Young M E, Patil S, Ying J, Depre C, Ahuja H S, Shipley G L, Stepkowski S M, Davies P J, Taegtmeyer H
Division of Cardiology, Department of Integrative Biology, University of Texas Houston Medical Center, Houston, Texas 77030, USA.
FASEB J. 2001 Mar;15(3):833-45. doi: 10.1096/fj.00-0351com.
Relatively little is known concerning the regulation of uncoupling proteins (UCPs) in the heart. We investigated in the adult rodent heart 1) whether changes in workload, substrate supply, or cytokine (TNF-alpha) administration affect UCP-2 and UCP-3 expression, and 2) whether peroxisome proliferator-activated receptor alpha (PPARalpha) regulates the expression of either UCP-2 or UCP-3. Direct comparisons were made between cardiac and skeletal muscle. UCP-2, UCP-3, and PPARalpha expression were reduced when cardiac workload was either increased (pressure overload by aortic constriction) or decreased (mechanical unloading by heterotopic transplantation). Similar results were observed during cytokine administration. Reduced dietary fatty acid availability resulted in decreased expression of both cardiac UCP-2 and UCP-3. However, when fatty acid (the natural ligand for PPARalpha) supply was increased (high-fat feeding, fasting, and STZ-induced diabetes), cardiac UCP-3 but not UCP-2 expression increased. Comparable results were observed in rats treated with the specific PPARalpha agonist WY-14,643. The level of cardiac UCP-3 but not UCP-2 expression was severely reduced (20-fold) in PPARalpha-/- mice compared to wild-type mice. These results suggest that in the adult rodent heart, UCP-3 expression is regulated by PPARalpha. In contrast, cardiac UCP-2 expression is regulated in part by a fatty acid-dependent, PPARalpha-independent mechanism.
关于心脏中解偶联蛋白（UCPs）的调节，人们所知相对较少。我们在成年啮齿动物心脏中进行了研究：1）工作量、底物供应或细胞因子（TNF-α）给药的变化是否会影响UCP-2和UCP-3的表达；2）过氧化物酶体增殖物激活受体α（PPARα）是否调节UCP-2或UCP-3的表达。对心脏和骨骼肌进行了直接比较。当心脏工作量增加（主动脉缩窄导致压力过载）或减少（异位移植导致机械卸载）时，UCP-2、UCP-3和PPARα的表达均降低。在给予细胞因子期间也观察到了类似结果。饮食中脂肪酸可利用性降低导致心脏UCP-2和UCP-3的表达均下降。然而，当脂肪酸（PPARα的天然配体）供应增加（高脂喂养、禁食和链脲佐菌素诱导的糖尿病）时，心脏UCP-3的表达增加，而UCP-2的表达未增加。在用特异性PPARα激动剂WY-14,643处理的大鼠中也观察到了类似结果。与野生型小鼠相比，PPARα基因敲除小鼠心脏中UCP-3的表达水平严重降低（20倍），而UCP-2的表达未受影响。这些结果表明，在成年啮齿动物心脏中，UCP-3的表达受PPARα调节。相比之下，心脏UCP-2的表达部分受脂肪酸依赖性、PPARα非依赖性机制调节。
