Targeting sigma-1 receptor with fluvoxamine ameliorates pressure-overload-induced hypertrophy and dysfunctions
Targeting sigma-1 receptor with fluvoxamine ameliorates pressure-overload-induced hypertrophy and dysfunctions
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DOI：
10.1517/14728222.2010.509348
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发表时间：
2010-10-01
影响因子：
5.8
通讯作者：
Fukunaga, Kohji
中科院分区：
文献类型：
--
作者：
Bhuiyan, Md. Shenuarin;Tagashira, Hideaki;Fukunaga, Kohji
目的：研究氟伏沙明刺激sigma-1受体（Sig-1R）对心肌肥厚、心功能恢复的影响，并明确其心脏保护作用的机制。方法：采用左、右肾动脉腹主动脉束带法治疗双侧卵巢切除术后的Wistar大鼠。为了证实Sig-1R刺激对心脏的保护作用，我们在主动脉束带发生后给大鼠口服Sig-1R激动剂（氟伏沙明，0.5和1mg /kg），每天1次，持续4周。结果：有趣的是，压力过载（PO）诱导的OVX大鼠左心室肥厚4周后，Sig-1R在左心室（LV）的表达显著降低。氟伏沙明可显著减轻po诱导的心肌肥厚，同时增加左室Sig-1R的表达。氟伏沙明也能减轻肥厚引起的左室功能受损。氟伏沙明的心脏保护作用被sigg - 1r拮抗剂（NE-100; 1 mg/kg）所抵消。氟伏沙明治疗可显著恢复po诱导的左室eNOS和Akt活性受损。结论：本研究首次发现心肌组织中Sig-1R表达在减轻po诱导的OVX大鼠心肌肥大中的潜在作用。氟伏沙明治疗通过上调sig1r和刺激sig1r介导的Akt-eNOS信号传导来保护去卵巢大鼠po诱导的心脏损伤。
Objective: We here investigated the effect of sigma-1 receptor (Sig-1R) stimulation with fluvoxamine on myocardial hypertrophy, cardiac functional recovery and defined mechanisms underlying its cardioprotective action.Methods: Wistar rats subjected to bilateral ovariectomy (OVX) were treated with abdominal aortic banding between the right and left renal arteries. To confirm the cardioprotective role of Sig-1R stimulation, we treated the rats with Sig-1R agonist (fluvoxamine, 0.5 and 1 mg/kg) orally once a day for 4 weeks after the onset of aortic banding.Results: Interestingly, the expression of Sig-1R in the left ventricle (LV) decreased significantly 4 weeks after pressure overload (PO)-induced hypertrophy in OVX rats. The fluvoxamine administration significantly attenuated PO-induced myocardial hypertrophy with concomitant increase in the expression of Sig-1R in LV. Fluvoxamine also attenuated hypertrophy-induced impaired LV functions. The cardioprotective effect of fluvoxamine was nullified by treatment with Sig-1R antagonist (NE-100; 1 mg/kg). Fluvoxamine treatment significantly restored PO-induced impaired eNOS and Akt activity in the LV.Conclusion: We here found, for the first time, the potential role of Sig-1R expression in the heart in attenuating PO-induced hypertrophy in OVX rats. Fluvoxamine treatment protects PO-induced cardiac injury via upregulation of Sig-1R and stimulation of Sig-1R-mediated Akt-eNOS signaling in ovariectomized rats.