The Mechanism Of Cardiovascular Pathophysiology In Cantu Syndrome And Response To Glibenclamide In Novel Katp Channel Mutant Mouse Models

Characterized by diverse features including hypertrichosis, craniofacial dysmorphology, and edema, Cantú syndrome (CS) arises from gain-of-function (GOF) mutations in the genes encoding the cardiovascular KATP channel subunits Kir6.1 and SUR2 (KCNJ8 and ABCC9, respectively). Multiple cardiovascular abnormalities are also reported in CS including vascular dilation and tortuosity, dramatic cardiomegaly, pulmonary hypertension and low systemic blood pressure. How KATP dysfunction results in these complex abnormalities is not fully understood and there are no known therapies for the disorder. Here, we use novel “Cantú mouse” models, in which disease-causing SUR2[A478V] and Kir6.1[V65M] mutations were introduced into KCNJ8 and ABCC9 using CRISPR/Cas9 genome editing, to dissect the pathophysiological mechanisms underlying CV remodeling and to test the efficacy of the KATP inhibitor glibenclamide in reversing abnormalities. Cantú mice exhibit decreased systemic blood pressures and cardiac hypertrophy - recapitulating clinical manifestations. We generated Cantú mice which also inducibly express dominant-negative Kit6.1 subunits specifically in smooth muscle. Following induction, downregulation of KATP in vascular smooth muscle cells (VSMC) reverses cardiac remodeling. This indicates that the complex CV abnormalities observed clinically arise secondary to smooth muscle KATP GOF and hypo-excitability. CS mice also exhibit systemic hypotension, associated with a compensatory upregulation of renin-angiotensin signaling (RAS), which we propose as the driver of cardiac hypertrophy. Finally, chronic administration of glibenclamide by slow-release pellets implanted subcutaneously in Cantú mice results in normalization of vascular consequences and reversal of cardiac hypertrophy over 3 weeks. These results demonstrate the in vivo efficacy of glibenclamide in targeting cardiovascular KATP channels, suggesting that the drug can be clinically repurposed for the treatment of CS specifically - and potentially for diverse cardiovascular conditions arising from decreased smooth muscle excitability in general.