Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Cardiovascular Drugs and Therapy
Published in: Cardiovascular Drugs and Therapy 6/2022

17-09-2021 | Erythropoietin | Invited Review Article

Prolyl Hydroxylase Inhibitors: a New Opportunity in Renal and Myocardial Protection

Authors: Juan Antonio Requena-Ibáñez, Carlos G. Santos-Gallego, Anderly Rodriguez-Cordero, M. Urooj Zafar, Juan José Badimon

Published in: Cardiovascular Drugs and Therapy | Issue 6/2022

Login to get access

Abstract

Hypoxia, via the activity of hypoxia-inducible factors (HIFs), plays a crucial role in fibrosis, inflammation, and oxidative injury, processes which are associated with progression of cardiovascular and kidney diseases. HIFs are key transcription heterodimers consisting of regulatory α-subunits (HIF-1α, HIF-2α, HIF-3α) and a constitutive β-subunit (HIF-β). The stability of HIFs is regulated by the prolyl hydroxylases (PHDs). Specific PHD inhibitors (PHD-i) are being investigated as a therapeutic approach to modulate the cellular signaling pathways and harness the native protective adaptive responses to hypoxia. Selective inhibition of PHD leads to the stabilization of the HIFs, which is the transcriptional gatekeeper of a multitude of genes involved in angiogenesis, energy metabolism, apoptosis, inflammation, and fibrosis. PHD-i downregulate hepcidin, improve iron absorption, and increase the endogenous production of erythropoietin. Furthermore, this pharmacological group has also been proven to ameliorate ischemic injuries in several organs, opening a new and promising field in cardiovascular research.. In this review, we present the basic and clinical potential of PHD-i treatment in different scenarios, such as ischemic heart disease, cardiac hypertrophy and heart failure, and their interplay with other pharmacological agents with proven cardiovascular benefits, such as sodium-glucose cotransporter 2 (SGLT2) inhibitors.
Literature
1.
2.
Choudhry H, Harris AL. Advances in hypoxia-inducible factor biology. Cell Metab. 2018;27(2):281–98.PubMedCrossRef
3.
4.
Kassebaum NJ, Jasrasaria R, Naghavi M, Wulf SK, Johns N, Lozano R, et al. A systematic analysis of global anemia burden from 1990 to 2010. Blood. 2014;123(5):615–24.PubMedPubMedCentralCrossRef
5.
Akizawa T, Okumura H, Alexandre AF, Fukushima A, Kiyabu G, Dorey J. Burden of anemia in chronic kidney disease patients in Japan: a literature review. Ther Apher Dial. 2018;22(5):444–56.PubMedCrossRef
6.
Locatelli F, Fishbane S, Block GA, Macdougall IC. Targeting hypoxia-inducible factors for the treatment of anemia in chronic kidney disease patients. Am J Nephrol. 2017;45(3):187–99.PubMedCrossRef
7.
8.
Yilmaz MI, Solak Y, Covic A, Goldsmith D, Kanbay M. Renal anemia of inflammation: The name is self-explanatory. Blood Purif. 2011;32(3):220–5.PubMedCrossRef
9.
10.
Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355(20):2085–98.PubMedCrossRef
11.
Szczech LA, Barnhart HX, Inrig JK, Reddan DN, Sapp S, Califf RM, et al. Secondary analysis of the CHOIR trial epoetin-alpha dose and achieved hemoglobin outcomes. Kidney Int. 2008;74(6):791–8.PubMedPubMedCentralCrossRef
12.
Pfeffer MA, Burdmann EA, Chen CY, Cooper ME, de Zeeuw D, Eckardt KU, et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med. 2009;361(21):2019–32.PubMedCrossRef
