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Title: Rosiglitazone-induced heart remodelling is associated with enhanced turnover of myofibrillar protein and mTOR activation.
Authors: Festuccia, William Tadeu Lara
Laplante, Mathieu
Brûlé, Sophie
Houde, Vanessa P.
Achouba, Adel
Lachance, Dominic
Pedrosa, Maria Lúcia
Silva, Marcelo Eustáquio
Cota, Renata Guerra de Sá
Couet, Jacques
Arsenault, Marie
Marette, André
Deshaies, Yves
Keywords: Protein synthesis
Issue Date: 2009
Citation: FESTUCCIA, W. T. L. et al. Rosiglitazone-induced heart remodelling is associated with enhanced turnover of myofibrillar protein and mTOR activation. Journal of Molecular and Cellular Cardiology, v. 47, p. 85-95, 2009. Disponível em: <>. Acesso em: 08 nov. 2014.
Abstract: We investigated cardiac hypertrophy elicited by rosiglitazone treatment at the level of protein synthesis/ degradation, mTOR, MAPK and AMPK signalling pathways, cardiac function and aspects of carbohydrate/ lipid metabolism. Hearts of rats treated or not with rosiglitazone (15 mg/kg day) for 21 days were evaluated for gene expression, protein synthesis, proteasome and calpain activities, signalling pathways, and function by echocardiography. Rosiglitazone induced eccentric heart hypertrophy associated with increased expression of ANP, BNP, collagen I and III and fibronectin, reduced heart rate and increased stroke volume. Rosiglitazone robustly increased heart glycogen content (∼400%), an effect associated with increases in glycogenin and UDPG-PPL mRNA levels and glucose uptake, and a reduction in glycogen phosphorylase expression and activity. Cardiac triglyceride content, lipoprotein lipase activity and mRNA levels of enzymes involved in fatty acid oxidation were also reduced by the agonist. Rosiglitazone-induced cardiac hypertrophy was associated with an increase in myofibrillar protein content and turnover (increased synthesis and an enhancement of calpain-mediated myofibrillar degradation). In contrast, 26S β5 chymotryptic proteasome activity and mRNA levels of 20S β2 and β5 and 19S RPN 2 proteasome subunits along with the ubiquitin ligases atrogin and CHIP were all reduced by rosiglitazone. These morphological and biochemical changes were associated with marked activation of the key growth-promoting mTOR signalling pathway, whose pharmacological inhibition with rapamycin completely blocked cardiac hypertrophy induced by rosiglitazone. The study demonstrates that both arms of protein balance are involved in rosiglitazone-induced cardiac hypertrophy, and establishes the mTOR pathway as a novel important mediator therein.
ISSN: 0022-2828
metadata.dc.rights.license: O periódico Journal of Molecular and Cellular Cardiology concede permissão para depósito deste artigo no Repositório Institucional da UFOP. Número da licença: 3530901251605.
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