Glibenclamide reverses cardiovascular abnormalities of Cantu syndrome driven by [K.sub.ATP] channel overactivity

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) [K.sub.ATP] 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 [K.sub.ATP] channel activity specifically in VSM, and by chronic administration of the clinically used [K.sub.ATP] channel inhibitor, glibenclamide. These findings demonstrate that VSM [K.sub.ATP] 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.
Introduction Cantu syndrome (CS) is a complex disorder with multiple cardiovascular abnormalities, including edema, dilated and tortuous blood vessels with decreased systemic vascular resistance, patent ductus arteriosus (PDA), and marked [...]