The mitochondrial splice variant of the sulfonylurea receptor (SUR2A-55) is associated with protection from myocardial ischemia-reperfusion (IR) injury, increased mitochondrial ATP sensitive K+ channel activity (mitoKATP) and altered glucose metabolism. While mitoKATP channels composed of CCDC51 and ABCB8 exist, the mitochondrial K+ pore regulated by SUR2A-55 is unknown. We explored whether SUR2A-55 regulates ROMK to form an alternate mitoKATP. We assessed glucose uptake in mice overexpressing SUR2A-55 (TGSUR2A−55) compared with WT mice during IR injury. We then examined the expression level of ROMK and the effect of ROMK modulation on mitochondrial membrane potential (Δψm) in WT and TGSUR2A−55 mice. TGSUR2A−55 had increased glucose uptake compared to WT mice during IR injury. The expression of ROMK was similar in WT compared to TGSUR2A−55 mice. ROMK inhibition hyperpolarized resting cardiomyocyte Δψm from TGSUR2A−55 mice but not from WT mice. In addition, TGSUR2A−55 and ROMK inhibitor treated WT isolated cardiomyocytes had enhanced mitochondrial uncoupling. ROMK inhibition blocked diazoxide induced Δψm depolarization and prevented preservation of Δψm from FCCP perfusion in WT and to a lesser degree TGSUR2A−55 mice. In conclusion, cardio-protection from SUR2A-55 is associated with ROMK regulation, enhanced mitochondrial uncoupling and increased glucose uptake.
Ryanodine receptor 2 (RyR2) is the Ca
2+
release channel of sarcoplasmic reticulum that provides the majority of Ca
2+
necessary for contractions of the heart. RyR2 mutations are linked to catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited arrhythmogenic disorder with normal heart structure. There are reports suggesting that RyR2 mutations can also lead to structural heart disease, notably arrhythmogenic right ventricular cardiomyopathy (ARVC); however, additional research is required to support this association. We generated a rabbit model carrying the missense mutation RyR2-V2475F, linked to CPVT in humans. Heterozygous (V2475F
+/-
) rabbits show a CPVT-like syndrome and display arrhythmia under pharmacological stress. Homozygotes (V2475F
+/+
) show a stronger phenotype, with 37% of the animals (13/35) experiencing sudden death at 22.5±3.8 weeks old during regular housing. Remarkably, gross examination of V2475F
+/+
hearts showed significant structural remodeling, characterized by fibrous infiltrations and thinning of the right ventricle with or without left ventricle involvement. This phenotype is reminiscent of ARVC. Lead II ECG obtained in conscious rabbits by telemetry showed that V2475F
+/+
animals have significant bradycardia (144.6±11.1 bpm) with prolonged QT interval (QTc: 180.4±8.2 ms, n=6) compared to WT (HR: 224.9±4.2 bpm, p=0.04; QTc: 157.4±5.3 ms, p=0.02, n=5). After subcutaneous injection of 0.5 mg/kg of isoproterenol, WT rabbits showed the expected positive chronotropic response (HR, 367±10 bpm, n=3) while V2475F
+/+
animals developed bouts of ventricular tachycardia. Mild emotional stress applied by transporting the animal around the laboratory, also induced ventricular arrhythmia in 100% (5/5) V2475F
+/+
rabbits, while WT littermates were unaffected. RyR2-V2475F expressed in a rabbit model triggers remarkably different phenotypes based on the zygosity of the animals, ranging from a purely arrhythmogenic syndrome (CPVT) in V2475F
+/-
animals to severe structural disease compatible with ARVC in V2475F
+/+
rabbits. The RyR2-V2475F rabbit model is therefore an excellent model to dissect the intersection of arrhythmic and structural phenotypes due to RyR2 dysfunction.
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