Targeting Hypoxia Inducible Factors-1α As a Novel Therapy in Fibrosis

Overview

Journal Front Pharmacol

Date 2017 Jun 15

PMID 28611671

Citations 42

Authors

Anji Xiong

Yi Liu

Affiliations

Soon will be listed here.

Abstract

Fibrosis, characterized by increased extracellular matrix (ECM) deposition, and widespread vasculopathy, has the prominent trait of chronic hypoxia. Hypoxia inducible factors-1α (HIF-1α), a key transcriptional factor in response to this chronic hypoxia, is involved in fibrotic disease, such as Systemic sclerosis (SSc). The implicated function of HIF-1α in fibrosis include stimulation of excessive ECM, vascular remodeling, and futile angiogenesis with further exacerbation of chronic hypoxia and deteriorate pathofibrogenesis. This review will focus on the molecular biological behavior of HIF-1α in regulating progressive fibrosis. Better understanding of the role for HIF-1α-regulated pathways in fibrotic disease will accelerate development of novel therapeutic strategies that target HIF-1α. Such new therapeutic strategies may be particularly effective for treatment of the prototypic, multisystem fibrotic, autoimmune disease SSc.

Citing Articles

miR-210 overexpression increases pressure overload-induced cardiac fibrosis.

Zaccagnini G, Baci D, Tastsoglou S, Cozza I, Made A, Voellenkle C Noncoding RNA Res. 2025; 12:20-33.

PMID: 40034123 PMC: 11874870. DOI: 10.1016/j.ncrna.2025.01.009.

The Physiological Functions and Therapeutic Potential of Hypoxia-Inducible Factor-1α in Vascular Calcification.

Zhang Z, Wang D, Xu R, Li X, Wang Z, Zhang Y Biomolecules. 2025; 14(12.

PMID: 39766299 PMC: 11674127. DOI: 10.3390/biom14121592.

High altitudes, deeper insights: multicenter cardiovascular magnetic resonance study on hypertrophic cardiomyopathy.

Chen Z, Sun Y, Yang N, Nan J, Cao L, Zhao L Eur Radiol. 2024; .

PMID: 39741217 DOI: 10.1007/s00330-024-11305-2.

A multi-omics approach identifies the key role of disorders of sphingolipid metabolism in Ang II-induced hypertensive cardiomyopathy myocardial remodeling.

Qu Y, Ma D, Wu T, Wang H, Tian Z, Liu X Sci Rep. 2024; 14(1):30379.

PMID: 39638825 PMC: 11621778. DOI: 10.1038/s41598-024-81611-8.

The role of hypoxic microenvironment in autoimmune diseases.

Gong X, Yang S, Wang Z, Tang M Front Immunol. 2024; 15:1435306.

PMID: 39575238 PMC: 11578973. DOI: 10.3389/fimmu.2024.1435306.

References

Halberg N, Khan T, Trujillo M, Wernstedt-Asterholm I, Attie A, Sherwani S . Hypoxia-inducible factor 1alpha induces fibrosis and insulin resistance in white adipose tissue. Mol Cell Biol. 2009; 29(16):4467-83. PMC: 2725728. DOI: 10.1128/MCB.00192-09. View

LeRoy E . Systemic sclerosis. A vascular perspective. Rheum Dis Clin North Am. 1996; 22(4):675-94. DOI: 10.1016/s0889-857x(05)70295-7. View

Kahaleh M, Sherer G, LeRoy E . Endothelial injury in scleroderma. J Exp Med. 1979; 149(6):1326-35. PMC: 2184886. DOI: 10.1084/jem.149.6.1326. View

Semenza G . Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 2003; 3(10):721-32. DOI: 10.1038/nrc1187. View

Kim M, Kwon H, Lee Y, Baek J, Jang J, Lee S . Histone deacetylases induce angiogenesis by negative regulation of tumor suppressor genes. Nat Med. 2001; 7(4):437-43. DOI: 10.1038/86507. View

Ceradini D, Kulkarni A, Callaghan M, Tepper O, Bastidas N, Kleinman M . Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med. 2004; 10(8):858-64. DOI: 10.1038/nm1075. View

