title: Toll-interacting protein (Tollip) negatively regulates pressure overload-induced ventricular hypertrophy in mice.
abstract: OBJECTIVE
  Toll-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.
  
  
  RESULTS
  First, 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.
  
  
  CONCLUSIONS
  Our results provide the first evidence that Tollip serves as a negative regulator of pathological cardiac hypertrophy by blocking the AKT signalling pathway.
authors.affiliation: College of Life Sciences, Wuhan University, Wuhan 430072, PR China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liu
authors.forename: Xiao-Li
authors.initials: XL
authors.lastname: Jiang
authors.forename: Yu
authors.initials: Y
authors.lastname: Liu
authors.forename: Ding-Sheng
authors.initials: DS
authors.lastname: Jiang
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Rui
authors.initials: R
authors.lastname: Zhang
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Chen
authors.forename: Qinglin
authors.initials: Q
authors.lastname: Yang
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Zhang
authors.forename: Guo-Chang
authors.initials: GC
authors.lastname: Fan
authors.forename: Hongliang
authors.initials: H
authors.lastname: Li
mesh_terms: D000804:Angiotensin II; D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism*; D015536:Down-Regulation; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism* / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D020257:Ventricular Remodeling
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C410602:TOLLIP protein, human; C485837:Tollip protein, mouse; D000804:Angiotensin II; D051057:Proto-Oncogene Proteins c-akt
keywords: AKT; Cardiac remodelling; Cardiomyocyte hypertrophy; Pressure overload; Tollip