Receptor activator of nuclear factor-κB ligand is a novel inducer of myocardial inflammation

Sangmi OCK; Jihyun AHN; Seok Hong Lee; Hongryeol PARK; Jang Won Son; Jae Gyun Oh; Dong Kwon Yang; Wang Soo Lee; Ho-Shik KIM; Jaerang RHO; Goo Taeg Oh; Evan Dale Abel; Woo Jin Park; Jeong-Ki MIN; Jaetaek KIM

doi:10.1093/cvr/cvs078

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Receptor activator of nuclear factor-κB ligand is a novel inducer of myocardial inflammation

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Receptor activator of nuclear factor-κB ligand is a novel inducer of myocardial inflammation

Sangmi OCK, Jihyun AHN, Seok Hong Lee, Hongryeol PARK, Jang Won Son, Jae Gyun Oh, Dong Kwon Yang, Wang Soo Lee, Ho-Shik KIM, Jaerang RHO, …

Cardiovascular research, Vol.94(1), pp.105-114

2012

DOI: 10.1093/cvr/cvs078

PMID: 22298642

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Abstract

Aims: Although increased levels of myocardial receptor activator of nuclear factor (NF)-κB ligand (RANKL) have been reported in heart failure, the role of this pathway in mediating activation of inflammatory pathways during myocardial remodelling is less well understood. This study sought to determine the role of myocardial RANKL in regulating cytokine expression. Methods and results: A marked increase in RANKL expression occurred as early as 6h following transverse aortic constriction (TAC) in mouse hearts and persisted at 3 and 17 days. An increase in tumour necrosis factor-α (TNF-α), interleukin (IL)-1α, and IL-1β was observed in the hypertrophied hearts only at 3 or 17 days after TAC. Treatment with losartan significantly attenuated TAC-induced cardiac hypertrophy, in parallel with decreased expression of RANKL, TNF-α, IL-1α, and IL-1β. Furthermore, injection of a RANKL-neutralizing monoclonal antibody attenuated RANKL-induced cytokine expression. RANKL stimulated expression of TNF-α, IL-1α, and IL-1β in neonatal rat cardiomyocytes via activation of NF-κB. RANKL-induced NF-κB activation and expression of these cytokines were both attenuated when RANK, receptor for RANKL, or TRAF2 or TRAF6, adaptors for RANK, was silenced by siRNA. Furthermore, inhibitors of phospholipase C (PLC), protein kinase C (PKC), and inhibitor of κB kinase also significantly inhibited RANKL-induced cellular activities, but inhibitors of phosphatidylinositol 3-kinase, extracellular signal-regulated kinase, or p38 mitogen-activated protein kinase were without effect. Conclusion: Our data demonstrate for the first time that the pressure-overloaded myocardium generates RANKL, which induces TNF-α, IL-1α, and IL-1β production via a RANK-TRAF2/TRAF6-PLC-PKC-NF-κB-mediated autocrine mechanism.

Cardiology. Vascular system

Biological and medical sciences

Medical sciences

Details

Title: Subtitle: Receptor activator of nuclear factor-κB ligand is a novel inducer of myocardial inflammation
Creators: Sangmi OCK - Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul 156-755, Korea, Republic of
Jihyun AHN - Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul 156-755, Korea, Republic of
Seok Hong Lee
Hongryeol PARK - Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul, Korea, Republic of
Jang Won Son - Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul 156-755, Korea, Republic of
Jae Gyun Oh - Global Research Laboratory and Department of Life Science, Gwangju Institute of Science and Technology, Gwangju, Korea, Republic of
Dong Kwon Yang - Global Research Laboratory and Department of Life Science, Gwangju Institute of Science and Technology, Gwangju, Korea, Republic of
Wang Soo Lee - Division of Cardiology, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, Korea, Republic of
Ho-Shik KIM - Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul, Korea, Republic of
Jaerang RHO - Department of Microbiology, College of Natural Sciences, Chungnam National University, Daejeon, Korea, Republic of
Goo Taeg Oh - Division of Life and Pharmaceutical Science, Ewha Womans University, Seoul, Korea, Republic of
Evan Dale Abel - Division of Endocrinology, Metabolism and Diabetes, Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, UT, United States
Woo Jin Park - Global Research Laboratory and Department of Life Science, Gwangju Institute of Science and Technology, Gwangju, Korea, Republic of
Jeong-Ki MIN - Department of Biomolecutar Science, University of Science and Technology, Daejeon, Korea, Republic of
Jaetaek KIM - Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul 156-755, Korea, Republic of
Resource Type: Journal article
Publication Details: Cardiovascular research, Vol.94(1), pp.105-114
DOI: 10.1093/cvr/cvs078
PMID: 22298642
NLM abbreviation: Cardiovasc Res
ISSN: 0008-6363
eISSN: 1755-3245
Publisher: Oxford University Press; Oxford
Language: English
Date published: 2012
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
Record Identifier: 9984024518902771

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