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sRAGE attenuates angiotensin II-induced cardiomyocyte hypertrophy by inhibiting RAGE-NFκB-NLRP3 activation

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Abstract

Objective and design

The receptor for advanced glycation endproducts (RAGE) is an innate immunity receptor that has been implicated in the pathogenesis of atherosclerotic cardiovascular disease. However, the possibility that RAGE-mediated signaling is involved in angiotensin II (Ang II)-induced cardiac left ventricular hypertrophy has yet to be investigated. We therefore determined whether RAGE has a role in regulating pathological cardiac hypertrophy.

Materials and subjects

Protein abundance was estimated using Western blotting and intracellular ROS level and phospho-p65 were detected using fluorescence microscopy. Enzyme-linked immunosorbent assay was used to detect HMGB1 and IL-1β. All in vitro experiments were performed using H9C2 cells.

Treatments

To induce cardiomyocyte hypertrophy, 300 nM Ang II was treated for 48 h and 2 µg/ml sRAGE was treated 1 h prior to addition of Ang II.

Results

sRAGE attenuated Ang II-induced cardiomyocyte hypertrophy by downregulating RAGE and angiotensin II type 1 receptor expression. Secretion levels of high motility group box 1 and interleukin-1β, estimated from a cell culture medium, were significantly reduced by sRAGE. Activated PKCs and ERK1/2, important signals in left ventricular hypertrophy (LVH) development, were downregulated by sRAGE treatment. Furthermore, we found that nuclear factor-κB and NOD-like receptor protein 3 (NLRP3) were associated with RAGE-mediated cardiomyocyte hypertrophy.

Conclusions

In the context of these results, we conclude that RAGE induces cardiac hypertrophy through the activation of the PKCs-ERK1/2 and NF-κB-NLRP3-IL1β signaling pathway, and suggest that RAGE-NLRP3 may be an important mediator of Ang II-induced cardiomyocyte hypertrophy. In addition, we determined that inhibition of RAGE activation with soluble RAGE (sRAGE) has a protective effect on Ang II-induced cardiomyocyte hypertrophy.

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Abbreviations

AT1R:

Angiotensin II receptor type I

RAGE:

Receptor for advanced glycation endproducts

Ang II:

Angiotensin II

NLRP3:

Nucleotide-binding oligomerization domain-like receptor protein 3

sRAGE:

Soluble RAGE

LVH:

Left ventricular hypertrophy

ROS:

Reactive oxygen species

HMGB1:

High-mobility group box 1

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Acknowledgements

This study was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT, and Future Planning (NRF-2015R1A2A2A01007346) and (NRF-2015R1C1A1A01054945), and by the Korea Health 21 R&D Project, Ministry of Health & Welfare, Republic of Korea (HI08C2149).

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Author notes

  1. Soyeon Lim and Myung Eun Lee are equally contributed to this article as co-first authors.

Authors and Affiliations

  1. Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung, Gangwon-do, 25601, Republic of Korea

    Soyeon Lim

  2. Severance Integrative Research Institute for Cerebral and Cardiovascular Diseases, Yonsei University College of Medicine, Seoul, Republic of Korea

    Myung Eun Lee, Jisu Jeong, Jiye Lee, Soyoung Cho, Miran Seo & Sungha Park

  3. Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea

    Sungha Park

  4. Graduate Program in Science for Aging and Yonsei Research Institute of Aging Science, Yonsei University, Seoul, Republic of Korea

    Jisu Jeong & Soyoung Cho

  5. Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Republic of Korea

    Sungha Park

  6. Brain Korea 21 Project for Medical Science, Yonsei University, Seoul, Republic of Korea

    Sungha Park

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  1. Soyeon Lim
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Contributions

MEL mainly participated in all experiments and editing manuscript and SL and SP mainly conceive the study and wrote the manuscript; JJ, JL, and SC performed the experiment and analyses; MS participated in the study design. All the authors read and approved the final manuscript.

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Correspondence to Sungha Park.

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The authors declare that they have no competing interests.

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Lim, S., Lee, M.E., Jeong, J. et al. sRAGE attenuates angiotensin II-induced cardiomyocyte hypertrophy by inhibiting RAGE-NFκB-NLRP3 activation. Inflamm. Res. 67, 691–701 (2018). https://doi.org/10.1007/s00011-018-1160-9

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