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  • Review Article
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Endoplasmic reticulum stress and unfolded protein response in cardiovascular diseases

Nature Reviews Cardiology volume 18, pages 499–521 (2021)Cite this article

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Abstract

Cardiovascular diseases (CVDs), such as ischaemic heart disease, cardiomyopathy, atherosclerosis, hypertension, stroke and heart failure, are among the leading causes of morbidity and mortality worldwide. Although specific CVDs and the associated cardiometabolic abnormalities have distinct pathophysiological and clinical manifestations, they often share common traits, including disruption of proteostasis resulting in accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER). ER proteostasis is governed by the unfolded protein response (UPR), a signalling pathway that adjusts the protein-folding capacity of the cell to sustain the cell’s secretory function. When the adaptive UPR fails to preserve ER homeostasis, a maladaptive or terminal UPR is engaged, leading to the disruption of ER integrity and to apoptosis. ER stress functions as a double-edged sword, with long-term ER stress resulting in cellular defects causing disturbed cardiovascular function. In this Review, we discuss the distinct roles of the UPR and ER stress response as both causes and consequences of CVD. We also summarize the latest advances in our understanding of the importance of the UPR and ER stress in the pathogenesis of CVD and discuss potential therapeutic strategies aimed at restoring ER proteostasis in CVDs.

Key points

  • The endoplasmic reticulum (ER) regulates crucial processes governing cardiovascular function; ER and mitochondria contacts assist in the transport of mitochondrial Ca2+, and abnormalities cause cardiomyocyte mitochondrial dysfunction.

  • ER stress can be beneficial through an adaptive unfolded protein response (UPR) or detrimental through a maladaptive UPR; excessive ER stress perturbs the function of secretory pathways, contributing to cardiovascular pathology.

  • ER stress can be either a cause or a consequence of cardiovascular disease (CVD); disrupted ER homeostasis provokes the onset of CVD, which further exacerbates ER stress, creating a vicious cycle.

  • Canonical and non-canonical ER stress signalling can contribute to either cardiovascular protection or pathology, depending on the cellular environment and disease progression status.

  • Classic ER stress sensors (such as inositol-requiring protein 1α) also have a non-canonical function, such as scaffolding between cellular organelles.

  • Strategies to reduce ER stress (such as small-molecule proteostasis promoters and gene therapy) help to stabilize misfolded proteins and promote correct protein folding, thereby contributing to the prevention and management of CVD.

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Fig. 1: ER contacts with organelles and ER function in protein, lipid and Ca2+ homeostasis.
Fig. 2: ER stress in cardiovascular disease.
Fig. 3: Adaptive and maladaptive unfolded protein response.
Fig. 4: Interplay between cardiovascular disease, ER stress and ER stress response.
Fig. 5: ER stress and Ca2+ homeostasis in cardiovascular disease.

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Acknowledgements

We express our sincere apology to those authors whose important work could not be included due to space limitations. We greatly appreciate the graphic design assistance of A. Ajoolabady (Tabriz University of Medical Sciences, Iran) and N.N. Wu (Zhongshan Hospital, Fudan University, China) for preparing the figures for initial submission. The authors’ research work was supported by the National Key R&D Program of China (2017YFA0506000), University of Wyoming Faculty Grant-in-Aid, FONDECYT 11180186, FONDAP program ANID/FONDAP/15150012, Millennium Institute P09-015-F, European Commission R&D MSCA-RISE 734749, Natural Science Foundation of China (91749128, 81770261, 81521001), Science and Technology Innovation Project of the Chinese Academy of Medical Sciences (Health and Longevity Pilot Special Project 2019-RC-HL-021) and the Training Program of Excellent Academic Leaders of Shanghai Health Mission (2018BR25).

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Authors and Affiliations

  1. Department of Cardiology and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China

    Jun Ren, Yaguang Bi & Yingmei Zhang

  2. Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, WY, USA

    Jun Ren

  3. Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA

    Jun Ren

  4. Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, USA

    James R. Sowers

  5. Diabetes and Cardiovascular Center, University of Missouri School of Medicine, Columbia, MO, USA

    James R. Sowers

  6. Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile

    Claudio Hetz

  7. FONDAP Center for Geroscience Brain Health and Metabolism, Santiago, Chile

    Claudio Hetz

  8. Program of Cellular and Molecular Biology, Institute of Biomedical Science, University of Chile, Santiago, Chile

    Claudio Hetz

  9. Buck Institute for Research on Aging, Novato, CA, USA

    Claudio Hetz

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  1. Jun Ren
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J.R. researched data for the article, contributed to discussion of the content, wrote the article and reviewed and/or edited the article before submission. Y.B., J.R.S, C.H. and Y.Z. contributed to discussion of the content and wrote the manuscript.

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Ren, J., Bi, Y., Sowers, J.R. et al. Endoplasmic reticulum stress and unfolded protein response in cardiovascular diseases. Nat Rev Cardiol 18, 499–521 (2021). https://doi.org/10.1038/s41569-021-00511-w

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