Project 02: Is increased Na+ influx a cause of mitochondrial redox stress, cardiomyopathy, and a therapeutic target?

PI Göttingen: S.E. Lehnart; PI London: M. Shattock; PhD student: Mufassra Mushtaq

Scientific background and preliminary results

Increased Na+ influx in cardiac myocytes, commonly observed in atrial fibrillation (AF) and heart failure (HF), was attributed to incomplete inactivation of the cardiac Na+ channel isoform NaV1.5 (Goette et al. 2017; Petitprez et al. 2011; Wan et al. 2016). Due to a dramatic increase of the ageing population with improved survival of cardiovascular morbidity, at least twice the number of patients with the the more severe form of AF combined with HF are expected. While there is a clear medical need for new therapeutic approaches for patients with combined AF/HF, the pathophysiological mechanisms are still incompletely understood (Goette et al. 2017). In fact, the precise contribution of ion and redox dysregulation in the ventricles due to AF is currently unknown. Moreover, we discovered recently that the transverse-axial tubule (TAT) system, the membrane invaginations that distribute voltage-regulated Na+ currents throughout cardiac myocytes, is differentially reorganized in a cell-specific fashion both during atrial (Brandenburg et al. 2016) and ventricular hypertrophic remodeling (Wagner et al. 2012). Consistent with progressive remodeling of the TAT network each in the atria and ventricles (Brandenburg et al. 2016; Wagner et al. 2012), AF permissive tissue substrates were recently classified as a stage-like progressive cardiomyopathy, which is initiated through cardiac myocyte dysfunction (Goette et al. 2017). In the ventricles, cardiomyopathic changes and electric instabilities from AF can increase reactive oxygen species (ROS) and intracellular Na+ load. To directly characterize the redox metabolism of mitochondria in living heart cells and tissues during Na+ overload under control conditions versus AF, we employ transgenic biosensor strategies such as mitochondrially targeted Grx1-roGFP2 to measure the glutathione redox potential (EGSH) in cardiac myocytes (Swain et al. 2016). Following initial training in these imaging techniques, the PhD candidate will be in a position to apply quantitative ROS biossensor imaging and to combine (electro)physiology, biochemical, and superresolution techniques. To investigate AF/HF, he/she will analyse a recently established transgenic NaV1.5 model with spontaneous AF episodes and cardiomyopathy. Finally, both genetic and pharmacological interventions are tested that potentially correct the mitochondrial dysfunction during Na+ overload. In summary, the PhD candidate will investigate a central pathophysiological hypotheses: how cardiomyopathy and AF synergize accelerated mitochondrial Ca2+ efflux and metabolic dysfunction due to intracellular Na+ overload, and lead to excess ROS formation with severe cardiac dysfunction (Aksentijevic et al. 2018; Iwai et al. 2002; Kohlhaas et al. 2010).

Prof. Dr. med. Stephan E. Lehnart
Heart Center Göttingen, Department of Cardiology and Pneumology
+49 (0)551-39 10574 or 10650

Research interests: Molecular function and nanoscopic organization of the intracellular calcium release unit, modulation of ion transport proteins by kinases

Prof. Dr. Michael J. Shattock
Cardiovascular Division, KCL

Research interests: Phospholemman and cardiomyocyte ionic homeostasis

Mufassra Mushtaq
PhD student 3rd cohort

RP 2.3: Is increased Na+ influx a cause of mitochondrial redox stress, cardiomyopathy, and a therapeutic target?