Toll-interacting protein (Tollip) negatively regulates pressure overload-induced ventricular hypertrophy in mice

Yi Liu, Xiao Li Jiang, Yu Liu, Ding Sheng Jiang, Yan Zhang, Rui Zhang, Yingjie Chen, Qinglin Yang, Xiao Dong Zhang, Guo Chang Fan, Hongliang Li

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

AimsToll-interacting protein (Tollip) is a critical regulator of the Toll-like receptor-mediated signalling pathway. However, the role of Tollip in chronic pressure overload-induced cardiac hypertrophy remains unclear. This study aimed to determine the functional significance of Tollip in the regulation of aortic banding-induced cardiac remodelling and its underlying mechanisms.Methods and resultsFirst, we observed that Tollip was down-regulated in human failing hearts and murine hypertrophic hearts, as determined by western blotting and RT-PCR. Using cultured neonatal rat cardiomyocytes, we found that adenovirus vector-mediated overexpression of Tollip limited angiotensin II-induced cell hypertrophy; whereas knockdown of Tollip by shRNA exhibited the opposite effects. We then generated a transgenic (TG) mouse model with cardiac specific-overexpression of Tollip and subjected them to aortic banding (AB) for 8 weeks. When compared with AB-treated wild-type mouse hearts, Tollip-TGs showed a significant attenuation of cardiac hypertrophy, fibrosis, and dysfunction, as measured by echocardiography, immune-staining, and molecular/biochemical analysis. Conversely, a global Tollip-knockout mouse model revealed an aggravated cardiac hypertrophy and accelerated maladaptation to chronic pressure overloading. Mechanistically, we discovered that Tollip interacted with AKT and suppressed its downstream signalling pathway. Pre-activation of AKT in cardiomyocytes largely offset the Tollip-elicited anti-hypertrophic effects.ConclusionOur results provide the first evidence that Tollip serves as a negative regulator of pathological cardiac hypertrophy by blocking the AKT signalling pathway.

Original languageEnglish (US)
Pages (from-to)87-96
Number of pages10
JournalCardiovascular Research
Volume101
Issue number1
DOIs
StatePublished - Jan 1 2014

Keywords

  • AKT
  • Cardiac remodelling
  • Cardiomyocyte hypertrophy
  • Pressure overload
  • Tollip

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    Liu, Y., Jiang, X. L., Liu, Y., Jiang, D. S., Zhang, Y., Zhang, R., Chen, Y., Yang, Q., Zhang, X. D., Fan, G. C., & Li, H. (2014). Toll-interacting protein (Tollip) negatively regulates pressure overload-induced ventricular hypertrophy in mice. Cardiovascular Research, 101(1), 87-96. https://doi.org/10.1093/cvr/cvt232