Xu Ya, Gen Michael, Lu Li, Fox Jennifer, Weiss Sara O, Brown R Dale, Perlov Daniel, Ahmad Hasan, Zhu Peili, Greyson Clifford, Long Carlin S, Schwartz Gregory G
Cardiology Section, Veterans Affairs Medical Center and University of Colorado Health Sciences Center, Denver, Colorado 80220, USA.
Am J Physiol Heart Circ Physiol. 2005 Mar;288(3):H1314-23. doi: 10.1152/ajpheart.00618.2004. Epub 2004 Nov 4.
Peroxisome proliferator-activated receptor (PPAR)-gamma modulates substrate metabolism and inflammatory responses. In experimental rats subjected to myocardial ischemia-reperfusion (I/R), thiazolidinedione PPAR-gamma activators reduce infarct size and preserve left ventricular function. Troglitazone is the only PPAR-gamma activator that has been shown to be protective in I/R in large animals. However, because troglitazone contains both alpha-tocopherol and thiazolidinedione moieties, whether PPAR-gamma activation per se is protective in myocardial I/R in large animals remains uncertain. To address this question, 56 pigs were treated orally for 8 wk with troglitazone (75 mg x kg(-1) x day(-1)), rosiglitazone (3 mg x kg(-1) x day(-1)), or alpha-tocopherol (73 mg x kg(-1) x day(-1), equimolar to troglitazone dose) or received no treatment. Pigs were then anesthetized and subjected to 90 min of low-flow regional myocardial ischemia and 90 min of reperfusion. Myocardial expression of PPAR-gamma, determined by ribonuclease protection assay, increased with troglitazone and rosiglitazone compared with no treatment. Rosiglitazone had no significant effect on myocardial contractile function (Frank-Starling relations), substrate uptake, or expression of proinflammatory cytokines during I/R compared with untreated pigs. In contrast, preservation of myocardial contractile function and lactate uptake were greater and cytokine expression was attenuated in pigs treated with troglitazone or alpha-tocopherol compared with untreated pigs. Multivariate analysis indicated that presence of an alpha-tocopherol, but not a thiazolidinedione, moiety in the test compound was significantly related to greater contractile function and lactate uptake and lower cytokine expression during I/R. We conclude that PPAR-gamma activation is not protective in a porcine model of myocardial I/R. Protective effects of troglitazone are attributable to its alpha-tocopherol moiety. These findings, in conjunction with prior rat studies, suggest interspecies differences in the response to PPAR-gamma activation in the heart.
过氧化物酶体增殖物激活受体（PPAR）-γ可调节底物代谢和炎症反应。在经历心肌缺血再灌注（I/R）的实验大鼠中，噻唑烷二酮类PPAR-γ激活剂可减小梗死面积并维持左心室功能。曲格列酮是唯一已被证明在大型动物的I/R中具有保护作用的PPAR-γ激活剂。然而，由于曲格列酮同时含有α-生育酚和噻唑烷二酮部分，PPAR-γ激活本身在大型动物心肌I/R中是否具有保护作用仍不确定。为解决这个问题，56头猪分别口服曲格列酮（75mg·kg⁻¹·天⁻¹）、罗格列酮（3mg·kg⁻¹·天⁻¹）或α-生育酚（73mg·kg⁻¹·天⁻¹，与曲格列酮剂量等摩尔）8周，或不接受任何治疗。然后将猪麻醉，使其经历90分钟的低流量局部心肌缺血和90分钟的再灌注。通过核糖核酸酶保护试验测定，与未治疗相比，曲格列酮和罗格列酮可使心肌PPAR-γ表达增加。与未治疗的猪相比，罗格列酮在I/R期间对心肌收缩功能（Frank-Starling关系）、底物摄取或促炎细胞因子表达没有显著影响。相反，与未治疗的猪相比，用曲格列酮或α-生育酚治疗的猪心肌收缩功能和乳酸摄取的保留情况更好，细胞因子表达减弱。多变量分析表明，受试化合物中存在α-生育酚部分而非噻唑烷二酮部分，与I/R期间更好的收缩功能、乳酸摄取以及更低的细胞因子表达显著相关。我们得出结论，PPAR-γ激活在猪心肌I/R模型中没有保护作用。曲格列酮的保护作用归因于其α-生育酚部分。这些发现与先前的大鼠研究一起，提示心脏对PPAR-γ激活的反应存在种间差异。
