We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Glibenclamide reverses cardiovascular abnormalities of Cantu syndrome driven by KATP channel overactivity.
- Authors
McClenaghan, Conor; Yan Huang; Zihan Yan; Harter, Theresa M.; Halabi, Carmen M.; Chalk, Rod; Kovacs, Attila; van Haaften, Gijs; Remedi, Maria S.; Nichols, Colin G.; Huang, Yan; Yan, Zihan; Harter, Theresa
- Abstract
Cantu syndrome (CS) is a complex disorder caused by gain-of-function (GoF) mutations in ABCC9 and KCNJ8, which encode the SUR2 and Kir6.1 subunits, respectively, of vascular smooth muscle (VSM) KATP channels. CS includes dilated vasculature, marked cardiac hypertrophy, and other cardiovascular abnormalities. There is currently no targeted therapy, and it is unknown whether cardiovascular features can be reversed once manifest. Using combined transgenic and pharmacological approaches in a knockin mouse model of CS, we have shown that reversal of vascular and cardiac phenotypes can be achieved by genetic downregulation of KATP channel activity specifically in VSM, and by chronic administration of the clinically used KATP channel inhibitor, glibenclamide. These findings demonstrate that VSM KATP channel GoF underlies CS cardiac enlargement and that CS-associated abnormalities are reversible, and provide evidence of in vivo efficacy of glibenclamide as a therapeutic agent in CS.
- Subjects
GAIN-of-function mutations; VASCULAR smooth muscle; GLIBENCLAMIDE; GENETIC regulation; HYPERKINESIA; HUMAN abnormalities; BIOLOGICAL models; RESEARCH; MULTIPLE epiphyseal dysplasia; HYPOGLYCEMIC sulfonylureas; HAIR diseases; CARDIAC hypertrophy; ANIMAL experimentation; RESEARCH methodology; EVALUATION research; MEDICAL cooperation; COMPARATIVE studies; MEMBRANE transport proteins; GENETIC techniques; MICE; PHARMACODYNAMICS
- Publication
Journal of Clinical Investigation, 2020, Vol 130, Issue 3, p1116
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI130571