapochnik, D.; Garcia Sola, M.; Coso O. Regulation of the Expression of Heme Oxygenase-1: Signal Transduction, Gene Promoter Activation, and Beyond. Antioxid. Redox Sign. 2020, 32, 1033–1044.
32.
Kawashima, A.; Oda, Y.; Yachie, A.; et al. Heme oxygenase-1 deficiency: The first autopsy case. Hum. Pathol 2002, 33, 125–130.
33.
Poss, K.D.; Tonegawa S. Reduced stress defense in heme oxygenase 1-deficient cells. Proc. Natl. Acad. Sci. USA 1997, 94, 10925–10930.
34.
Peterson, S.J.; Frishman, W.H.; Abraham, N.G. Targeting heme oxygenase: Therapeutic implications for diseases of the cardiovascular system. Cardiol. Rev. 2009, 17, 99–111.
35.
Bellner, L.; Lebovics, N.B.; Rubinstein, R.; et al. Heme Oxygenase-1 Upregulation: A Novel Approach in the Treatment of Cardiovascular Disease. Antioxid. Redox Sign. 2020, 32, 1045–1060.
36.
Otterbein, L.E.; Foresti, R.; Motterlini R. Heme Oxygenase-1 and Carbon Monoxide in the Heart: The Balancing Act Between Danger Signaling and Pro-Survival. Circ. Res. 2016, 118, 1940–1959.
37.
Shan, H.; Li, T.; Zhang, L.; et al. Heme oxygenase-1 prevents heart against myocardial infarction by attenuating ischemic injury-induced cardiomyocytes senescence. EBioMedicine 2019, 39, 59–68.
38.
Evans, J.M.; Navarro, S.; Doki, T.; et al. Gene transfer of heme oxygenase-1 using an adeno-associated virus serotype 6 vector prolongs cardiac allograft survival. J. Transplant. 2012, 2012, 740653.
39.
Hinkel, R.; Lange, P.; Petersen, B.; et al. Heme Oxygenase-1 Gene Therapy Provides Cardioprotection Via Control of Post-Ischemic Inflammation: An Experimental Study in a Pre-Clinical Pig Model. J. Am. Coll. Cardiol. 2015, 66, 154–165.
40.
Ohta, K.; Yachie, A.; Fujimoto, K.; et al. Tubular injury as a cardinal pathologic feature in human heme oxygenase-1 deficiency. Am. J. Kidney Dis. 2000, 35, 863–870.
41.
Csonka, C.; Varga, E.; Kovacs, P.; et al. Heme oxygenase and cardiac function in ischemic/reperfused rat hearts. Free Radic. Biol. Med. 1999, 27, 119–126.
42.
Raju, V.S.; Maines, M.D. Renal ischemia/reperfusion up-regulates heme oxygenase-1 (HSP32) expression and increases cGMP in rat heart. J. Pharmacol. Exp. Ther 1996, 277, 1814–1822.
43.
Zhao, Y.; Zhang, L.; Qiao, Y.; et al. Heme oxygenase-1 prevents cardiac dysfunction in streptozotocin-diabetic mice by reducing inflammation, oxidative stress, apoptosis and enhancing autophagy. PLoS ONE 2013, 8, e75927.
44.
Choi, Y.K.; Kim, Y.M. Beneficial and Detrimental Roles of Heme Oxygenase-1 in the Neurovascular System. Int J. Mol. Sci. 2022, 23, 7041.
45.
Heitmeier, M.R.; Payne, M.A.; Weinheimer, C.; et al. Metabolic and Cardiac Adaptation to Chronic Pharmacologic Blockade of Facilitative Glucose Transport in Murine Dilated Cardiomyopathy and Myocardial Ischemia. Sci. Rep. 2018, 8, 6475.
46.
Fajardo, V.M.; Feng, I.; Chen, B.Y.; et al. GLUT1 overexpression enhances glucose metabolism and promotes neonatal heart regeneration. Sci. Rep. 2021, 11, 8669.
47.