13.
Macdougall IC, Cooper AC. Hyporesponsiveness to erythropoietic therapy due to chronic inflammation. Eur J Clin Invest. 2005;35(Suppl 3):32–5.PubMedCrossRef
14.
Li ZL, Tu Y, Liu BC. Treatment of renal anemia with roxadustat: Advantages and achievement. Kidney Dis (Basel). 2020;6(2):65–73.CrossRef
15.
Pergola PE, Spinowitz BS, Hartman CS, Maroni BJ, Haase VH. Vadadustat, a novel oral HIF stabilizer, provides effective anemia treatment in nondialysis-dependent chronic kidney disease. Kidney Int. 2016;90(5):1115–22.PubMedCrossRef
16.
Yan Z, Xu G. A Novel choice to correct inflammation-induced anemia in CKD: Oral hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat. Front Med (Lausanne). 2020;7:393.CrossRef
17.
Gupta N, Wish JB. Hypoxia-inducible factor prolyl hydroxylase inhibitors: A potential new treatment for anemia in patients with CKD. Am J Kidney Dis. 2017;69(6):815–26.PubMedCrossRef
18.
19.
Packer M. Mechanisms leading to differential hypoxia-inducible factor signaling in the diabetic kidney: Modulation by SGLT2 inhibitors and hypoxia mimetics. Am J Kidney Dis. 2021;77(2):280–6.PubMedCrossRef
20.
Packer M. Role of impaired nutrient and oxygen deprivation signaling and deficient autophagic flux in diabetic CKD development: Implications for understanding the effects of sodium-glucose cotransporter 2-inhibitors. J Am Soc Nephrol. 2020;31(5):907–19.PubMedPubMedCentralCrossRef
21.
Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E, Wenger RH, et al. Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. Genes Dev. 1998;12(2):149–62.PubMedPubMedCentralCrossRef
22.
Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol. 1992;12(12):5447–54.PubMedPubMedCentral
23.
Kim JW, Tchernyshyov I, Semenza GL, Dang CV. HIF-1-mediated expression of pyruvate dehydrogenase kinase: A metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 2006;3(3):177–85.PubMedCrossRef
24.
Loboda A, Jozkowicz A, Dulak J. HIF-1 and HIF-2 transcription factors—Similar but not identical. Mol Cells. 2010;29(5):435–42.PubMedCrossRef
25.
Willam C, Maxwell PH, Nichols L, Lygate C, Tian YM, Bernhardt W, et al. HIF prolyl hydroxylases in the rat; organ distribution and changes in expression following hypoxia and coronary artery ligation. J Mol Cell Cardiol. 2006;41(1):68–77.PubMedCrossRef
26.
Hu CJ, Wang LY, Chodosh LA, Keith B, Simon MC. Differential roles of hypoxia-inducible factor 1alpha (HIF-1alpha) and HIF-2alpha in hypoxic gene regulation. Mol Cell Biol. 2003;23(24):9361–74.PubMedPubMedCentralCrossRef
27.
Tanaka T, Nangaku M. Recent advances and clinical application of erythropoietin and erythropoiesis-stimulating agents. Exp Cell Res. 2012;318(9):1068–73.PubMedCrossRef
28.
29.
Covello KL, Kehler J, Yu H, Gordan JD, Arsham AM, Hu CJ, et al. HIF-2alpha regulates Oct-4: Effects of hypoxia on stem cell function, embryonic development, and tumor growth. Genes Dev. 2006;20(5):557–70.PubMedPubMedCentralCrossRef
30.
31.
Czibik G. Complex role of the HIF system in cardiovascular biology. J Mol Med (Berl). 2010;88(11):1101–11.CrossRef
32.
Siddiq A, Aminova LR, Ratan RR. Hypoxia inducible factor prolyl 4-hydroxylase enzymes: Center stage in the battle against hypoxia, metabolic compromise and oxidative stress. Neurochem Res. 2007;32(4–5):931–46.PubMedPubMedCentralCrossRef
33.
