Fasudil alleviates the vascular endothelial dysfunction and several phenotypes of Fabry disease

Area of Science:

• Biochemistry
• Genetics
• Pharmacology

Background:

• Fabry disease (FD) is a genetic lysosomal storage disorder caused by deficient alpha-galactosidase (GLA) activity.
• This deficiency leads to globotriaosylceramide (Gb3) accumulation, causing severe complications like left ventricular hypertrophy (LVH), kidney failure, and stroke.
• Current enzyme replacement therapy (ERT) has limitations due to short half-life and immunogenicity, especially in advanced disease stages.

Purpose of the Study:

• To identify chemical compounds that can downregulate thrombospondin-1 (TSP1) and SMAD2 signaling in FD vascular endothelial cells (VECs).
• To evaluate the therapeutic potential of fasudil in preclinical models of Fabry disease.

Main Methods:

• Screening of chemical compounds targeting TSP1 and SMAD2 signaling pathways.
• In vitro analysis of FD-VECs treated with fasudil, assessing p-SMAD2, TSP1, angiogenic factors, endothelial-to-mesenchymal transition (EndMT), and mitochondrial function.
• In vivo study involving oral administration of fasudil to FD mice to assess therapeutic effects on disease phenotypes.

Main Results:

• Fasudil significantly reduced p-SMAD2 and TSP1 levels in FD-VECs.
• Fasudil treatment increased the expression of angiogenic factors and downregulated EndMT and mitochondrial dysfunction in FD-VECs.
• Oral fasudil administration in FD mice ameliorated key disease manifestations, including LVH, renal fibrosis, anhidrosis, and heat intolerance.

Conclusions:

• Fasudil demonstrates significant therapeutic potential by targeting key molecular pathways implicated in Fabry disease.
• The drug effectively alleviates multiple FD-related pathologies in both cellular and animal models.
• Fasudil represents a novel and promising therapeutic candidate for managing Fabry disease.