Glibenclamide reverses cardiovascular abnormalities of Cantu syndrome driven by KATP channel overactivity
Conor McClenaghan, … , Maria S. Remedi, Colin G. Nichols
Conor McClenaghan, … , Maria S. Remedi, Colin G. Nichols
Published March 2, 2020; First published December 10, 2019
Citation Information: J Clin Invest. 2020;130(3):1116-1121. https://doi.org/10.1172/JCI130571.
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Concise Communication Cardiology Vascular biology

Glibenclamide reverses cardiovascular abnormalities of Cantu syndrome driven by KATP channel overactivity

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.

Authors

Conor McClenaghan, Yan Huang, Zihan Yan, Theresa M. Harter, Carmen M. Halabi, Rod Chalk, Attila Kovacs, Gijs van Haaften, Maria S. Remedi, Colin G. Nichols

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Figure 3

Chronic high-dose glibenclamide induces only transient hypoglycemia.

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Chronic high-dose glibenclamide induces only transient hypoglycemia. (A)...
(A) Summary of blood glucose levels in fed WT and SUR2wt/AV mice on day 0 prior to pellet implantation. (B) Mean blood glucose measurements from WT mice implanted with placebo pellets (black diamonds, solid line; n = 6), approximately 1 mg/kg/day glibenclamide pellets (light gray circles, dotted line; n = 4), and approximately 19 mg/kg/day glibenclamide pellets (dark gray triangles, dashed line; n = 4). (C) Summary of blood glucose measurements for WT mice implanted with placebo pellets (black bars) or approximately 19 mg/kg/day glibenclamide pellets (gray bars) on day 0, 1, and 18. (D) Mean blood glucose measurements from SUR2wt/AV mice implanted with placebo pellets (dark orange circles, solid line; n = 4), approximately 1 mg/kg/day glibenclamide pellets (light orange diamonds, dotted line; n = 7), and approximately 19 mg/kg/day glibenclamide pellets (brown squares, dashed line; n = 8). (E) Summary of blood glucose measurements for SUR2wt/AV mice implanted with placebo pellets (orange bars) or approximately 19 mg/kg/day glibenclamide pellets (brown bars) on day 0, 1, and 18. (F) Fasted BG in mice which had been implanted with either placebo or high-dose glibenclamide more than 30 days prior. Glucose tolerance test data for WT (G) and SUR2wt/AV (H) mice implanted with placebo or approximately 19 mg/kg/day glibenclamide pellets. For summary figures, individual data points are represented as open circles, bars show mean ± SEM. Statistical significance was determined by 1-way ANOVA and subsequent post hoc Tukey’s test for pairwise comparison. *P < 0.05 from pairwise post hoc Tukey’s test.