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Inflamm Res. 2018 Aug;67(8):691-701. doi: 10.1007/s00011-018-1160-9. Epub 2018 May 23.

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

Lim S1, Lee ME2, Jeong J2,3, Lee J2, Cho S2,3, Seo M2, Park S4,5,6,7.

Author information

1
Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung, Gangwon-do, 25601, Republic of Korea.
2
Severance Integrative Research Institute for Cerebral and Cardiovascular Diseases, Yonsei University College of Medicine, Seoul, Republic of Korea.
3
Graduate Program in Science for Aging and Yonsei Research Institute of Aging Science, Yonsei University, Seoul, Republic of Korea.
4
Severance Integrative Research Institute for Cerebral and Cardiovascular Diseases, Yonsei University College of Medicine, Seoul, Republic of Korea. shpark0530@yuhs.ac.
5
Cardiovascular Research Institute, Yonsei University College of Medicine, Seoul, Republic of Korea. shpark0530@yuhs.ac.
6
Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-752, Republic of Korea. shpark0530@yuhs.ac.
7
Brain Korea 21 Project for Medical Science, Yonsei University, Seoul, Republic of Korea. shpark0530@yuhs.ac.

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.

KEYWORDS:

Cardiac hypertrophy; NLRP3; RAGE; Soluble RAGE

PMID:
29796842
DOI:
10.1007/s00011-018-1160-9
[Indexed for MEDLINE]

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