Department of Anatomy and Physiology, Faculty of Medicine and Laval Hospital Research Center, Laval University, Quebec, Canada G1V 4G5.
J Mol Cell Cardiol. 2009 Jul;47(1):85-95. doi: 10.1016/j.yjmcc.2009.04.011. Epub 2009 May 3.
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 ( approximately 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 beta5 chymotryptic proteasome activity and mRNA levels of 20S beta2 and beta5 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.
我们研究了罗格列酮治疗在蛋白质合成/降解、mTOR、MAPK 和 AMPK 信号通路、心脏功能和碳水化合物/脂质代谢方面引起的心肌肥厚。通过超声心动图评估了用或不用罗格列酮（15mg/kg/天）治疗 21 天的大鼠心脏的基因表达、蛋白质合成、蛋白酶体和钙蛋白酶活性、信号通路和功能。罗格列酮诱导偏心性心脏肥厚，伴有 ANP、BNP、胶原 I 和 III 以及纤维连接蛋白表达增加，心率降低，心排量增加。罗格列酮显著增加心脏糖原含量（约 400%），这与糖原合酶和 UDPG-PPL mRNA 水平和葡萄糖摄取增加以及糖原磷酸化酶表达和活性降低有关。激动剂还降低了心脏甘油三酯含量、脂蛋白脂肪酶活性和参与脂肪酸氧化的酶的 mRNA 水平。罗格列酮诱导的心肌肥厚与肌原纤维蛋白含量和周转率增加（合成增加和钙蛋白酶介导的肌原纤维降解增强）有关。相比之下，26Sβ5 糜蛋白酶体活性和 20Sβ2、β5 和 19S RPN 2 蛋白酶体亚基以及泛素连接酶 atrogin 和 CHIP 的 mRNA 水平均被罗格列酮降低。这些形态和生化变化与关键生长促进 mTOR 信号通路的显著激活有关，用雷帕霉素抑制该通路可完全阻断罗格列酮诱导的心肌肥厚。该研究表明，蛋白质平衡的两个方面都参与了罗格列酮诱导的心肌肥厚，并确立了 mTOR 通路作为其中的一个新的重要介导物。