Lieb ME, Menzies K, Moschella MC, Ni R, Taubman MB. Mammalian EGLN genes have distinct patterns of mRNA expression and regulation. Biochem Cell Biol. 2002;80(4):421–6.PubMedCrossRef
34.
Appelhoff RJ, Tian YM, Raval RR, Turley H, Harris AL, Pugh CW, et al. Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor. J Biol Chem. 2004;279(37):38458–65.PubMedCrossRef
35.
Moran AE, Forouzanfar MH, Roth GA, Mensah GA, Ezzati M, Murray CJ, et al. Temporal trends in ischemic heart disease mortality in 21 world regions, 1980 to 2010: The Global Burden of Disease 2010 study. Circulation. 2014;129(14):1483–92.PubMedPubMedCentralCrossRef
36.
Severino P, D’Amato A, Pucci M, Infusino F, Adamo F, Birtolo LI, et al. Ischemic heart disease pathophysiology paradigms overview: From plaque activation to microvascular dysfunction. Int J Mol Sci. 2020;21(21).
37.
Schreiber T, Salhofer L, Quinting T, Fandrey J. Things get broken: The hypoxia-inducible factor prolyl hydroxylases in ischemic heart disease. Basic Res Cardiol. 2019;114(3):16.PubMedCrossRef
38.
Holscher M, Silter M, Krull S, von Ahlen M, Hesse A, Schwartz P, et al. Cardiomyocyte-specific prolyl-4-hydroxylase domain 2 knock out protects from acute myocardial ischemic injury. J Biol Chem. 2011;286(13):11185–94.PubMedPubMedCentralCrossRef
39.
Shyu KG, Wang MT, Wang BW, Chang CC, Leu JG, Kuan P, et al. Intramyocardial injection of naked DNA encoding HIF-1alpha/VP16 hybrid to enhance angiogenesis in an acute myocardial infarction model in the rat. Cardiovasc Res. 2002;54(3):576–83.PubMedCrossRef
40.
Kido M, Du L, Sullivan CC, Li X, Deutsch R, Jamieson SW, et al. Hypoxia-inducible factor 1-alpha reduces infarction and attenuates progression of cardiac dysfunction after myocardial infarction in the mouse. J Am Coll Cardiol. 2005;46(11):2116–24.PubMedCrossRef
41.
Huang B, Qian J, Ma J, Huang Z, Shen Y, Chen X, et al. Myocardial transfection of hypoxia-inducible factor-1alpha and co-transplantation of mesenchymal stem cells enhance cardiac repair in rats with experimental myocardial infarction. Stem Cell Res Ther. 2014;5(1):22.PubMedPubMedCentralCrossRef
42.
Eckle T, Kohler D, Lehmann R, El Kasmi K, Eltzschig HK. Hypoxia-inducible factor-1 is central to cardioprotection: A new paradigm for ischemic preconditioning. Circulation. 2008;118(2):166–75.PubMedCrossRef
43.
Zheng J, Chen P, Zhong J, Cheng Y, Chen H, He Y, et al. HIF1alpha in myocardial ischemiareperfusion injury (Review). Mol Med Rep. 2021;23(5).
44.
Cadenas S. ROS and redox signaling in myocardial ischemia-reperfusion injury and cardioprotection. Free Radic Biol Med. 2018;117:76–89.PubMedCrossRef
45.
Deguchi H, Ikeda M, Ide T, Tadokoro T, Ikeda S, Okabe K, et al. Roxadustat markedly reduces myocardial ischemia reperfusion injury in mice. Circ J. 2020;84(6):1028–33.PubMedCrossRef
46.
Adluri RS, Thirunavukkarasu M, Dunna NR, Zhan L, Oriowo B, Takeda K, et al. Disruption of hypoxia-inducible transcription factor-prolyl hydroxylase domain-1 (PHD-1-/-) attenuates ex vivo myocardial ischemia/reperfusion injury through hypoxia-inducible factor-1alpha transcription factor and its target genes in mice. Antioxid Redox Signal. 2011;15(7):1789–97.PubMedPubMedCentralCrossRef
47.
