Interplay between HSP90 and Nrf2 pathways in diabetes-associated atherosclerosis

Area of Science:

• Cardiovascular Research
• Molecular Biology
• Metabolic Diseases

Background:

• Oxidative stress and inflammation drive diabetic vascular complications.
• Heat shock protein 90 (HSP90) overexpression promotes inflammation in atherosclerotic plaques.
• Targeted HSP90 inhibition shows potential for preventing atherosclerosis.

Purpose of the Study:

• Investigate if HSP90 inhibition enhances antioxidant defenses via Nrf2 in diabetes-driven atherosclerosis.
• Determine the role of Nrf2 activation in HSP90 inhibitor-mediated atheroprotection.

Main Methods:

• Utilized streptozotocin-induced diabetic apolipoprotein E-deficient mice.
• Administered HSP90 inhibitor (17-dimethylaminoethylamino-17-demethoxygeldanamycin) or vehicle for 10 weeks.
• Analyzed aortic root sections for plaque characteristics, transcription factor activity, and inflammatory/antioxidant markers; conducted in vitro studies on murine macrophages.

Main Results:

• HSP90 inhibition activated Nrf2 in aortic tissue and cultured cells, reducing nuclear factor-κB (NF-κB) activity.
• Significant reduction in atherosclerotic lesion size and inflammatory markers observed.
• Induced cytoprotective heat shock protein 70 (HSP70), antioxidant enzymes, and autophagy machinery.

Conclusions:

• HSP90 inhibition confers atheroprotection in experimental diabetes.
• Protection is mediated by Nrf2-dependent induction of cytoprotective and antioxidant mechanisms.
• Reinforces the therapeutic potential of HSP90 inhibition for diabetic vascular complications.