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The TIR/BB-loop mimetic AS-1 prevents cardiac hypertrophy by inhibiting IL-1R-mediated MyD88-dependent signaling

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Abstract

Activation of NF-κB contributes to cardiac hypertrophy and the interleukin-1 receptor (IL-1R)-mediated MyD88-dependent signaling pathway predominately activates NF-κB. Recent studies have shown that the TIR/BB-Loop mimetic (AS-1) disrupted the interaction of MyD88 with the IL-1R, resulting in blunting of NF-κB activation. We have examined the effects of AS-1 on the IL-1β-induced hypertrophic response using cultured neonatal cardiac myocytes in vitro and transverse aortic constriction (TAC) pressure overload-induced cardiac hypertrophy in vivo. Neonatal cardiac myocytes were treated with AS-1 15 min prior to IL-1β stimulation for 24 h. AS-1 treatment significantly attenuated IL-1β-induced hypertrophic responses of cardiac myocytes. In vivo experiments showed that AS-1 administration prevented cardiac hypertrophy and dysfunction induced by pressure overload. AS-1 administration disrupted the interaction of IL-1R with MyD88 in the pressure overloaded hearts and prevented activation of NF-κB. In addition, AS-1 prevented increases in activation of the MAPK pathway (p38 and p-ERK) in TAC-induced hypertrophic hearts. Our data suggest that the IL-1R-mediated MyD88-dependent signaling pathway plays a role in the development of cardiac hypertrophy and AS-1 attenuation of cardiac hypertrophy is mediated by blocking the interaction between IL-1R and MyD88, resulting in decreased NF-κB binding activity and decreased MAPK activation.

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Acknowledgments

This work was supported by the National Natural Science Foundation of China (No. 30571842, No. 30971258 to Dr. Yuehua Li, No. 30730044 to Dr. Qi Chen).

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Authors and Affiliations

  1. Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Pathophysiology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, 210029, Jiangsu, China

    Yun Zhu, Ting Li, Juan Song, Chunyang Liu, Yulong Hu, Lingli Que, Qi Chen & Yuehua Li

  2. Department of Surgery, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA

    Tuanzhu Ha & Chuanfu Li

  3. Department of Internal Medicine, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, 37614, USA

    Jim Kelley

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  1. Yun Zhu
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  2. Ting Li
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  3. Juan Song
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  5. Yulong Hu
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  10. Chuanfu Li
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  11. Yuehua Li
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Correspondence to Yuehua Li.

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Y. Zhu and T. Li contributed equally to the work.

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Zhu, Y., Li, T., Song, J. et al. The TIR/BB-loop mimetic AS-1 prevents cardiac hypertrophy by inhibiting IL-1R-mediated MyD88-dependent signaling. Basic Res Cardiol 106, 787–799 (2011). https://doi.org/10.1007/s00395-011-0182-z

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  • DOI: https://doi.org/10.1007/s00395-011-0182-z

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