Laszlo Deres
University of Pecs, Hungary
Title: Effect of PARP-1 inhibition on the mitochondrial fragmentation in an in vivo SHR model
Biography
Biography: Laszlo Deres
Abstract
Introduction: Mitochondria form a highly dynamic network, which current state is determined by fusion-fission processes. Oxidative stress induced fragmentation of cardiac mitochondria is a well known phenomenon, which has profound effects on cell viability. Thus, influencing these processes may have therapeutic importance. In our experiment, we evaluated the effect of PARP-1 inhibition on cardiac mitochondrial changes due to persistent hypertension.
Methods: 10 weeks old male SHR rats received 5 mg/kg/day L-2286 PARP-1 inhibitor (SHR-L) or placebo (SHR-C) treatment for 32 weeks. Normotensive controls were male Wistar rats (WKY). After the treatment, electron microscopic preparations were made from cardiac tissues. We evaluated the average areas of inter-fibrillar mitochondria (IFM) on longitudinal sections. The levels of proteins involved in mitochondrial dynamics (the pro-fission Drp1 GTPase and cristae membrane integrity influencing Opa1) were monitored by fractioned Western blot samples.
Results: Mitochondria showed greater heterogeneity in both shape and size in the SHR-C group, and dilatation of cristae spaces were observed. These alterations were less pronounced in the treatment group. We found increased fragmentation of mitochondria in the SHR-C group (p<0.05 vs. WKY), which was significantly attenuated by the L-2286 treatment. Western blot analysis showed decreased translocation of the pro-fission Drp1 protein into the mitochondria in the SHR-L group compared to the SHR-C group. No significant changes were observed in the level of Opa1 expression.
Discussion: In a hypertensive animal model, the oxidative stress-induced cardiac mitochondrial fragmentation was significantly attenuated by L-2286 treatment. This may be due to the favorable signaling effect of PARP-1 inhibition beside its well-known effect on increased oxidative stress resistance and on increased bioenergetic stability of the heart.