Abstract 21125: Deletion of Abcc9 Encoding Sulfonylurea-Sensitive and -Insensitive Katp Channels Leads to Cardiomyopathy and Neonatal Death
Background: ATP-sensitive potassium (KATP) channels sense the intracellular energy state and, in response, regulate membrane potential. The regulatory subunit of the major KATP channel in ventricular cardiomyocytes is sulfonylurea receptor 2 (SUR2). SUR2 is encoded by the gene Abcc9 and is a multi-transmembrane spanning protein with two large intracellular nucleotide binding regions. Deletion of the first nucleotide binding region in mice was previously shown to produce coronary artery vascular spasm, hypertension and, paradoxically, enhanced cardioprotection. Recently, smaller proteins encoded by the Abcc9 gene have been described. These shorter proteins contribute to KATP channels that are relatively insensitive to sulfonylureas but retain ATP sensitivity.
Methods: We now evaluated the role of these shorter forms by generating mice with an Abcc9 gene deletion targeting both full length and Abcc9 short forms.
Results: In contrast to the previously generated Abcc9 deleted mice (Ex14/18) which survive to adulthood, mice deleted for exon 5 (Ex5) of Abcc9 die within 14 days of birth. Echocardiography of neonatal mice demonstrated that Ex5 mice develop progressive cardiac contractile dysfunction and have enlarged hearts compared to littermate control mice (6.0 ± 0.1 vs 8.9 ± 0.2 heart weight (mg)/body weight (g); n=6 and n=4, respectively, p<0.05). Introducing full length Abcc9 only in ventricular cardiomyocytes improved lifespan in Abcc9 Ex5 mice. Because KATP channels have been implicated in stress response and mitochondrial function, we used TMRE fluorescence to study mitochondrial membrane potential in response to cell stress in neonatal cardiomyocytes. Cell stress induced by H2O2 resulted in more rapid collapse of mitochondria membrane potential in Ex5 mitochondria (5.2 ± 0.3s, n=5) compared to littermate control (15.1 ± 0.6s, n=6) and Ex14/18 (13.1 ± 0.6s, n=5). Similar results were obtained with metabolic stressors deoxyglucose and cyanide. Diazoxide depolarized control to 39±5% but not the ABCC9 neonatal cardiomyocytes (5±4%) after 30 mins.
Conclusions: Multiple proteins produced from Abcc9 contribute to mitochondrial function and neonatal cardiomyopathy.
- © 2010 by American Heart Association, Inc.