Mechanisms of sulfonylurea receptor mediated cardiomyopathy

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DESCRIPTION (provided by applicant): ATP-sensitive potassium (KATP) channels response to the intracellular energy state of the cell through directly nucleotide binding. KATP channels sense intracellular ADP content and, in response, regulate membrane potential. The major KATP regulatory component found in the ventricular cardiomyocyte is the sulfonylurea receptor (SUR)-2, encoded by the Abcc9 gene. Like other ABC transporter proteins, SUR2 is a multi- transmembrane protein with two nucleotide-binding folds. Glyburide, a sulfonylurea antagonist, is used commonly to treat diabetes, although this class of medications has been reported to increase cardiovascular risk in diabetics. The clinical use of drugs that act through the SURs, as well as the possibility to develop additional agents that utilize these pathways, argues for improved understanding of SURs and their role especially in high energy demand tissue like the heart. Mutations in the Abcc9/SUR2 gene cause dilated cardiomyopathy and more recently have been linked to Cantu syndrome, a rare multisystem disorder that includes cardiomegaly (Harakalova et al., 2012; van Bon et al., 2012). The Abcc9 gene undergoes alternative splicing to produce SUR2, a characteristic ATP binding cassette protein, and also a smaller 55 KDa protein, which we termed SUR2- 55. Like SUR2, SUR2-55 can couple with the partner potassium channel but SUR2-55 is enriched in mitochondria. Deletion of the Abcc9 gene in a manner that leaves SUR2-55 intact, leads to coronary artery vascular spasm, hypertension, sudden cardiac death. In contrast, deletion of Abcc9 in a manner that ablate both SUR2 and SUR2-55 leads to neonatal cardiomyopathy in the first 10 days of life. The newborn heart is known to transition from glucose to oxidative metabolism during this window, and this transition is impaired in Abcc9 deleted mice. In separate experiments, we found that transgenic overexpression of SUR-55 in the heart protects the heart from ischemic reperfusion injury. We hypothesize that Abcc9-encoded proteins, through KATP channels, contribute to the metabolic balance especially under stress conditions such as the newborn heart and in ischemic myocardium. Ablation of Abbc9 in the newborn and adult myocardium will be used to define SUR2 complexes and their role in the heart.