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首页> 外文期刊>American Journal of Physiology >PGC-1 upregulation via estrogen receptors: a common mechanism of salutary effects of estrogen and flutamide on heart function after trauma-hemorrhage.
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PGC-1 upregulation via estrogen receptors: a common mechanism of salutary effects of estrogen and flutamide on heart function after trauma-hemorrhage.

机译：PGC-1通过雌激素受体上调：雌激素和氟他胺对创伤性出血后心脏功能的有益作用的常见机制。

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摘要

Flutamide, an androgen receptor antagonist, is thought to improve cardiovascular function by blocking the androgen receptor after trauma-hemorrhage (T-H). Although 17beta-estradiol (E2) and flutamide improve cardiac function after T-H, whether E2 and flutamide produce their salutary effect via the same or a different mechanism is unknown. We hypothesized that E2 and flutamide mediate their effects via estrogen receptor (ER)-mediated upregulation of peroxisome proliferator-activated receptor coactivator 1 (PGC-1). PGC-1, a key regulator of cardiac mitochondrial function, induces mitochondrial genes by activating transcription factors such as nuclear respiratory factor 2 (NRF-2), which regulates mitochondrial proteins [i.e., mitochondrial transcription factor A (Tfam), cytochrome-c oxidase subunit IV, and beta-ATP synthase]. Adult male rats underwent T-H [5-cm midline incision and hemorrhage (blood pressure = 40 mmHg for approximately 90 min)] and resuscitation. At the onset of resuscitation, rats received vehicle, flutamide (25 mg/kg), or E2 (50 microg/kg). Another group received the ER antagonist ICI-182780 (3 mg/kg) with or without flutamide. Flutamide or E2 administration after T-H restored depressed cardiac function. Moreover, E2 and flutamide normalized expression of cardiac PGC-1, NRF-2, Tfam, cytochrome-c oxidase subunit IV, and the mitochondrial DNA-encoded gene cytochrome-c oxidase subunit I and beta-ATP synthase, mitochondrial ATP, and cytochrome-c oxidase activity. However, if the ER antagonist ICI-182780 was administered with flutamide, flutamide-mediated PGC-1 upregulation was totally abolished. These results indicate that E2 and flutamide upregulate PGC-1 via the ER. Thus PGC-1 upregulation appears to be the common mechanism by which E2 and flutamide mediate their salutary effects on cardiac function after T-H.
机译：Flutamide是一种雄激素受体拮抗剂，被认为可以通过在创伤性出血（T-H）后阻断雄激素受体来改善心血管功能。尽管17β-雌二醇（E2）和氟他胺可改善T-H后的心脏功能，但E2和氟他胺是否通过相同或不同的机制产生有益的作用尚不清楚。我们假设E2和氟他胺通过雌激素受体（ER）介导的过氧化物酶体增殖物激活受体共激活因子1（PGC-1）上调介导其作用。 PGC-1是心脏线粒体功能的关键调节剂，它通过激活转录因子（如核呼吸因子2（NRF-2））来诱导线粒体基因，该因子可调节线粒体蛋白[即线粒体转录因子A（Tfam），细胞色素C氧化酶IV亚基和β-ATP合酶]。成年雄性大鼠进行T-H [5厘米中线切开和出血（血压= 40 mmHg，持续约90分钟）]并进行复苏。复苏开始时，大鼠接受赋形剂，氟他胺（25毫克/千克）或E2（50微克/千克）。另一组接受或不联合氟他胺的ER拮抗剂ICI-182780（3 mg / kg）。 T-H后给予氟他胺或E2可恢复心脏功能低下。此外，E2和氟他胺使心脏PGC-1，NRF-2，Tfam，细胞色素C氧化酶亚基IV和线粒体DNA编码的基因细胞色素C氧化酶亚基I和β-ATP合酶，线粒体ATP和细胞色素的表达正常化-c氧化酶活性。但是，如果将ER拮抗剂ICI-182780与氟他胺一起使用，则氟他酰胺介导的PGC-1上调将完全被消除。这些结果表明，E2和氟他胺通过ER上调PGC-1。因此，PGC-1上调似乎是E2和氟他胺介导T-H后对心脏功能的有益作用的常见机制。

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