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Targeting Mitochondrial Calcium Handling and Reactive Oxygen Species in Heart Failure

  • Experimental Therapeutics (L.S. Maier, Section Editor)
  • Published:
Current Heart Failure Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

In highly prevalent cardiac diseases, new therapeutic approaches are needed. Since the first description of oxidative stress in heart failure, reactive oxygen species (ROS) have been considered as attractive drug targets. Though clinical trials evaluating antioxidant vitamins as ROS-scavenging agents yielded neutral results in patients at cardiovascular risk, the knowledge of ROS as pathophysiological factors has considerably advanced in the past few years and led to novel treatment approaches. Here, we review recent new insights and current strategies in targeting mitochondrial calcium handling and ROS in heart failure.

Recent Findings

Mitochondria are an important ROS source, and more recently, drug development focused on targeting mitochondria (e.g. by SS-31 or MitoQ). Important advancement has also been made to decipher how the matching of energy supply and demand through calcium (Ca2+) handling impacts on mitochondrial ROS production and elimination. This opens novel opportunities to ameliorate mitochondrial dysfunction in heart failure by targeting cytosolic and mitochondrial ion transporters to improve this matching process. According to this approach, highly specific substances as the preclinical CGP-37157, as well as the clinically used ranolazine and empagliflozin, provide promising results on different levels of evidence. Furthermore, the understanding of redox signalling relays, resembled by catalyst-mediated protein oxidation, is about to change former paradigms of ROS signalling. Novel methods, as redox proteomics, allow to precisely analyse key regulatory thiol switches, which may induce adaptive or maladaptive signalling. Additionally, the generation of genetically encoded probes increased the spatial and temporal resolution of ROS imaging and opened a new methodological window to subtle, formerly obscured processes.

Summary

These novel insights may broaden our understanding of why previous attempts to target oxidative stress have failed, and at the same time provide us with new targets for drug development.

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Acknowledgements

AD is supported by a research grant of the German Cardiac Society (DGK). CM is supported by the Deutsche Forschungsgemeinschaft (DFG; Heisenberg Professur; Sonderforschungsbereich SFB 894; research grant Ma 2528/7-1), Corona Stiftung and Deutsche Herzstiftung.

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  1. Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, 66421, Homburg, Germany

    Alexander Dietl & Christoph Maack

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Alexander Dietl declares no conflict of interest.

Christoph Maack has received speaker honoraria from Stealth Biotherapeutics, Boehringer Ingelheim and Berlin Chemie and has been an advisor to Stealth Biotherapeutics.

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Dietl, A., Maack, C. Targeting Mitochondrial Calcium Handling and Reactive Oxygen Species in Heart Failure. Curr Heart Fail Rep 14, 338–349 (2017). https://doi.org/10.1007/s11897-017-0347-7

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