Slot, J.W.; Geuze, H.J.; Gigengack, S.; et al. Translocation of the glucose transporter GLUT4 in cardiac myocytes of the rat. Proc. Natl. Acad. Sci. USA 1991, 88, 7815–7819.
48.
Olson, A.L. Regulation of GLUT4 and Insulin-Dependent Glucose Flux. ISRN Mol. Biol 2012, 2012, 856987.
49.
Navale, A.M.; Paranjape, A.N. Glucose transporters: Physiological and pathological roles. Biophys. Rev. 2016, 8, 5–9.
50.
Wang, F.; Liang, G.Y.; Liu, D.X.; et al. Effect of Si-RNA-silenced HIF-1alpha gene on myocardial ischemia-reperfusion-induced insulin resistance. Int J. Clin. Exp. Med. 2015, 8, 15514–15520.
51.
Santalucia, T.; Moreno, H.; Palacin, M.; et al. A novel functional co-operation between MyoD, MEF2 and TRalpha1 is sufficient for the induction of GLUT4 gene transcription. J. Mol. Biol 2001, 314, 195–204.
52.
Sun, D.; Nguyen, N.; DeGrado, T.R.; et al. Ischemia induces translocation of the insulin-responsive glucose transporter GLUT4 to the plasma membrane of cardiac myocytes. Circulation 1994, 89, 793–798.
53.
Tian, R.; Abel, E.D. Responses of GLUT4-deficient hearts to ischemia underscore the importance of glycolysis. Circulation 2001, 103, 2961–2966.
54.
Egert, S.; Nguyen, N.; Brosius F.C., 3rd; et al. Effects of wortmannin on insulin- and ischemia-induced stimulation of GLUT4 translocation and FDG uptake in perfused rat hearts. Cardiovasc. Res. 1997, 35, 283–293.
55.
Marsin, A.S.; Bertrand, L.; Rider, M.H.; et al. Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia. Curr. Biol. 2000, 10, 1247–1255.
56.
Hue, L.; Beauloye, C.; Marsin, A.S.; et al. Insulin and ischemia stimulate glycolysis by acting on the same targets through different and opposing signaling pathways. J. Mol. Cell. Cardiol. 2002, 34, 1091–1097.
57.
Maria, Z.; Campolo, A.R.; Lacombe, V.A. Diabetes Alters the Expression and Translocation of the Insulin-Sensitive Glucose Transporters 4 and 8 in the Atria. PLoS ONE 2015, 10, e0146033.
58.
Dutka, D.P.; Pitt, M.; Pagano, D.; et al. Myocardial glucose transport and utilization in patients with type 2 diabetes mellitus, left ventricular dysfunction, and coronary artery disease. J. Am. Coll. Cardiol. 2006, 48, 2225–2231.
59.
Shao, D.; Tian R. Glucose Transporters in Cardiac Metabolism and Hypertrophy. Compr. Physiol. 2015, 6, 331–351.
60.
Volpe, C.M.O.; Villar-Delfino, P.H.; Dos Anjos, P.M.F.; et al. Cellular death, reactive oxygen species (ROS) and diabetic complications. Cell Death Dis. 2018, 9, 119.
61.
Davargaon, R.S.; Sambe, A.D.; Muthangi V.V.S. Trolox prevents high glucose-induced apoptosis in rat myocardial H9c2 cells by regulating GLUT-4 and antioxidant defense mechanism. IUBMB Life 2019, 71, 1876–1895.
62.
Nanduri, J.; Peng, Y.J.; Yuan, G.; et al. Hypoxia-inducible factors and hypertension: Lessons from sleep apnea syndrome. J. Mol. Med. 2015, 93, 473–480.
63.
Peng, Y.J.; Yuan, G.; Ramakrishnan, D.; et al. Heterozygous HIF-1alpha deficiency impairs carotid body-mediated systemic responses and reactive oxygen species generation in mice exposed to intermittent hypoxia. J. Physiol. 2006, 577, 705–716.
64.
