Heart failure is an enormous public health problem in the United States. Over the past two decades, there has been considerable progress in the treatment of chronic heart failure yet, even with the best of modern therapy, heart failure is stil associated with a 5-year mortality rate of 50%. Therefore, the search for new approaches to treatment and prevention of heart failure is one of the major challenges in medicine. The ATP-sensitive potassium (KATP) channel, one of the most abundant cardiac membrane protein complexes, has the unique ability to adjust membrane excitability in response to changes in the energetic status of the cell. When activated by increased cellular metabolic demand, KATP channel-dependent potassium efflux shortens cardiac action potential duration (APD). This potassium efflux limits sodium and calcium entry into the cell and thus reduces energy requirements for ion homeostasis and contraction, as well as prolongs the diastolic interval that supports myocardial relaxation and replenishment of ATP. Our recent work uncovered that that the ability of the heart to optimize APD and energy utilization depends on the membrane expression level of KATP channels which affects how quickly and efficiently KATP current can adapt to changes in workload. A complete understanding of mechanisms that control membrane KATP channel expression may reveal new avenues to promote cardiac energy efficiency and resistance to heart failure. Based on our preliminary data, we hypothesize that membrane KATP channel expression is coupled with overall cardiac function by calcium/calmodulin dependent protein kinase II (CaMKII). This densely expressed multifunctional kinase targets numerous proteins involved in excitation contraction coupling and excitability to support enhanced cardiac performance, while its persistent activation under pathophysiological conditions promotes cardiomyocyte death and dysfunction. We propose a previously unrecognized downstream signaling pathway of CaMKII activation through phosphorylation of the Kir6.2 pore-forming KATP channel subunit and consequent endocytosis of KATP channels. Under persistent CaMKII activation, the consequent reduction in KATP channel expression would aggravate depletion of cardiac energy resources thus contributing to myocardial injury, cell death and heart failure. We predict that the known beneficial effects on cardiac stress resistance that occur with CaMKII inhibition will depend significantly on membrane retention of KATP channels.
In Aim1 we will define the mechanism for CaMKII-dependent endocytosis of KATP channels by use of tagged recombinant KATP channel subunits, confocal immunofluorescence imaging, and molecular biology and patch clamp techniques in cardiomyocytes and HEK293T cells.
In Aim 2 we will study heart failure, induced in genetic mouse models with KATP channel expression deficits and cardioselective CaMKII inhibition, to understand the role of CaMKII-dependent KATP channel expression regulation in the generation of the energetic and functional deficits defining heart failure.
Heart failure is an enormous public health problem in the United States where the incidence and mortality are high such that the search for new approaches to treatment and prevention is one of the major challenges in medicine. Membrane expression of KATP channels affects optimization of cardiac energy consumption and resistance to injury. This project will define a novel mechanism for control of KATP channel membrane expression, and will determine the potential for its manipulation in improvement of myocardial energetics and heart failure resistance.
|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|
|Subbotina, E; Koganti, S R K; Hodgson-Zingman, D M et al. (2016) Morpholino-driven gene editing: A new horizon for disease treatment and prevention. Clin Pharmacol Ther 99:21-5|
|Gao, Zhan; Sierra, Ana; Zhu, Zhiyong et al. (2016) Loss of ATP-Sensitive Potassium Channel Surface Expression in Heart Failure Underlies Dysregulation of Action Potential Duration and Myocardial Vulnerability to Injury. PLoS One 11:e0151337|
|Subbotina, Ekaterina; Sierra, Ana; Zhu, Zhiyong et al. (2015) Musclin is an activity-stimulated myokine that enhances physical endurance. Proc Natl Acad Sci U S A 112:16042-7|
|Koganti, Siva Rama Krishna; Zhu, Zhiyong; Subbotina, Ekaterina et al. (2015) Disruption of KATP channel expression in skeletal muscle by targeted oligonucleotide delivery promotes activity-linked thermogenesis. Mol Ther 23:707-16|
|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|
|Sierra, Ana; Zhu, Zhiyong; Sapay, Nicolas et al. (2013) Regulation of cardiac ATP-sensitive potassium channel surface expression by calcium/calmodulin-dependent protein kinase II. J Biol Chem 288:1568-81|
|Zhu, Zhiyong; Burnett, Colin M-L; Maksymov, Gennadiy et al. (2011) Reduction in number of sarcolemmal KATP channels slows cardiac action potential duration shortening under hypoxia. Biochem Biophys Res Commun 415:637-41|
|Zingman, Leonid V; Zhu, Zhiyong; Sierra, Ana et al. (2011) Exercise-induced expression of cardiac ATP-sensitive potassium channels promotes action potential shortening and energy conservation. J Mol Cell Cardiol 51:72-81|