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

• DOI: 10.1016/j.ymthe.2023.02.003
• Publication Date: 2023-02-08T07:22:22Z
• Authors: Jong Bin Choi; Dong-Won Seol; Hyo-Sang Do; Hee-Young Yang; Taek-Min Kim; Youkyeong Gloria ...; 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
• Keywords: Fasudil; Globotriaosylceramide; Endothelial Dysfunction; Empagliflozin

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