Stimulation of Sigma-1 receptor signaling by dehydroepiandrosterone ameliorates pressure overload-induced hypertrophy and dysfunctions in ovariectomized rats
Stimulation of Sigma-1 receptor signaling by dehydroepiandrosterone ameliorates pressure overload-induced hypertrophy and dysfunctions in ovariectomized rats
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DOI：
10.1517/14728220903264064
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发表时间：
2009-11-01
影响因子：
5.8
通讯作者：
Fukunaga, Kohji
中科院分区：
文献类型：
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作者：
Bhuiyan, Md. Shenuarin;Fukunaga, Kohji
目标：脱氢表雄酮（DHEA）水平降低与内皮功能障碍和绝经后妇女心血管死亡率增加有关。我们研究了DHEA（也称为sigma-1受体（Sig-1 R）激动剂）在心肌肥大、心脏功能恢复和明确的心脏保护作用机制中的作用。方法：Wistar大鼠双侧卵巢切除术（OVX）后行腹主动脉狭窄治疗。DHEA（15和30 mg/kg）口服给药，每天一次，从主动脉结扎后2周开始，持续14天。结果如下：时间进程研究表明，压力超负荷后1 ~ 4周，左心室重量与体重比值呈时间依赖性增加，且Sig-1 R表达呈明显的反向调节。用Sig-1 R激动剂DHEA治疗显著减弱PO诱导的心肌肥大，增加LV中Sig-1 R的表达。DHEA还可降低肥厚引起的左室舒张末期压、左室发展压和左室收缩力（+/- dp/dt（max））。DHEA治疗显著恢复PO诱导的左心室eNOS和Akt活性受损。结论：我们报告，为我们所知的第一次，在心脏中的Sig-1 R表达的潜在作用，以减轻卵巢切除大鼠PO诱导的肥大。DHEA治疗通过上调Sig-1 R和刺激Sig-1 R介导的Akt-eNOS信号传导来保护PO诱导的心脏损伤。
Objective: Decreased dehydroepiandrosterone (DHEA) levels are associated with endothelial dysfunction and increased cardiovascular mortality in postmenopausal women. We investigated the role of DHEA, also known as sigma-1 receptor (Sig-1R) agonist, in myocardial hypertrophy, cardiac functional recovery and defined mechanisms of cardioprotective action. Methods: Wistar rats subjected to bilateral ovariectomy (OVX) were further treated with abdominal aortic stenosis. DHEA (15 and 30 mg/kg) was administered orally once a day for 14 days starting from 2 weeks after aortic banding. Results: Time course study indicated that left ventricle (W) weight:body weight (BW) ratio increased time-dependently from 1 to 4 weeks after pressure-overload (PO) with significant inversed regulation of Sig-1R expression. Treatment with the Sig-1R agonist, DHEA, significantly attenuated PO-induced myocardial hypertrophy with increased expression of Sig-1R in the LV. DHEA also attenuated hypertrophy-induced impaired LV end diastolic pressure, LV developed pressure and LV contractility (+/- dp/dt(max)). DHEA treatment significantly restored PO-induced impaired eNOS and Akt activity in the LV. Conclusion: We report, for the first time to our knowledge, the potential role of Sig-1R expression in the heart to attenuate PO-induced hypertrophy in ovariectomized rats. DHEA treatment protects against PO-induced cardiac injury via upregulation of Sig-1R and stimulation of Sig-1R-mediated Akt-eNOS signaling.