Nrf2 Activation With CDDO-Methyl Promotes Beneficial and Deleterious Clinical Effects in Transgenic Mice With Sickle...

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 (ET_A and ET_B) 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.