Journal
CARDIOVASCULAR RESEARCH
Volume 101, Issue 1, Pages 87-96Publisher
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvt232
Keywords
Tollip; Cardiac remodelling; Pressure overload; AKT; Cardiomyocyte hypertrophy
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Funding
- National Science and Technology Support Project [2011BAI15B02, 2012BAI39B05]
- National Natural Science Foundation of China [81070089, 81100230, 81200071]
- National Natural Science Foundation [81330005]
- National Basic Research Program of China [2011CB503902]
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL105406] Funding Source: NIH RePORTER
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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. First, we observed that Tollip was down-regulated in human failing hearts and murine hypertrophic hearts, as determined by western blotting and RTPCR. 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. Our results provide the first evidence that Tollip serves as a negative regulator of pathological cardiac hypertrophy by blocking the AKT signalling pathway.
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