Natarajan R, Salloum FN, Fisher BJ, Ownby ED, Kukreja RC, Fowler AA 3rd. Activation of hypoxia-inducible factor-1 via prolyl-4 hydoxylase-2 gene silencing attenuates acute inflammatory responses in postischemic myocardium. Am J Physiol Heart Circ Physiol. 2007;293(3):H1571–80.PubMedCrossRef
48.
Natarajan R, Salloum FN, Fisher BJ, Kukreja RC, Fowler AA 3rd. Hypoxia inducible factor-1 activation by prolyl 4-hydroxylase-2 gene silencing attenuates myocardial ischemia reperfusion injury. Circ Res. 2006;98(1):133–40.PubMedCrossRef
49.
Bautista L, Castro MJ, Lopez-Barneo J, Castellano A. Hypoxia inducible factor-2alpha stabilization and maxi-K+ channel beta1-subunit gene repression by hypoxia in cardiac myocytes: role in preconditioning. Circ Res. 2009;104(12):1364–72.PubMedCrossRef
50.
Kojima I, Tanaka T, Inagi R, Kato H, Yamashita T, Sakiyama A, et al. Protective role of hypoxia-inducible factor-2alpha against ischemic damage and oxidative stress in the kidney. J Am Soc Nephrol. 2007;18(4):1218–26.PubMedCrossRef
51.
Ralph GS, Parham S, Lee SR, Beard GL, Craigon MH, Ward N, et al. Identification of potential stroke targets by lentiviral vector mediated overexpression of HIF-1 alpha and HIF-2 alpha in a primary neuronal model of hypoxia. J Cereb Blood Flow Metab. 2004;24(2):245–58.PubMedCrossRef
52.
Zhou T, Chuang CC, Zuo L. Molecular Characterization of reactive oxygen species in myocardial ischemia-reperfusion injury. Biomed Res Int. 2015;2015:864946.PubMedPubMedCentralCrossRef
53.
Zhou T, Prather ER, Garrison DE, Zuo L. Interplay between ROS and antioxidants during ischemia-reperfusion injuries in cardiac and skeletal muscle. Int J Mol Sci. 2018;19(2).
54.
Oka T, Akazawa H, Naito AT, Komuro I. Angiogenesis and cardiac hypertrophy: Maintenance of cardiac function and causative roles in heart failure. Circ Res. 2014;114(3):565–71.PubMedCrossRef
55.
Sano M, Minamino T, Toko H, Miyauchi H, Orimo M, Qin Y, et al. p53-induced inhibition of Hif-1 causes cardiac dysfunction during pressure overload. Nature. 2007;446(7134):444–8.PubMedCrossRef
56.
Guo J, Mihic A, Wu J, Zhang Y, Singh K, Dhingra S, et al. Canopy 2 attenuates the transition from compensatory hypertrophy to dilated heart failure in hypertrophic cardiomyopathy. Eur Heart J. 2015;36(37):2530–40.PubMedPubMedCentralCrossRef
57.
Holscher M, Schafer K, Krull S, Farhat K, Hesse A, Silter M, et al. Unfavourable consequences of chronic cardiac HIF-1alpha stabilization. Cardiovasc Res. 2012;94(1):77–86.PubMedCrossRef
58.
Bekeredjian R, Walton CB, MacCannell KA, Ecker J, Kruse F, Outten JT, et al. Conditional HIF-1alpha expression produces a reversible cardiomyopathy. PLoS One. 2010;5(7):e11693.PubMedPubMedCentralCrossRef
59.
Lei L, Mason S, Liu D, Huang Y, Marks C, Hickey R, 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(11):3790–803.PubMedPubMedCentralCrossRef
60.
Zinman B, Lachin JM, Inzucchi SE. Empagliflozin, Cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2016;374(11):1094.PubMed
61.
Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347–57.PubMedCrossRef
62.
Neal B, Perkovic V, Matthews DR. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(21):2099.PubMed
63.
Santos-Gallego CG, Requena-Ibanez JA, San Antonio R, Garcia-Ropero A, Ishikawa K, Watanabe S, et al. Empagliflozin ameliorates diastolic dysfunction and left ventricular fibrosis/stiffness in nondiabetic heart failure: A multimodality study. JACC Cardiovasc Imaging. 2021;14(2):393–407.PubMedCrossRef
