Hsieh Ya-Ching, Choudhry Mashkoor A, Yu Huang-Ping, Shimizu Tomoharu, Yang Shaolong, Suzuki Takao, Chen Jianguo, Bland Kirby I, Chaudry Irshad H
Center for Surgical Research and Department of Surgery, University of Alabama at Birmingham, 1670 University Blvd, Volker Hall, Rm. G094, Birmingham, Alabama 35294-0019, USA.
FASEB J. 2006 Jun;20(8):1109-17. doi: 10.1096/fj.05-5549com.
PGC-1alpha (peroxisome proliferator-activated receptor [PPARgamma] coactivator-1alpha) activates PPARalpha and mitochondrial transcription factor A (Tfam), which regulate proteins, fatty acid and ATP metabolism (i.e., FAT/CD36, MCAD, and COX I). Recently we found that the salutary effects of estradiol (E2) on cardiac function following trauma-hemorrhage (T-H) are mediated via estrogen receptor (ER)beta. In this study we tested the hypothesis that ERbeta-mediated cardioprotection is induced via up-regulation of PGC-1alpha through PPARalpha or Tfam-dependent pathway. Male rats underwent T-H and received ERalpha agonist propylpyrazole-triol (PPT), ERbeta agonist diarylpropionitrile (DPN), E2, or vehicle. Another group was treated with antisense PGC-1alpha oligonucleotides prior to administration of DPN. E2 and DPN treatments attenuated the decrease in cardiac mitochondrial ATP, abrogated the T-H-induced lipid accumulation, and normalized PGC-1alpha, PPARalpha, FAT/CD36, MCAD, Tfam, and COX I after T-H. In contrast, PPT administration did not abrogate lipid accumulation. Moreover, in PPT-treated animals mitochondrial ATP remained significantly lower than those observed in DPN- or E2-treated animals. Prior administration of antisense PGC-1alpha prevented DPN-mediated cardioprotection and increase in ATP levels and Tfam but not in PPARalpha following T-H. These findings suggest that the salutary effects of E2 on cardiac function following T-H are mediated via ERbeta up-regulation of PGC-1alpha through Tfam-dependent pathway.
过氧化物酶体增殖物激活受体γ共激活因子1α（PGC-1α）可激活过氧化物酶体增殖物激活受体α（PPARα）和线粒体转录因子A（Tfam），它们可调节蛋白质、脂肪酸和ATP代谢（即脂肪酸转运蛋白/脂肪酸转位酶[FAT/CD36]、中链酰基辅酶A脱氢酶[MCAD]和细胞色素c氧化酶亚基I[COX I]）。最近我们发现，创伤性出血（T-H）后雌二醇（E2）对心脏功能的有益作用是通过雌激素受体（ER）β介导的。在本研究中，我们检验了以下假设：ERβ介导的心脏保护作用是通过PPARα或Tfam依赖途径上调PGC-1α诱导的。雄性大鼠接受T-H处理，并给予ERα激动剂丙基吡唑三醇（PPT）、ERβ激动剂二芳基丙腈（DPN）、E2或溶剂。另一组在给予DPN之前用反义PGC-1α寡核苷酸处理。E2和DPN处理可减轻心脏线粒体ATP的降低，消除T-H诱导的脂质蓄积，并使T-H后PGC-1α、PPARα、FAT/CD36、MCAD、Tfam和COX I恢复正常。相比之下，给予PPT并未消除脂质蓄积。此外，在接受PPT处理的动物中，线粒体ATP仍显著低于接受DPN或E2处理的动物。预先给予反义PGC-1α可阻止DPN介导的心脏保护作用以及T-H后ATP水平和Tfam的升高，但不能阻止PPARα的升高。这些发现表明，T-H后E2对心脏功能的有益作用是通过ERβ经Tfam依赖途径上调PGC-1α介导的。
