Pneumologie 2015; 69 - A43
DOI: 10.1055/s-0035-1556635

Preserved right ventricular function in mitochondrial uncoupling protein 2 deficient mice in pressure overload induced right ventricular insufficiency

A Esfandiary 1, N Sommer 1, O Pak 1, B Kojonazarov 1, A Sydykov 1, D Haag 1, M Hecker 1, W Seeger 1, 2, HA Ghofrani 1, R Schermuly 1, N Weissmann 1, R Schulz 3, R Schreckenberg 3, KD Schlüter 3
  • 1Excellence Cluster Cardio-Pulmonary System (ECCPS), Universities of Gießen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Gießen, Germany
  • 2Department of Lung Development and Remodeling, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany
  • 3Institute of Physiology, Justus-Liebig University, Gießen, Germany

Right ventricular (RV) insufficiency is caused by RV pressure overload, when mechanisms compensating the increased afterload cannot maintain RV function. Similar to the left ventricle, compensatory and decompensatory mechanisms may be regulated by cellular calcium dynamics and reactive oxygen species (ROS). The mitochondrial uncoupling protein 2 (UCP2) can regulate mitochondrial calcium and ROS, and thus may interfere with development of RV insufficiency.

RV pressure-overload was induced in UCP2-KO and wild type (WT) mice by pulmonary arterial banding (PAB). Three weeks after PAB or sham operation RV function was determined by invasive hemodynamics and echocardiography. Contraction and relaxation of cardiomyocytes isolated from these mice, as well as cellular calcium dynamics and mitochondrial superoxide release were measured by fluorescence microscopy. Expression of the cardiac calcium handling proteins sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA2a) and the sodium/calcium exchanger (NCX) were determined by immunoblotting. Mitochondrial respiration of RV muscle fibers was determined by high resolution respirometry

RV function was preserved in UCP2-KO mice after PAB, while it decreased in WT mice. The maintenance of RV function on organ level correlated to better contraction and relaxation of isolated cardiomyocytes in UCP2-KO mice after PAB and was associated with higher systolic calcium transients and diastolic calcium extrusion compared to WT mice. SERCA2a protein levels, but not NCX levels were increased in isolated cardiomyocytes from UCP2-KO mice after PAB compared to WT mice. While mitochondrial superoxide levels were increased in UCP2-KO mice after PAB, mitochondrial respiration was not different in RV muscle fibers of all groups.

We conclude that UCP2 deficiency protects from pressure-overload induced RV insufficiency via improved cardiomyocyte calcium dynamics due to increased SERCA2a expression, which may be regulated by mitochondrial ROS release. Thus UCP2, as well as SERCA2a may provide novel therapeutic targets to inhibit development of RV insufficiency.

*Presenting author