Vascular endothelial σ1-receptor stimulation with SA4503 rescues aortic relaxation via Akt/eNOS signaling in ovariectomized rats with aortic banding.
Vascular endothelial σ1-receptor stimulation with SA4503 rescues aortic relaxation via Akt/eNOS signaling in ovariectomized rats with aortic banding.
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DOI：
10.1253/circj.cj-13-0256
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发表时间：
2013-10
期刊：
影响因子：
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通讯作者：
H. Tagashira;T. Matsumoto;K. Taguchi;Chen Zhang-;F. Han;K. Ishida;Shingo Nemoto;Tsuneo Kobayashi;K. Fukunaga
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文献类型：
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作者：
H. Tagashira;T. Matsumoto;K. Taguchi;Chen Zhang-;F. Han;K. Ishida;Shingo Nemoto;Tsuneo Kobayashi;K. Fukunaga
背景：我们曾报道去卵巢大鼠腹主动脉结扎造成压力超负荷后，胸主动脉σ1受体(σ1R)表达下降。在此，我们探讨了选择性激动剂SA4503刺激σ-1R是否能使去卵巢大鼠血管损伤后的血管舒缩功能恢复。方法与结果去卵巢大鼠口服SA45 0 3(0.3~1.0 mg/kg)和σ1R拮抗剂NE 10 0(1.0 mg/kg)，每日1次，连续4周。用苯肾上腺素(PE)或内皮素-1(ET-1)引起的血管收缩和乙酰胆碱(ACh)或可乐定(CLO)引起的血管扩张分别测定血管功能。SA4503可拮抗PO诱导的血管内皮细胞和血管内皮细胞σ-1R的减少。SA4503治疗还挽救了PO诱导的ACh和可乐定诱导的血管扩张损伤，而不影响PE和ET-1诱导的血管收缩。ACh和可乐定诱导的血管扩张的改善与Akt活性增加密切相关，进而与内皮型一氧化氮合酶(ENOS)磷酸化密切相关。NE-100可阻断SA4503介导的血管扩张改善作用。结论PO诱导的去卵巢大鼠内皮损伤后，σ1R表达下调。选择性σ1R激动剂SA4503通过刺激σ1R，增强血管内皮细胞eNOS-cGMP信号转导，改善去卵巢大鼠主动脉内皮依赖性血管扩张功能。这些观察结果鼓励了针对σ1R的新疗法的开发，以防止血管疾病中的血管内皮损伤。
BACKGROUND We previously reported that σ1-receptor (σ1R) expression in the thoracic aorta decreased after pressure overload (PO) induced by abdominal aortic banding in ovariectomized (OVX) rats. Here, we asked whether stimulation of σ1R with the selective agonist SA4503 elicits functional recovery of aortic vasodilation and constriction following vascular injury in OVX rats with PO. METHODS AND RESULTS SA4503 (0.3-1.0mg/kg) and NE-100 (a σ1R antagonist, 1.0mg/kg) were administered orally for 4 weeks (once daily) to OVX-PO rats. Vascular functions of isolated descending aorta were measured following phenylephrine (PE)- or endothelin-1 (ET-1)-induced vasoconstriction and acetylcholine (ACh)- or clonidine-induced vasodilation. SA4503 administration rescued PO-induced σ1R decreases in aortic smooth muscle and endothelial cells. SA4503 treatment also rescued PO-induced impairments in ACh- and clonidine-induced vasodilation without affecting PE- and ET-1-induced vasoconstriction. Ameliorated ACh- and clonidine-induced vasodilation was closely associated with increased Akt activity and in turn endothelial nitric oxide synthase (eNOS) phosphorylation. The SA4503-mediated improvement of vasodilation was blocked by NE-100 treatment. CONCLUSIONS σ1R is downregulated following PO-induced endothelial injury in OVX rats. The selective σ1R agonist SA4503 rescues impaired endothelium-dependent vasodilation in the aorta from OVX-PO rats through σ1R stimulation, enhancing eNOS-cGMP signaling in vascular endothelial cells. These observations encourage development of novel therapeutics targeting σ1R to prevent vascular endothelial injury in vascular diseases.