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HMGB1/TLR4 axis contributes to A/R‐induced cardiomyocyte apoptosis through potentiating TNFα/JNK pathway
Author(s) -
Xu Xuemei,
Yao Yongwei,
Kao Raymond,
Martin Claudio M,
Rui Tao
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1000.4
Subject(s) - apoptosis , myocyte , tumor necrosis factor alpha , western blot , hmgb1 , chemistry , microbiology and biotechnology , tlr4 , programmed cell death , signal transduction , biology , endocrinology , receptor , biochemistry , gene
The present study is to explore the role of HMGB1/TLR4 axis in the myocyte apoptosis‐induced by A/R (an in vitro counterpart to I/R). Methods cardiomyocytes derived from wild type or TLR4 deficient mice were challenged with an A/R. HMGB1, TNFα expression (Western blot and ELISA), myocyte apoptosis (caspase 3 activity and cell death ELISA) and JNK and NFκB activation (p65 phosphorylation) (Western blot) assessed. Results A/R challenge to myocytes resulted in an increase in HMGB1 expression and extracellular release. Inhibition of HMGB1 attenuated the apoptosis and A/R‐induced TNFα production. Treatment of cardiomyocytes with recombinant HMGB1 (1–5 μg/ml) did not lead to myocyte apoptosis and TNFα production. Exogenous TNFα induced a moderate pro‐apoptotic effect on the myocytes; an effect substantially potentiated by HMGB1. TNFα activated both JNK and NFκB. However, degree of TNFα–induced JNK activation was greater than NFκB in the presence of HMGB1. Inhibition of JNK diminished the myocytes apoptosis‐induced by either TNFα or TNFα/HMGB1 cocktail. A/R‐challenge to TLR4 deficient myocytes increased HMGB1 but not apoptosis, TNFα production and JNK activation. Conclusions our results indicate myocyte HMGB1/TLR4 axis and TNFα work in concert to promote A/R‐induced myocyte apoptosis via JNK activation. (HSFO NA‐6316).