Author + information
- aBaylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, Texas
- bImperial College, London, United Kingdom
- ↵∗Address for correspondence:
Dr. Milton Packer, Baylor Heart and Vascular Institute, 621 North Hall Street, Dallas, Texas 75226.
• HIF-1α and HIF-2α promote cellular adaptation to acute hypoxia, but during prolonged activation, these isoforms exert mutually antagonistic effects on the redox state and on proinflammatory pathways.
• Imbalances in HIF-1α and HIF-2α may contribute to the evolution and progression of chronic cardiac, vascular, and renal disorders.
• Selective activation of HIF-2α can be achieved with drugs that inhibit isoform-selective PHDs or that promote the redox sensor, SIRT-1 (e.g., SGLT2 inhibitors).
Hypoxia-inducible factor (HIF)-1α and HIF-2α promote cellular adaptation to acute hypoxia, but during prolonged activation, these isoforms exert mutually antagonistic effects on the redox state and on proinflammatory pathways. Sustained HIF-1α signaling can increase oxidative stress, inflammation, and fibrosis, actions that are opposed by HIF-2α. Imbalances in the interplay between HIF-1α and HIF-2α may contribute to the progression of chronic heart failure, atherosclerotic and hypertensive vascular disorders, and chronic kidney disease. These disorders are characterized by activation of HIF-1α and suppression of HIF-2α, which are potentially related to mitochondrial and peroxisomal dysfunction and suppression of the redox sensor, sirtuin-1. Hypoxia mimetics can potentiate HIF-1α and/or HIF-2α; ideally, such agents should act preferentially to promote HIF-2α while exerting little effect on or acting to suppress HIF-1α. Selective activation of HIF-2α can be achieved with drugs that: 1) inhibit isoform-selective prolyl hydroxylases (e.g., cobalt chloride and roxadustat); or 2) promote the actions of the redox sensor, sirtuin-1 (e.g., sodium-glucose cotransporter 2 inhibitors). Selective HIF-2α signaling through sirtuin-1 activation may explain the effect of sodium-glucose cotransporter 2 inhibitors to simultaneously promote erythrocytosis and ameliorate the development of cardiomyopathy and nephropathy.
- cobalt chloride
- hypoxia-inducible factor-1α
- hypoxia-inducible factor-2α
- sodium-glucose cotransporter 2 inhibitors
Dr. Packer has consulted for Abbvie, Actavis, Akcea, Amarin, Amgen, AstraZeneca, Boehringer Ingelheim, Cardiorentis, Daiichi Sankyo, Johnson & Johnson, Novartis, NovoNordisk, Pfizer, Relypsa, Sanofi, Synthetic Biologics, and Theravance.
The author attests they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Received March 30, 2020.
- Revision received May 7, 2020.
- Accepted May 7, 2020.
- 2020 The Author
- Central Illustration
- Oxygen-Related Activation of HIF-1α and HIF-2α and the Interplay of These Isoforms to Modulating the Cellular Redox State and the Inflammatory Set Point
- Modulation of HIF-1α/HIF-2α Signaling in the Ischemic and Failing Heart
- Modulation of HIF-1α/HIF-2α Signaling in Vascular Disorders
- Effect of Hypoxia Mimetics (PHD Inhibitors and SIRT1 Activators) on Chronic Cardiac, Renal, and Vascular Injury