The cardiac ATP sensitive potassium channel (KATP) in surface sarcolemmal membrane and in mitochondria have both been implicated in the pathogenesis of cardiac ischemia, particularly in an important protective phenomenon called ischemic preconditioning (IPC). Proposed mechanisms for IPC are complex and the role and relative importance of KATP for IPC remains controversial, in part because of heavy reliance on KATP pharmacology. The sulfonylurea receptor subunit SUR2 regulates pharmacology and nucleotide interactions for surface KATP, but the molecular nature of the subunit for mitochondria is unknown. In the last period of this project we described novel SUR2 splice variants in heart involving exons 14 and 17. Experiments in Aim 1 will address the hypotheses that 1A) the pharmacology of SUR2 splice variants accounts for the pharmacology of mitochondrial KATP, and 1B) a splice variant of SUR2 is targeted to mitochondria and accounts for mitochondrial KATP activity. These hypotheses are based upon our characterization of an SUR2 knockout mouse developed during the last period that lacks cardiac KATP activity at both the surface and in mitochondria. This mouse provides a novel non-pharmacological model to assess the role of KATP in IPC. Experiments in Aim 2 will address the hypotheses that 2A) KATP is required for early IPC and 2B) KATP openers and blockers and other triggers of IPC such as adenosine affect IPC by non-KATP mechanisms. Experiments in Aim 3 will address the hypotheses that 3A) KATP is required for a type of protection called delayed IPC, and 3B) KATP underlies late but not early ST elevation in ischemia.
Aim 4 will develop novel transgenic mice that """"""""rescue"""""""" SUR2 in a tissue and splice variant specific manner. These mice will serve as models to further elucidate the relative role of mitochondrial versus sarcolemmal SUR2 and KATP in the mechanism of lPC. This proposal utilizing transgenic animals represents a novel approach to elucidating the mechanism of IPC, a means of cardioprotection with important clinical implications, and it will also suggest more specific therapeutic targets in the SUR2 variants to be studied. It will also provide important new information on mitochondrial structure and function in heart.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL057414-08
Application #
6935834
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Program Officer
Przywara, Dennis
Project Start
1997-09-01
Project End
2007-08-31
Budget Start
2005-09-01
Budget End
2006-08-31
Support Year
8
Fiscal Year
2005
Total Cost
$352,375
Indirect Cost
Name
University of Wisconsin Madison
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Yang, Kai-Chien; Kyle, John W; Makielski, Jonathan C et al. (2015) Mechanisms of sudden cardiac death: oxidants and metabolism. Circ Res 116:1937-55
Fahrenbach, John P; Stoller, Douglas; Kim, Gene et al. (2014) Abcc9 is required for the transition to oxidative metabolism in the newborn heart. FASEB J 28:2804-15
Aggarwal, Nitin T; Shi, Nian-Qing; Makielski, Jonathan C (2013) ATP-sensitive potassium currents from channels formed by Kir6 and a modified cardiac mitochondrial SUR2 variant. Channels (Austin) 7:493-502
Aggarwal, Nitin T; Makielski, Jonathan C (2013) Redox control of cardiac excitability. Antioxid Redox Signal 18:432-68
Stoller, Douglas A; Fahrenbach, John P; Chalupsky, Karel et al. (2010) Cardiomyocyte sulfonylurea receptor 2-KATP channel mediates cardioprotection and ST segment elevation. Am J Physiol Heart Circ Physiol 299:H1100-8
Aggarwal, Nitin T; Pravdic, Danijel; McNally, Elizabeth M et al. (2010) The mitochondrial bioenergetic phenotype for protection from cardiac ischemia in SUR2 mutant mice. Am J Physiol Heart Circ Physiol 299:H1884-90
Ye, Bin; Kroboth, Stacie L; Pu, Jie-Lin et al. (2009) Molecular identification and functional characterization of a mitochondrial sulfonylurea receptor 2 splice variant generated by intraexonic splicing. Circ Res 105:1083-93
Pu, Jie-Lin; Ye, Bin; Kroboth, Stacie L et al. (2008) Cardiac sulfonylurea receptor short form-based channels confer a glibenclamide-insensitive KATP activity. J Mol Cell Cardiol 44:188-200
Eckhardt, Lee L; Farley, Amanda L; Rodriguez, Esther et al. (2007) KCNJ2 mutations in arrhythmia patients referred for LQT testing: a mutation T305A with novel effect on rectification properties. Heart Rhythm 4:323-9
Kakkar, Rahul; Ye, Bin; Stoller, Douglas A et al. (2006) Spontaneous coronary vasospasm in KATP mutant mice arises from a smooth muscle-extrinsic process. Circ Res 98:682-9

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