Prabhakar, N.R.; Semenza, G.L. Regulation of carotid body oxygen sensing by hypoxia-inducible factors. Pflugers Arch. 2016, 468, 71–75.
65.
Pullamsetti, S.S.; Mamazhakypov, A.; Weissmann, N.; et al. Hypoxia-inducible factor signaling in pulmonary hypertension. J. Clin. Investig. 2020, 130, 5638–5651.
66.
Jiang, Y.; Zhou, Y.; Peng, G.; et al. Topotecan prevents hypoxia-induced pulmonary arterial hypertension and inhibits hypoxia-inducible factor-1alpha and TRPC channels. Int. J. Biochem. Cell. Biol. 2018, 104, 161–170.
67.
Kurosawa, R.; Satoh, K.; Kikuchi, N.; et al. Identification of Celastramycin as a Novel Therapeutic Agent for Pulmonary Arterial Hypertension. Circ. Res. 2019, 125, 309–327.
68.
Huh, J.W.; Kim, S.Y.; Lee, J.H.; et al. YC-1 attenuates hypoxia-induced pulmonary arterial hypertension in mice. Pulm. Pharmacol. Ther. 2011, 24, 638–646.
69.
Hosick, P.A.; Stec, D.E. Heme oxygenase, a novel target for the treatment of hypertension and obesity? Am. J. Physiol. Regul. Intgr. Comp. Physiol. 2012, 302, R207–R214.
70.
Li VoltiG.; Sacerdoti, D.; Di Giacomo, C.; et al. Natural heme oxygenase-1 inducers in hepatobiliary function. World J. Gastroenterol. 2008, 14, 6122–6132.
71.
Yao, Y.; Wang, W.; Li, M.; et al. Curcumin Exerts its Anti-hypertensive Effect by Down-regulating the AT1 Receptor in Vascular Smooth Muscle Cells. Sci. Rep. 2016, 6, 25579.
72.
Osei, K. Insulin resistance and systemic hypertension. Am. J. Cardiol. 1999, 84, 33J–36J.
73.
Fang, P.; He, B.; Yu, M.; et al. Treatment with celastrol protects against obesity through suppression of galanin-induced fat intake and activation of PGC-1alpha/GLUT4 axis-mediated glucose consumption. Biochim. Biophys. Acta Mol. Basis Dis. 2019, 1865, 1341–1350.
74.
Thomas, C.; Leleu, D.; Masson D. Cholesterol and HIF-1alpha: Dangerous Liaisons in Atherosclerosis. Front. Immunol. 2022, 13, 868958.
75.
Parathath, S.; Mick, S.L.; Feig, J.E.; et al. Hypoxia is present in murine atherosclerotic plaques and has multiple adverse effects on macrophage lipid metabolism. Circ. Res. 2011, 109, 1141–1152.
76.
Gao, L.; Chen, Q.; Zhou, X.; et al. The role of hypoxia-inducible factor 1 in atherosclerosis. J. Clin. Pathol. 2012, 65, 872–876.
77.
Aarup, A.; Pedersen, T.X.; Junker, N.; et al. Hypoxia-Inducible Factor-1alpha Expression in Macrophages Promotes Development of Atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 2016, 36, 1782–1790.
78.
Wang, P.; Zeng, G.; Yan, Y.; et al. Disruption of adipocyte HIF-1alpha improves atherosclerosis through the inhibition of ceramide generation. Acta Pharm. Sin. B 2022, 12, 1899–1912.
79.
Chaudhari, S.M.; Sluimer, J.C.; Koch, M.; et al. Deficiency of HIF1alpha in Antigen-Presenting Cells Aggravates Atherosclerosis and Type 1 T-Helper Cell Responses in Mice. Arterioscler. Thromb. Vasc. Biol. 2015, 35, 2316–2325.
80.
Rahtu-Korpela, L.; Maatta, J.; Dimova, E.Y.; et al. Hypoxia-Inducible Factor Prolyl 4-Hydroxylase-2 Inhibition Protects Against Development of Atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 2016, 36, 608–617.
81.
