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

Abstract

Fabry disease (FD), a lysosomal storage disorder, is caused by defective α-galactosidase (GLA) activity, which results in the accumulation of globotriaosylceramide (Gb3) in endothelial cells and leads to life-threatening complications such as left ventricular hypertrophy (LVH), renal failure, and stroke. Enzyme replacement therapy (ERT) results in Gb3 clearance; however, because of a short half-life in the body and the high immunogenicity of FD patients, ERT has a limited therapeutic effect, particularly in patients with late-onset disease or progressive complications. Because vascular endothelial cells (VECs) derived from FD-induced pluripotent stem cells display increased thrombospondin-1 (TSP1) expression and enhanced SMAD2 signaling, we screened for chemical compounds that could downregulate TSP1 and SMAD2 signaling. Fasudil reduced the levels of p-SMAD2 and TSP1 in FD-VECs and increased the expression of angiogenic factors. Furthermore, fasudil downregulated the endothelial-to-mesenchymal transition (EndMT) and mitochondrial function of FD-VECs. Oral administration of fasudil to FD mice alleviated several FD phenotypes, including LVH, renal fibrosis, anhidrosis, and heat insensitivity. Our findings demonstrate that fasudil is a novel candidate for FD therapy.

• Authors: Jong Bin Choi, Dong-Won Seol, Hyo-Sang Do, Hee-Young Yang, Taek-Min Kim, Youkyeong Gloria Byun, Jae-Min Park, Jinhyuk Choi, Seon Pyo Hong, Won-Suk Chung, Jae Myoung Suh, Gou Young Koh, Beom Hee Lee, Gabbine Wee, Yong-Mahn Han
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 31 Issue 4 Pg. 1002-1016 (04 05 2023) ISSN: 1525-0024 [Electronic] United States
• PMID: 36755495 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Chemical References

• fasudil
• alpha-Galactosidase

Topics

• Animals
• Mice
• Fabry Disease (drug therapy, genetics)
• Endothelial Cells (metabolism)
• alpha-Galactosidase (genetics)
• Phenotype
• Enzyme Replacement Therapy