Glibenclamide reverses cardiovascular abnormalities of Cantu syndrome driven by KATP channel overactivity
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
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
View: Text | PDF
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

×

Figure 2

Glibenclamide reverses cardiac hypertrophy in SUR2wt/AV mice.

Options: View larger image (or click on image) Download as PowerPoint
Glibenclamide reverses cardiac hypertrophy in SUR2wt/AV mice. (A) Left: ...
(A) Left: Representative hearts from placebo-implanted WT (black), placebo-implanted SUR2wt/AV (orange), and approximately 19 mg/kg/day glibenclamide pellet implanted SUR2wt/AV (brown) mice. Right: Summary of heart size (weight normalized to tibia length; HW/TL) for WT and SUR2wt/AV mice implanted with either placebo pellets (Glib = 0), or pellets releasing approximately 1 mg/kg/day and approximately 19 mg/kg/day. (B) Summary of MAP in anesthetized placebo-pellet (Glib = 0) and approximately 19 mg/kg/day glibenclamide pellet–implanted WT and SUR2wt/AV mice. In all experiments, pellets were implanted at 8 weeks of age, and phenotypes were assessed 4 weeks later. (C) Systemic vascular resistance (SVR) and (D) cardiac index in placebo-implanted WT mice and placebo- or glibenclamide pellet–implanted SUR2wt/AV mice. (E) Gomori-stained left ventricular free wall sections. Scale bars: 500 μm. (F) Ejection fraction of placebo-implanted WT mice and placebo- or glibenclamide pellet–implanted SUR2wt/AV mice. Carotid artery compliance measurements from (G) placebo-implanted or approximately 19 mg/kg/day glibenclamide pellet–implanted WT and SUR2wt/AV mice, or (H) WT, SUR2wt/AV, and SMDNwt/AV mice. Individual data points are represented as open circles, bars show mean ± SEM. Statistical significance was determined by 1-way ANOVA (A–F) and 2-way ANOVA (G and H) with subsequent post hoc Tukey’s test for pairwise comparison. *P < 0.05; **P < 0.01 from pairwise post hoc Tukey’s test. For G and H, color-coded statistical significance indicators are shown for comparison with placebo-implanted WT mice (black).