Abstract 011: Cardiovascular Consequences of Cantu Syndrome and Response to Glibenclamide Treatment in Two Novel KATP Channel Mutant Mouse Models

The rare heritable disorder Cantů syndrome (CS) arises from gain-of-function mutations in the genes encoding the cardiovascular KATP channel subunits Kir6.1 and SUR2 ( KCNJ8 and ABCC9 , respectively). CS is characterized by diverse features including hypertrichosis, osteochondrodysplasia and craniofacial dysmorphology. Multiple cardiovascular abnormalities are also reported in CS including vascular dilation and tortuosity, dramatic cardiomegaly, pulmonary hypertension and low systemic blood pressure. We have developed and characterized two novel mouse models of Cantu Syndrome in which disease causing amino acid substitutions have been engineered into either Kir6.1 (p.V65M) or SUR2 (p.A478V) using CRISPR/Cas9 genome editing. Electrophysiological assessment of isolated vascular smooth muscle cells (VSMCs) showed that both mutations result in increased basal activity of VSM KATP channels. Mutant mice also exhibit vascular dilation, low blood pressure, and pulmonary hypertension. In addition, mutant mice exhibited hypertrophic, hyper-contractile hearts. The latter findings are not trivially predictable as a consequence of KATP gain-of-function, but also recapitulates key clinical features of CS. The severity of pathophysiological remodeling correlated with the molecular effects of the substitution. These models provide novel insights to the cardiovascular consequences of KATP over-activity. Little is known about the long-term effects of human CS, nor reversibility of pathophysiological consequences. Chronic administration of the sulfonylurea KATP inhibitor glibenclamide (glyburide) by slow-release pellets implanted under the skin resulted in normalization of vascular consequences and reversal of cardiac hypertrophy in SUR2(A478V) mice over 3 weeks. Kir6.1(V65M) mice are less sensitive to glibenclamide treatment, as predicted from studies of recombinant channels. These results suggest that glibenclamide represents a promising pharmacotherapy for CS (but that sensitivity may be patient- and mutation-dependent), and perhaps for diverse cardiovascular conditions arising from decreased smooth muscle excitability in general.