The mitochondrial membrane potential (DYm) is a key regulator of mitochondrial function that drives the production of ATP and reactive oxygen species (ROS). Dynamic oscillations of DYm in isolated cardiac myocytes can result in electrophysiological oscillations that significantly impact myocyte function and lead to inexcitability at the cellular level. However, technical challenges in measuring spatio-temporal gradients in metabolic function within the intact heart have precluded a direct investigation of the functional consequences of unstable mitochondrial properties in mediating global oxidative stress and associated mechano-electrical dysfunction. Since the original submission of this proposal, we have developed a semi-quantitative imaging technique for measuring the spatio-temporal dynamics of DYm with subcellular resolution at the organ level. In this proposal, we extend our measurements to perform ROS imaging in order to investigate if ROS-induced ROS-release is a mechanism of DYm instability within the intact normal and hypertrophied heart. Previous work identified the mitochondrial benzodiazepine receptor (mBZR) as a potentially attractive candidate for preventing arrhythmias. However, pharmacological interventions that target mBzR significantly impact contractile and calcium handling properties by directly suppressing the L-type calcium current. This may limit the clinical utility of these agents and raises important questions regarding the direct relevance of DYm stability per se in altering mechano-electrical properties. We will directly address this important issue by using a gene transfer approach that targets mBZR expression. This will uncover the role of IMAC through mBZR overexpression in altering mitochondrial, mechanical, and electrical properties. From a practical perspective, these studies will help us determine if modulation of mBZR expression is a viable strategy for altering mechano-electrical properties. If so, future gene silencing to mimic IMAC blockade may be warranted.
This proposal is dedicated to: 1) developing integrative imaging techniques to uncover mechanisms by which altered metabolic properties in cardiac hypertrophy predispose to electrical and contractile dysfunction;and 2) using gene transfer approaches to modulate electrical and contractile properties by regulating mitochondrial function through the expression levels of a key receptor.
|Xie, Chaoqin; Hu, Jun; Motloch, Lukas J et al. (2015) The Classically Cardioprotective Agent Diazoxide Elicits Arrhythmias in Type 2 Diabetes Mellitus. J Am Coll Cardiol 66:1144-1156|
|Kim, Grace E; Ross, Jenna L; Xie, Chaoqin et al. (2015) LKB1 deletion causes early changes in atrial channel expression and electrophysiology prior to atrial fibrillation. Cardiovasc Res 108:197-208|
|Chaanine, Antoine H; Nonnenmacher, Mathieu; Kohlbrenner, Erik et al. (2014) Effect of bortezomib on the efficacy of AAV9.SERCA2a treatment to preserve cardiac function in a rat pressure-overload model of heart failure. Gene Ther 21:379-386|
|Xie, Chaoqin; Biary, Nora; Tocchetti, Carlo G et al. (2013) Glutathione oxidation unmasks proarrhythmic vulnerability of chronically hyperglycemic guinea pigs. Am J Physiol Heart Circ Physiol 304:H916-26|
|Nederlof, Rianne; Xie, Chaoqin; Eerbeek, Otto et al. (2013) Pathophysiological consequences of TAT-HKII peptide administration are independent of impaired vascular function and ensuing ischemia. Circ Res 112:e8-13|
|Karam, Caline S; Akar, Fadi G (2012) Genetic silencing of pacemaker cells: local intervention with global implications. J Am Heart Assoc 1:e001412|
|Akar, Fadi G; O'Rourke, Brian (2011) Mitochondria are sources of metabolic sink and arrhythmias. Pharmacol Ther 131:287-94|
|Salama, Guy; Akar, Fadi G (2011) Deciphering Arrhythmia Mechanisms - Tools of the Trade. Card Electrophysiol Clin 3:11-21|
|Biary, Nora; Xie, Chaoqin; Kauffman, Justin et al. (2011) Biophysical properties and functional consequences of reactive oxygen species (ROS)-induced ROS release in intact myocardium. J Physiol 589:5167-79|
|Hajjar, Roger J; Akar, Fadi G (2010) Regression of cardiac hypertrophy by cyclic guanosine monophosphate-dependent protein kinase signaling are myocytes active sources or mere beneficiaries? J Am Coll Cardiol 56:2031-2|