Journal
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
Volume 79, Issue -, Pages 303-314Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.yjmcc.2014.12.007
Keywords
Cardiac hypertrophy; Angiotensin II; Ubiquitin-proteasome system; Bortezomib; Angiotensin II type 1 receptor-associated protein
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Funding
- National Natural Science Foundation of China [81330003,, 81025001, 510025]
- International S&T Cooperation Program of China [2014DFA31930]
- Changjiang Scholar Program of Chinese Ministry of Education [12011160]
- Importation and Development of High Caliber Talents Project of Beijing Municipal Institutions [CITTCD201404180]
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Proteasomal degradation is critical to maintaining cardiac function and is altered in various diseases. Angiotensin II (Ang II) acts as a growth factor to induce cardiac growth. Here we aimed to test whether proteasome is involved in the development of Ang II-induced cardiac hypertrophy and dissect its molecular mechanisms. Cardiac hypertrophy was induced by Ang II infusion (1000 ng/kg/min) using mini-osmotic pumps. Starting 1 day before implantation, the mice were injected with the proteasome inhibitor bortezomib (BTZ, 50 mu g/kg, 3 times per week) or with vehicle. After 14 days, the pool of ubiquitinated proteins was reduced but the protein expression of proteasome subunits (including beta 1i, beta 2i and beta 5/beta 5i) was markedly up-regulated in left ventricular hypertrophy versus control, which was accompanied by a significant increase in proteasome activities. Furthermore, Ang II-treated mice showed a significant increase in blood pressure but decrease in cardiac contractile function, and significant left ventricular hypertrophy, fibrosis and inflammation, which were all attenuated in BTZ-treated mice. Mechanistically, these beneficial effects were associated with the inhibition of degradation of angiotensin II type 1 receptor-associated protein (ATRAP) and inactivation of AT1R-mediated p38 MAPK and STAT3 signaling pathways. In conclusion, our data indicate that the activation of proteasome is required for the Ang II-induced cardiac hypertrophy, and suggest that the inhibition of proteasome activity by BTZ could be a potential therapeutic strategy for the treatment of cardiac hypertrophy and other heart diseases. (C) 2014 Elsevier Ltd. All rights reserved.
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