64.
Bessho R, Takiyama Y, Takiyama T, Kitsunai H, Takeda Y, Sakagami H, et al. Hypoxia-inducible factor-1alpha is the therapeutic target of the SGLT2 inhibitor for diabetic nephropathy. Sci Rep. 2019;9(1):14754.PubMedPubMedCentralCrossRef
65.
Lassila M, Fukami K, Jandeleit-Dahm K, Semple T, Carmeliet P, Cooper ME, et al. Plasminogen activator inhibitor-1 production is pathogenetic in experimental murine diabetic renal disease. Diabetologia. 2007;50(6):1315–26.PubMedCrossRef
66.
Nayak BK, Shanmugasundaram K, Friedrichs WE, Cavaglierii RC, Patel M, Barnes J, et al. HIF-1 mediates renal fibrosis in OVE26 type 1 diabetic mice. Diabetes. 2016;65(5):1387–97.PubMedPubMedCentralCrossRef
67.
Umino H, Hasegawa K, Minakuchi H, Muraoka H, Kawaguchi T, Kanda T, et al. High basolateral glucose increases sodium-glucose cotransporter 2 and reduces sirtuin-1 in renal tubules through glucose transporter-2 detection. Sci Rep. 2018;8(1):6791.PubMedPubMedCentralCrossRef
68.
Cai T, Ke Q, Fang Y, Wen P, Chen H, Yuan Q, et al. Sodium-glucose cotransporter 2 inhibition suppresses HIF-1alpha-mediated metabolic switch from lipid oxidation to glycolysis in kidney tubule cells of diabetic mice. Cell Death Dis. 2020;11(5):390.PubMedPubMedCentralCrossRef
69.
Eckardt KU, Kurtz A. Regulation of erythropoietin production. Eur J Clin Invest. 2005;35(Suppl 3):13–9.PubMedCrossRef
70.
Olmos G, Munoz-Felix JM, Mora I, Muller AG, Ruiz-Torres MP, Lopez-Novoa JM, et al. Impaired erythropoietin synthesis in chronic kidney disease is caused by alterations in extracellular matrix composition. J Cell Mol Med. 2018;22(1):302–14.PubMedCrossRef
71.
Mazer CD, Hare GMT, Connelly PW, Gilbert RE, Shehata N, Quan A, et al. Effect of empagliflozin on erythropoietin levels, iron stores, and red blood cell morphology in patients with type 2 diabetes mellitus and coronary artery disease. Circulation. 2020;141(8):704–7.PubMedCrossRef
Metadata
Title
Prolyl Hydroxylase Inhibitors: a New Opportunity in Renal and Myocardial Protection
Authors
Juan Antonio Requena-Ibáñez
Carlos G. Santos-Gallego
Anderly Rodriguez-Cordero
M. Urooj Zafar
Juan José Badimon
Publication date
17-09-2021
Publisher
Springer US
Published in
Cardiovascular Drugs and Therapy / Issue 6/2022
Print ISSN: 0920-3206
Electronic ISSN: 1573-7241
DOI
https://doi.org/10.1007/s10557-021-07257-0

Other articles of this Issue 6/2022

Cardiovascular Drugs and Therapy 6/2022 Go to the issue

Correction

Correction to: The Role of Combined SGLT1/SGLT2 Inhibition in Reducing the Incidence of Stroke and Myocardial Infarction in Patients with Type 2 Diabetes Mellitus

Correction

Correction to: Real-World Dual Antiplatelet Therapy Following Polymer-Free Sirolimus-Eluting Stent Implantations to Treat Coronary Artery Disease

Correction

Correction to: Association of Antihypertensive Agents with the Risk of In-Hospital Death in Patients with Covid-19

Editorial

Dual Anti-platelet Therapy After Transcatheter Aortic Valve Implantation: Double Trouble?

Letter to the Editor

Pharmacologic Cardioversion of Paroxysmal Atrial Fibrillation in the Emergency Department in the Novel Anticoagulants’ Era

Original Article

Switch to SGLT2 Inhibitors and Improved Endothelial Function in Diabetic Patients with Chronic Heart Failure