Review Article | Published:

Cysteine protease cathepsins in cardiovascular disease: from basic research to clinical trials

Nature Reviews Cardiologyvolume 15pages351370 (2018) | Download Citation

Abstract

Cysteine protease cathepsins have traditionally been considered as lysosome-restricted proteases that mediate proteolysis of unwanted proteins. However, studies from the past decade demonstrate that these proteases are localized not only in acidic compartments (endosomes and lysosomes), where they participate in intracellular protein degradation, but also in the extracellular milieu, plasma membrane, cytosol, nucleus, and nuclear membrane, where they mediate extracellular matrix protein degradation, cell signalling, and protein processing and trafficking through the plasma and nuclear membranes and between intracellular organelles. Studies in experimental disease models and on cathepsin-selective inhibitors, as well as plasma and tissue biomarker data from animal models and humans, have verified the participation of cysteinyl cathepsins in the pathogenesis of many cardiovascular diseases, including atherosclerosis, myocardial infarction, cardiac hypertrophy, cardiomyopathy, abdominal aortic aneurysms, and hypertension. Clinical trials of cathepsin inhibitors in chronic inflammatory diseases suggest the utility of these inhibitors for the treatment of cardiovascular diseases and associated complications. Moreover, development of cell transfer technologies that enable ex vivo cell treatment with cathepsin inhibitors might limit the unwanted systemic effects of cathepsin inhibition and provide new avenues for targeting cysteinyl cathepsins. In this Review, we summarize the available evidence implicating cysteinyl cathepsins in the pathogenesis of cardiovascular diseases, discuss their potential as biomarkers of disease progression, and explore the potential of cathepsin inhibitors for the treatment of cardiovascular diseases.

Key points

  • Cysteine protease cathepsins act beyond the lysosomes and have widespread physiological and pathological actions, although some cysteinyl cathepsins show tissue-specificity or cell-type-specificity.

  • Cathepsin activity is generally increased in the heart and arterial wall in patients with cardiovascular diseases, and studies in mouse models have established the participation of cathepsins B, C, K, L, and S, and their endogenous inhibitor cystatin C, in various cardiovascular diseases.

  • Cathepsin actions in cardiovascular diseases include the regulation of cell–cell interactions, intracellular signalling, protein expression, angiogenesis, cholesterol metabolism, cell migration, and apoptosis.

  • Cathepsins contribute to cardiovascular inflammation directly and indirectly by regulating innate and adaptive immunity.

  • Plasma cathepsins and cystatins might serve as biomarkers of cardiovascular disease in humans.

  • The development of selective cathepsin antagonists and the results of their preliminary clinical evaluation warrant further clinical trials of cathepsin inhibitors for treatment of certain cardiovascular conditions.

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Acknowledgements

The authors thank C. Swallom (Brigham and Women’s Hospital, Boston, MA, USA) for editorial assistance. The authors are supported by grants from the AHA (17POST33670564 to C.-L.L.), the National Natural Science Foundation of China (81460042 and 81770487 to J.G.), the US National Institutes of Health (HL080472 to P.L. and HL123568 and HL60942 to G.-P.S.), and the Robert R. McCormick Charitable Fund (P.L.).

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  1. These authors contributed equally: Cong-Lin Liu, Junli Guo

Affiliations

  1. Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

    • Cong-Lin Liu
    •  & Guo-Ping Shi
  2. Institute of Cardiovascular Research, the First Affiliated Hospital, Emergency and Trauma College, Hainan Medical University, Haikou, China

    • Junli Guo
    •  & Guo-Ping Shi
  3. Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

    • Cong-Lin Liu
    • , Junli Guo
    • , Xian Zhang
    • , Galina K. Sukhova
    • , Peter Libby
    •  & Guo-Ping Shi

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Contributions

C.-L.L., J.G., X.Z., G.K.S., and G.-P.S. researched the data for the article. C.-L.L., J.G., P.L., and G.-P.S. provided substantial contribution to discussions of the content. P.L. and G.-P.S. wrote the article and reviewed and/or edited the manuscript before submission.

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The authors declare no competing interests.

Corresponding author

Correspondence to Guo-Ping Shi.

Supplementary information

Glossary

Predomain

A short signal peptide located at the amino-terminal domain of cathepsin precursors that is removed during intracellular trafficking.

Prodomain

An amino-terminal peptide of cathepsin precursors that is removed during cathepsin maturation and activation.

M2 macrophages

Alternatively activated macrophages characterized by the production of high levels of anti-inflammatory cytokines.

Buried fibrous caps

Fibrous caps that are unstable and prone to rupture.

Neointima

A new or thickened layer of arterial intima formed in the aorta by migration and proliferation of cells from the media.

M1 macrophages

Classically activated macrophages characterized by the production of high levels of pro-inflammatory cytokines.

Fractional shortening

The fraction of any diastolic dimension that is lost in systole, which is used as measure of cardiac function.

Morphea

A skin condition that causes painless and discoloured patches.

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https://doi.org/10.1038/s41569-018-0002-3