Review Article | Published:

Proteostasis in cardiac health and disease

Nature Reviews Cardiology volume 14, pages 637653 (2017) | Download Citation

Abstract

The incidence and prevalence of cardiac diseases, which are the main cause of death worldwide, are likely to increase because of population ageing. Prevailing theories about the mechanisms of ageing feature the gradual derailment of cellular protein homeostasis (proteostasis) and loss of protein quality control as central factors. In the heart, loss of protein patency, owing to flaws in genetically-determined design or because of environmentally-induced 'wear and tear', can overwhelm protein quality control, thereby triggering derailment of proteostasis and contributing to cardiac ageing. Failure of protein quality control involves impairment of chaperones, ubiquitin–proteosomal systems, autophagy, and loss of sarcomeric and cytoskeletal proteins, all of which relate to induction of cardiomyocyte senescence. Targeting protein quality control to maintain cardiac proteostasis offers a novel therapeutic strategy to promote cardiac health and combat cardiac disease. Currently marketed drugs are available to explore this concept in the clinical setting.

Key points

  • Gradual derailment of cellular protein homeostasis (proteostasis) and loss of protein quality control underlie development of common cardiac diseases

  • Loss of protein patency can be triggered by genetic mutations and environmentally-induced 'wear and tear'

  • Failure of the protein quality control system might relate to the induction of cardiac senescence

  • Targeting protein quality control to maintain cardiac proteostasis is a novel therapeutic option in cardiac diseases

  • Several marketed drugs that target proteostasis have already been explored in the clinical setting for other indications

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Acknowledgements

The authors thank Michelle Michels (Erasmus Medical Center, The Netherlands) for providing human cardiomyocyte samples, Larissa Dorsch and Marit Wiersma (both VU Medical Center, The Netherlands) for providing information for Table 1, and Roelien Meijering and Deli Zhang (ACS Biomarker and VU Medical Center, The Netherlands, respectively) for contributions to the design of Figure 2. Furthermore, we acknowledge the support from The Netherlands Cardiovascular Research Initiative and Dutch Heart Foundation CVON2014-40 DOSIS and CVON-STW2016-14728 AFFIP, Dutch Heart Foundation (2013T096 and 2013T144), and LSH-TKI (40-43100-98-008).

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Affiliations

  1. Department of Clinical Pharmacy and Pharmacology, University Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.

    • Robert H. Henning
  2. Department of Physiology, Amsterdam Cardiovascular Sciences, VU University Medical Center, De Boelelaan 1117, 1081 HZ Amsterdam, The Netherlands.

    • Bianca J. J. M. Brundel

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Both authors researched data for the article, discussed its content, wrote the manuscript, and reviewed and edited it before submission.

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The authors declare no competing financial interests.

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Correspondence to Bianca J. J. M. Brundel.

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https://doi.org/10.1038/nrcardio.2017.89

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