Liu Jing, Tsang Sharon, Wong Tak Ming
Department of Physiology, Faculty of Medicine, The University of Hong Kong, 4/F Laboratory Block, Faculty of Medicine Buildings, 21 Sassoon Road, Pokfulam, Hong Kong SAR, China.
Endocrinology. 2006 Oct;147(10):4569-77. doi: 10.1210/en.2006-0297. Epub 2006 Jun 22.
Ischemic preconditioning fails to confer immediate cardioprotection in the absence of testosterone, indicating that the hormone is required for the process. Here we set out to determine whether testosterone is also necessary for delayed cardioprotection and, if so, how it acts. Male Sprague Dawley rats (7-8 wk) underwent sham operation or gonadectomy without (G) or with testosterone replacement (GT) for 8 wk. Isolated ventricular myocytes were preconditioned either by metabolic inhibition or with U50,488H, a kappa-opioid receptor agonist. In intact rats, U50,488H was administered systemically and 24 h later the hearts were removed. Ventricular myocytes were then subjected to metabolic inhibition and anoxia and isolated hearts to regional ischemia, followed by reperfusion to induce injury. Both types of preconditioning significantly increased the viability and decreased the lactate dehydrogenase release in ventricular myocytes from sham rats. They also activated heat shock transcription factor-1 and increased heat shock protein 70 expression. In contrast, all these effects were absent in myocytes from G rats and were restored by testosterone replacement. Parallel results were found in isolated hearts. In addition, preconditioning improved contractile functions impaired by ischemic insults in sham and rats gonadectomized with testosterone replacement but not G rats. The effects of testosterone replacement in ventricular myocytes were abolished by androgen receptor blockade. In conclusion, preconditioning requires testosterone to increase heat shock protein 70 synthesis, which mediates delayed cardioprotection in the male. These effects of testosterone are mediated by the androgen receptor.
在缺乏睾酮的情况下，缺血预处理无法立即提供心脏保护作用，这表明该激素是此过程所必需的。在此，我们着手确定睾酮对于延迟性心脏保护是否也是必需的，若如此，其作用机制如何。雄性Sprague Dawley大鼠（7 - 8周龄）接受假手术或去势手术，去势大鼠分为未接受睾酮替代（G组）或接受睾酮替代（GT组），持续8周。分离的心室肌细胞通过代谢抑制或使用κ-阿片受体激动剂U50,488H进行预处理。在完整大鼠中，全身性给予U50,488H，24小时后取出心脏。然后将心室肌细胞进行代谢抑制和缺氧处理，将分离的心脏进行局部缺血处理，随后再灌注以诱导损伤。两种预处理方式均显著提高了假手术大鼠心室肌细胞的活力并降低了乳酸脱氢酶的释放。它们还激活了热休克转录因子-1并增加了热休克蛋白70的表达。相比之下，G组大鼠的心肌细胞中所有这些效应均不存在，而睾酮替代可使其恢复。在分离的心脏中也发现了类似的结果。此外，预处理改善了假手术大鼠以及接受睾酮替代去势大鼠因缺血损伤而受损的收缩功能，但G组大鼠未改善。雄激素受体阻断可消除睾酮替代对心室肌细胞的影响。总之，预处理需要睾酮来增加热休克蛋白70的合成，从而介导雄性大鼠的延迟性心脏保护作用。睾酮的这些作用是由雄激素受体介导的。
