σ1-Receptor stimulation with fluvoxamine ameliorates transverse aortic constriction-induced myocardial hypertrophy and dysfunction in mice
σ1-Receptor stimulation with fluvoxamine ameliorates transverse aortic constriction-induced myocardial hypertrophy and dysfunction in mice
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DOI：
10.1152/ajpheart.00198.2010
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发表时间：
2010-11-01
影响因子：
4.8
通讯作者：
Fukunaga, Kohji
中科院分区：
文献类型：
--
作者：
Tagashira, Hideaki;Bhuiyan, Shenuarin;Fukunaga, Kohji
张文忠，张文忠.用氟伏沙明刺激σ（1）受体可改善小鼠横主动脉缩窄诱导的心肌肥大和功能障碍Am J Physiol Heart Circ Physiol 299：H1535-H1545，2010.首次发表于2010年8月27日; doi：10.1152/ajpheart.00198.2010.-已知选择性5-羟色胺再摄取抑制剂（SSRI）可降低心肌梗死后诱导的发病率和死亡率。然而，SSRI诱导的心脏保护作用的分子机制仍不清楚。在此，我们研究了氟伏沙明刺激sigma（1）受体（sigma R-1）对心肌肥厚和心功能恢复的作用。雄性ICR小鼠进行横向主动脉缩窄（TAC）在心脏主动脉弓。为了确认由西格玛R-1刺激的氟伏沙明的心脏保护作用，我们治疗小鼠氟伏沙明（0.5或1毫克/公斤）口服4周后，每天一次的主动脉束带的发病。有趣的是，在未治疗的小鼠中，随着TAC诱导的肥大增加，左心室（LV）中的sigma R-1表达在4周内显著降低。相比之下，氟伏沙明给药显著减弱TAC诱导的心肌肥大，伴随着LV中σ R-1表达的恢复。氟伏沙明也减弱肥厚诱导的受损LV缩短分数。氟伏沙明的心脏保护作用通过用σ R-1拮抗剂[NE-100（1 mg/kg）]处理而无效。重要的是，另一种对sigma（1）Rs亲和力很低的SSRI，帕罗西汀，在TAC小鼠和培养的心肌细胞中没有引起抗肥大作用。氟伏沙明治疗显着恢复TAC诱导受损Akt和内皮型一氧化氮合酶（eNOS）磷酸化在LV。我们的研究结果表明，氟伏沙明通过上调sigma R-1表达和刺激sigma R-1介导的Akt-eNOS信号传导来保护小鼠免受TAC诱导的心功能障碍。这是第一次报道氟伏沙明刺激sigma R-1在减轻TAC小鼠心脏肥大和恢复收缩性中的潜在作用。
Tagashira H, Bhuiyan S, Shioda N, Hasegawa H, Kanai H, Fukunaga K. sigma(1)-Receptor stimulation with fluvoxamine ameliorates transverse aortic constriction-induced myocardial hypertrophy and dysfunction in mice. Am J Physiol Heart Circ Physiol 299: H1535-H1545, 2010. First published August 27, 2010; doi:10.1152/ajpheart.00198.2010.-Selective serotonin reuptake inhibitors (SSRIs) are known to reduce post-myocardial infarction-induced morbidity and mortality. However, the molecular mechanism underlying SSRI-induced cardioprotection remains unclear. Here, we investigated the role of sigma(1)-receptor (sigma R-1) stimulation with fluvoxamine on myocardial hypertrophy and cardiac functional recovery. Male ICR mice were subjected to transverse aortic constriction (TAC) in the cardiac aortic arch. To confirm the cardioprotective role of fluvoxamine by sigma R-1 stimulation, we treated mice with fluvoxamine (0.5 or 1 mg/kg) orally once per day for 4 wk after the onset of aortic banding. Interestingly, in untreated mice, sigma R-1 expression in the left ventricle (LV) decreased significantly over the 4 wk as TAC-induced hypertrophy increased. In contrast, fluvoxamine administration significantly attenuated TAC-induced myocardial hypertrophy concomitant with recovery of sigma R-1 expression in the LV. Fluvoxamine also attenuated hypertrophy-induced impaired LV fractional shortening. The fluvoxamine cardioprotective effect was nullified by treatment with a sigma R-1 antagonist [NE-100 (1 mg/kg)]. Importantly, another SSRI with very low affinity for sigma(1)Rs, paroxetine, did not elicit antihypertrophic effects in TAC mice and cultured cardiomyocytes. Fluvoxamine treatment significantly restored TAC-induced impaired Akt and endothelial nitric oxide synthase (eNOS) phosphorylation in the LV. Our findings suggest that fluvoxamine protects against TAC-induced cardiac dysfunction via upregulated sigma R-1 expression and stimulation of sigma R-1-mediated Akt-eNOS signaling in mice. This is the first report of a potential role for sigma R-1 stimulation by fluvoxamine in attenuating cardiac hypertrophy and restoring contractility in TAC mice.