Higgins D, Biju M, Akai Y, Wutz A, Johnson R, Haase V . Hypoxic induction of Ctgf is directly mediated by Hif-1. Am J Physiol Renal Physiol. 2004; 287(6):F1223-32. DOI: 10.1152/ajprenal.00245.2004. View

Zhou G, Dada L, Wu M, Kelly A, Trejo H, Zhou Q . Hypoxia-induced alveolar epithelial-mesenchymal transition requires mitochondrial ROS and hypoxia-inducible factor 1. Am J Physiol Lung Cell Mol Physiol. 2009; 297(6):L1120-30. PMC: 2793183. DOI: 10.1152/ajplung.00007.2009. View

Collen D, Lijnen H . Basic and clinical aspects of fibrinolysis and thrombolysis. Blood. 1991; 78(12):3114-24. View

10.

Higgins D, Kimura K, Bernhardt W, Shrimanker N, Akai Y, Hohenstein B . Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition. J Clin Invest. 2007; 117(12):3810-20. PMC: 2082142. DOI: 10.1172/JCI30487. View

11.

Fine L, Orphanides C, Norman J . Progressive renal disease: the chronic hypoxia hypothesis. Kidney Int Suppl. 1998; 65:S74-8. View

12.

Xu W, Koeck T, Lara A, Neumann D, DiFilippo F, Koo M . Alterations of cellular bioenergetics in pulmonary artery endothelial cells. Proc Natl Acad Sci U S A. 2007; 104(4):1342-7. PMC: 1783136. DOI: 10.1073/pnas.0605080104. View

13.

Del Rey M, Izquierdo E, Caja S, Usategui A, Santiago B, Galindo M . Human inflammatory synovial fibroblasts induce enhanced myeloid cell recruitment and angiogenesis through a hypoxia-inducible transcription factor 1alpha/vascular endothelial growth factor-mediated pathway in immunodeficient mice. Arthritis Rheum. 2009; 60(10):2926-34. DOI: 10.1002/art.24844. View

14.

Oleggini R, Gastaldo N, Di Donato A . Regulation of elastin promoter by lysyl oxidase and growth factors: cross control of lysyl oxidase on TGF-beta1 effects. Matrix Biol. 2007; 26(6):494-505. DOI: 10.1016/j.matbio.2007.02.003. View

15.

Nayak B, Shanmugasundaram K, Friedrichs W, Cavaglierii R, Patel M, Barnes J . HIF-1 Mediates Renal Fibrosis in OVE26 Type 1 Diabetic Mice. Diabetes. 2016; 65(5):1387-97. PMC: 4839204. DOI: 10.2337/db15-0519. View

16.

Petersen P, Lei X, Wolf R, Rodriguez S, Tan S, Little H . CTRP7 deletion attenuates obesity-linked glucose intolerance, adipose tissue inflammation, and hepatic stress. Am J Physiol Endocrinol Metab. 2017; 312(4):E309-E325. PMC: 5406989. DOI: 10.1152/ajpendo.00344.2016. View

17.

Zhang Q, Wu Y, Ann D, Messadi D, Tuan T, Kelly A . Mechanisms of hypoxic regulation of plasminogen activator inhibitor-1 gene expression in keloid fibroblasts. J Invest Dermatol. 2004; 121(5):1005-12. DOI: 10.1046/j.1523-1747.2003.12564.x. View

18.

Sercombe L, Veerati T, Moheimani F, Wu S, Sood A, Hua S . Advances and Challenges of Liposome Assisted Drug Delivery. Front Pharmacol. 2015; 6:286. PMC: 4664963. DOI: 10.3389/fphar.2015.00286. View

19.

Pullen M, Thomas K, Wu H, Nambi P . Stimulation of Hyaluronan synthetase by platelet-derived growth factor bb in human prostate smooth muscle cells. Pharmacology. 2001; 62(2):103-6. DOI: 10.1159/000056079. View

20.

Baan C, van Gelder T, Peeters A, Mol W, Niesters H, Weimar W . Living kidney donors and hypoxia-inducible factor-1alpha. Transplantation. 2003; 75(4):570-1. DOI: 10.1097/01.TP.0000034241.55602.AD. View