Bell David, McDermott Barbara J
Department of Therapeutics and Pharmacology, Cardioendocrine Research Group, Centre for Cardiovascular Research, The School of Medicine, The Queen's University of Belfast, Northern Ireland, UK.
Eur J Pharmacol. 2005 Jan 31;508(1-3):69-76. doi: 10.1016/j.ejphar.2004.12.027. Epub 2005 Jan 12.
Chronic administration of thiazolidinediones might predispose to cardiac hypertrophy. The aim was to investigate direct effects of rosiglitazone in rat ventricular cardiomyocytes maintained in vitro (24 h). Rosiglitazone (< or =10(-5) M) did not increase protein synthesis and produced small inconsistent increases in cellular protein. In the presence of serum (10% v/v), but not insulin-like growth factor (IGF-1, 10(-8) M) or insulin (1 U/ml), an interaction with rosiglitazone to stimulate protein synthesis was observed. The hypertrophic responses to noradrenaline (5x10(-6) M), PMA (10(-7) M) and ET-1 (10(-7) M) were not attenuated by rosiglitazone. Rosiglitazone (10(-7) M) did not influence protein synthesis in response to insulin (1 U/ml) and elevated glucose (2.5x10(-2) M) alone or in combination, but attenuated the increase in protein mass observed in response to elevated glucose alone. In re-differentiated cardiomyocytes, a model of established hypertrophy, rosiglitazone (10(-8) M-10(-6) M) increased protein synthesis. Together, these data indicate that rosiglitazone does not initiate cardiomyocyte hypertrophy directly in vitro. However, during chronic administration, the interaction of rosiglitazone with locally-derived growth-regulating factors may make a modest contribution to cardiac remodelling and influence the extent of compensatory hypertrophy of the compromised rat heart.
长期服用噻唑烷二酮类药物可能会导致心脏肥大。本研究旨在探讨罗格列酮对体外培养24小时的大鼠心室心肌细胞的直接作用。罗格列酮（≤10⁻⁵M）不会增加蛋白质合成，且对细胞蛋白质的增加作用微小且不稳定。在存在血清（10% v/v）的情况下，但在胰岛素样生长因子（IGF-1，10⁻⁸M）或胰岛素（1 U/ml）不存在时，观察到罗格列酮与血清相互作用刺激蛋白质合成。罗格列酮对去甲肾上腺素（5×10⁻⁶M）、佛波酯（PMA，10⁻⁷M）和内皮素-1（ET-1，10⁻⁷M）引起的肥大反应没有减弱作用。罗格列酮（10⁻⁷M）单独或联合胰岛素（1 U/ml）和高糖（2.5×10⁻²M）时，对蛋白质合成没有影响，但减弱了单独高糖引起的蛋白质质量增加。在已建立肥大模型的再分化心肌细胞中，罗格列酮（10⁻⁸M - 10⁻⁶M）增加了蛋白质合成。总之，这些数据表明罗格列酮在体外不会直接引发心肌细胞肥大。然而，在长期给药过程中，罗格列酮与局部产生的生长调节因子的相互作用可能对心脏重塑有一定作用，并影响受损大鼠心脏代偿性肥大的程度。
