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Nrf2 Activation With CDDO-Methyl Promotes Beneficial and Deleterious Clinical Effects in Transgenic Mice With Sickle
Chibueze A Ihunnah1,2, Samit Ghosh1,2,3, Scott Hahn2
1Department of Medicine, Center for Translational and International Hematology, Vascular Medicine Institute, School of Medicine University of Pittsburgh, Pittsburgh, PA, United States.
Abstract:
Activation of Nrf2, a major transcription factor that drives the antioxidant defense system, is an emerging therapeutic strategy in Sickle Cell Disease (SCD). In this study, transgenic Sickle Cell Anemia mice (SS mice) treated with CDDO-Methyl (CDDO-Me), a potent Nrf2 activator, showed reduced progression of hemolytic anemia with aging, but surprisingly also showed reduced endothelial function. Pulmonary vessels isolated from SS mice treated for 4 months with CDDO-Me displayed a diminished response to nitric oxide (NO)-induced vasodilation compared to littermates given vehicle. It is unclear what molecular mechanism underly the vascular impairment, however, our in vitro assays revealed that CDDO-Me induced the expression of the endothelin receptor (ETA and ETB) in vascular smooth muscle cells. Endothelin signaling is associated with increased vascular tone and vasoconstriction. This study underscores the importance of pre-clinical benefit-risk investigations of Nrf2 activating compounds which may be used to treat patients with SCD.
Insights
Activation of Nrf2 (Nuclear factor erythroid 2-related factor 2) may worsen sickle cell disease vascular issues. While Nrf2 activators reduced anemia in mice, they impaired blood vessel function by increasing endothelin receptors.
Area of Science:
- Biomedical Science
- Pharmacology
- Vascular Biology
Background:
- Sickle Cell Disease (SCD) is a genetic blood disorder with anemia and vascular complications.
- Nuclear factor erythroid 2-related factor 2 (Nrf2) activation is a potential therapeutic target for SCD's antioxidant defense.
- Endothelial dysfunction contributes significantly to SCD morbidity.
Purpose of the Study:
- To investigate the effects of a potent Nrf2 activator, CDDO-Methyl (CDDO-Me), on the progression of sickle cell anemia and associated vascular function in a mouse model.
- To explore the molecular mechanisms underlying potential vascular impairments observed with Nrf2 activation in SCD.
Main Methods:
- Transgenic Sickle Cell Anemia (SS) mice were treated with CDDO-Me or vehicle for four months.
- Pulmonary vessels were isolated to assess responses to nitric oxide (NO)-induced vasodilation.
- In vitro assays were performed on vascular smooth muscle cells to evaluate gene expression changes.
Main Results:
- CDDO-Me treatment reduced the progression of hemolytic anemia in aging SS mice.
- Surprisingly, CDDO-Me treated mice exhibited reduced endothelial function, with diminished NO-induced vasodilation in pulmonary vessels.
- In vitro studies showed CDDO-Me induced endothelin receptors (ETA and ETB) in vascular smooth muscle cells.
Conclusions:
- While Nrf2 activation shows promise for anemia in SCD, it may paradoxically impair vascular function.
- Increased endothelin receptor expression driven by CDDO-Me could mediate vasoconstriction and contribute to vascular impairment.
- Pre-clinical benefit-risk assessments are crucial for Nrf2-activating compounds intended for SCD treatment.
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