Data for: Mitochondrial Ca2+-coupled generation of reactive oxygen species, peroxynitrite formation, and endothelial dysfunction in Cantú syndrome

Cantú syndrome is a multisystem disorder caused by gain-of-function (GOF)
mutations in KCNJ8 and ABCC9, the genes
encoding the pore-forming inward rectifier Kir6.1 and regulatory
sulfonylurea receptor SUR2B subunits, respectively, of vascular
ATP-sensitive K+ channels (KATP). In this study, we investigated
changes in the vascular endothelium in mice in which Cantú syndrome
-associated Kcnj8 or Abcc9 mutations were
knocked-in to the endogenous loci. We found that endothelium-dependent
dilation was impaired in small mesenteric arteries from Cantú mice. Loss
of endothelium-dependent vasodilation led to increased vasoconstriction in
response to intraluminal pressure or treatment with the adrenergic
receptor agonist phenylephrine. We also found that either
KATP GOF or acute activation of KATP channels with
pinacidil increased the amplitude and frequency of wave-like
Ca2+ events generated in the endothelium in response to the
vasodilator agonist carbachol. Increased cytosolic Ca2+ signaling
activity in arterial endothelial cells from Cantú mice was associated with
elevated mitochondrial [Ca2+] and enhanced reactive oxygen species (ROS)
and peroxynitrite levels. Scavenging intracellular or mitochondrial ROS
restored endothelium-dependent vasodilation in the arteries of mice with
KATP GOF mutations. We conclude that mitochondrial Ca2+ overload
and ROS generation, which subsequently leads to nitric oxide consumption
and peroxynitrite formation, cause endothelial dysfunction in mice with
Cantú syndrome.