Araujo, J.A.; Zhang, M.; Yin F. Heme oxygenase-1, oxidation, inflammation, and atherosclerosis. Front. Pharmacol. 2012, 3, 119.
82.
Yachie, A.; Niida, Y.; Wada, T.; et al. Oxidative stress causes enhanced endothelial cell injury in human heme oxygenase-1 deficiency. J. Clin. Invest. 1999, 103, 129–135.
83.
Alonso-Pineiro, J.A.; Gonzalez-Rovira, A.; Sanchez-Gomar, I.; et al. Nrf 2 and Heme Oxygenase-1 Involvement in Atherosclerosis Related Oxidative Stress. Antioxidants 2021, 10, 1463.
84.
Ayer, A.; Zarjou, A.; Agarwal, A.; Stocker R. Heme Oxygenases in Cardiovascular Health and Disease. Physiol. Rev. 2016, 96, 1449–1508.
85.
Ishikawa, K.; Sugawara, D.; Wang, X.; et al. Heme oxygenase-1 inhibits atherosclerotic lesion formation in ldl-receptor knockout mice. Circ. Res. 2001, 88, 506–512.
86.
Loboda, A.; Damulewicz, M.; Pyza, E.; et al. Role of Nrf 2/HO-1 system in development, oxidative stress response and diseases: An evolutionarily conserved mechanism. Cell. Mol. Life Sci. 2016, 73, 3221–3247.
87.
Karampetsou, N.; Alexopoulos, L.; Minia, A.; et al. Epicardial Adipose Tissue as an Independent Cardiometabolic Risk Factor for Coronary Artery Disease. Cureus 2022, 14, e25578.
88.
Salgado-Somoza, A.; Teijeira-Fernandez, E.; Rubio, J.; et al. Coronary artery disease is associated with higher epicardial retinol-binding protein 4 (RBP4) and lower glucose transporter (GLUT) 4 levels in epicardial and subcutaneous adipose tissue. Clin. Endocrinol. 2012, 76, 51–58.
89.
Dozio, E.; Vianello, E.; Briganti, S.; et al. Expression of the Receptor for Advanced Glycation End Products in Epicardial Fat: Link with Tissue Thickness and Local Insulin Resistance in Coronary Artery Disease. J. Diabetes Res. 2016, 2016, 2327341.
90.
Kampmann, U.; Christensen, B.; Nielsen, T.S.; et al. GLUT4 and UBC9 protein expression is reduced in muscle from type 2 diabetic patients with severe insulin resistance. PLoS ONE 2011, 6, e27854.
91.
Ganjayi, M.S.; Karunakaran, R.S.; Gandham, S.; et al. Quercetin-3-O-rutinoside from Moringa oleifera Downregulates Adipogenesis and Lipid Accumulation and Improves Glucose Uptake by Activation of AMPK/Glut-4 in 3T3-L1 Cells. Rev. Bras. Farmacogn. 2023, 33, 334–343.
92.
Li, X.; Liu, J.; Lu, Q.; et al. AMPK: A therapeutic target of heart failure-not only metabolism regulation. Biosci. Rep. 2019, 39, BSR20181767.
93.
Li, L.; Aslam, M.; Siegler, B.H.; et al. Comparative Analysis of CTRP-Mediated Effects on Cardiomyocyte Glucose Metabolism: Cross Talk between AMPK and Akt Signaling Pathway. Cells 2021, 10, 905.
Issue
Volume 3, Issue 3How to Cite
Chong, L., Dushaj, N., Rakoubian, A., Yarbro, J., Kobayashi, S., & Liang, Q. (2024). Unraveling the Roles of HIF-1, HO-1, GLUT-1 and GLUT-4 in Myocardial Protection. International Journal of Drug Discovery and Pharmacology, 3(3), 100016. https://doi.org/10.53941/ijddp.2024.100016
RIS
BibTex
Copyright & License
Copyright (c) 2024 by the authors.
This work is licensed under a This work is licensed under a Creative Commons Attribution 4.0 International License.