Heart disease remains the leading cause of death in the United States and other developed countries. Most deaths are associated with cardiac ischemia and arrhythmias. Sarcolemmal KATP channels in the myocardium open with elevated heart rates and during stress conditions, such as cardiac ischemia. Opening of KATP channels modulate the action potential duration and intracellular Ca2+. As such they have an important role in determining contractility, arrhythmias and electrical conduction. It is well established tht KATP channel opening protects the heart during stress. However, a detailed understanding of the KATP channel function during ischemia, reperfusion and ischemic preconditioning is lacking, which hinders the development of therapeutic strategies. Our preliminary data point to novel subcellular localization patterns of KATP channels within the cardiac myocyte. We further find that myocardial ischemia decreases the surface KATP channel density, which reduces the number of channels that are available for cardioprotection. This proposal is driven by our preliminary observations that a) ischemic preconditioning prevents ischemia-induced internalization of KATP channels and that b) the protective effects of ischemic preconditioning on infarct size are abolished in mice with cardiac-specific knockout of the KATP channel subunit, Kir6.2. We hypothesize that enhancing KATP channel surface density through specific subcellular trafficking pathways is an important element of the protective mechanism of ischemic preconditioning. We will investigate molecular mechanisms that stabilize surface KATP channels (Aim 1), cellular processes that regulate internalization (Aim 2) and potential mechanisms to restore the KATP channel surface density during an ischemic insult (Aim 3). The proposed studies will establish a framework in which to understand novel roles of KATP channels in the heart and will provide molecular insights their cardioprotective function during ischemic pre-conditioning.
Heart disease is the leading cause of death in the United States and other developed countries and almost half of these deaths occur suddenly from ischemia and heart rhythm abnormalities. Our research is directed toward understanding the mechanisms responsible for these events and identifying potential new therapeutic targets.
|Yang, Hua Qian; Jana, Kundan; Rindler, Michael J et al. (2018) The trafficking protein, EHD2, positively regulates cardiac sarcolemmal KATP channel surface expression: role in cardioprotection. FASEB J 32:1613-1625|
|Foster, Monique N; Coetzee, William A (2016) KATP Channels in the Cardiovascular System. Physiol Rev 96:177-252|
|Sierra, Ana; Subbotina, Ekaterina; Zhu, Zhiyong et al. (2016) Disruption of ATP-sensitive potassium channel function in skeletal muscles promotes production and secretion of musclin. Biochem Biophys Res Commun 471:129-34|
|Yang, Hua-Qian; Foster, Monique N; Jana, Kundan et al. (2016) Plasticity of sarcolemmal KATP channel surface expression: relevance during ischemia and ischemic preconditioning. Am J Physiol Heart Circ Physiol 310:H1558-66|
|Yang, Hua-Qian; Subbotina, Ekaterina; Ramasamy, Ravichandran et al. (2016) Cardiovascular KATP channels and advanced aging. Pathobiol Aging Age Relat Dis 6:32517|
|Zhu, Zhiyong; Sierra, Ana; Burnett, Colin M-L et al. (2014) Sarcolemmal ATP-sensitive potassium channels modulate skeletal muscle function under low-intensity workloads. J Gen Physiol 143:119-34|
|Coetzee, William A (2013) Multiplicity of effectors of the cardioprotective agent, diazoxide. Pharmacol Ther 140:167-75|