Toll-like receptor (tlr) 2 and tlr4 differentially regulate doxorubicin induced cardiomyopathy in mice

Yonggang Ma, Xiaowei Zhang, Huayan Bao, Su Mi, Wenfeng Cai, Huimin Yan, Qingqing Wang, Ziyan Wang, Jun Yan, Guochang Fan, Merry L Lindsey, Zhuowei Hu

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

Recent evidence indicates that toll-like receptor (TLR) 2 and 4 are involved in the pathogenesis of dilated cardiomyopathy (DCM), but the exact mechanisms of their actions have not been elucidated. We explored the therapeutic potential of blocking TLRs in mice with established cardiomyopathy. Cardiomyopathy was generated by a single intraperitoneal injection of doxorubicin (10 mg/kg). Two weeks later, the mice were treated with TLR2 or TLR4 neutralizing antibody. Blocking TLR2, but not TLR4, activity not only reduced mortality, but also attenuated doxorubicin-induced cardiac dysfunction by 20% and inhibited myocardial fibrosis. To determine the differential effects of blocking TLR2 and TLR4 in chronic cardiomyopathy, mice were injected with doxorubicin (3.5 mg/kg) once a week for 8 weeks, followed by treatment with TLR2 or TLR4 neutralizing antibody for 40 days. Blocking TLR2 activity blunted cardiac dysfunction by 13% and inhibited cardiac fibrosis, which was associated with a significant suppression of myocardial inflammation. The underlying mechanism involved interrupting the interaction of TLR2 with its endogenous ligands, resulting in attenuation of inflammation and fibrosis. In contrast, blocking TLR4 exacerbated cardiac dysfunction and fibrosis by amplifying inflammation and suppressing autophagy. Our studies demonstrate that TLR2 and TLR4 play distinct roles in the progression of doxorubicin-induced DCM. TLR4 activity is crucial for the resolution of inflammation and cardiac fibrosis, while blocking TLR2 activity has therapeutic potential for the treatment of DCM.

Original languageEnglish (US)
Article numbere40763
JournalPloS one
Volume7
Issue number7
DOIs
StatePublished - Jul 13 2012

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Toll-Like Receptor 2
doxorubicin
cardiomyopathy
Cardiomyopathies
Doxorubicin
fibrosis
Fibrosis
Dilated Cardiomyopathy
mice
Inflammation
inflammation
Neutralizing Antibodies
neutralizing antibodies
Toll-Like Receptor 4
Autophagy
Therapeutics
therapeutics
Intraperitoneal Injections
autophagy
intraperitoneal injection

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Toll-like receptor (tlr) 2 and tlr4 differentially regulate doxorubicin induced cardiomyopathy in mice. / Ma, Yonggang; Zhang, Xiaowei; Bao, Huayan; Mi, Su; Cai, Wenfeng; Yan, Huimin; Wang, Qingqing; Wang, Ziyan; Yan, Jun; Fan, Guochang; Lindsey, Merry L; Hu, Zhuowei.

In: PloS one, Vol. 7, No. 7, e40763, 13.07.2012.

Research output: Contribution to journalArticle

Ma, Y, Zhang, X, Bao, H, Mi, S, Cai, W, Yan, H, Wang, Q, Wang, Z, Yan, J, Fan, G, Lindsey, ML & Hu, Z 2012, 'Toll-like receptor (tlr) 2 and tlr4 differentially regulate doxorubicin induced cardiomyopathy in mice', PloS one, vol. 7, no. 7, e40763. https://doi.org/10.1371/journal.pone.0040763
Ma, Yonggang ; Zhang, Xiaowei ; Bao, Huayan ; Mi, Su ; Cai, Wenfeng ; Yan, Huimin ; Wang, Qingqing ; Wang, Ziyan ; Yan, Jun ; Fan, Guochang ; Lindsey, Merry L ; Hu, Zhuowei. / Toll-like receptor (tlr) 2 and tlr4 differentially regulate doxorubicin induced cardiomyopathy in mice. In: PloS one. 2012 ; Vol. 7, No. 7.
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