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Acid sphingomyelinase downregulation alleviates vascular endothelial leptin resistance in rats.
Acta Pharmacologica Sinica ( IF 6.9 ) Pub Date : 2019-12-17 , DOI: 10.1038/s41401-019-0328-3 Bei-Bo Cai 1 , Yi-Ni Lu 1 , Ming Xu 1
Acta Pharmacologica Sinica ( IF 6.9 ) Pub Date : 2019-12-17 , DOI: 10.1038/s41401-019-0328-3 Bei-Bo Cai 1 , Yi-Ni Lu 1 , Ming Xu 1
Affiliation
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Leptin resistance in endothelial cells leads to vascular endothelial dysfunction, which is the beginning and crucial link of atherosclerosis. However, the mechanism of leptin resistance remains obscure. Acid sphingomyelinase (ASM) catalyzes the hydrolysis of sphingomyelin to produce ceramide, which plays an important role in the progression of metabolic and cardiovascular diseases. In this study, we investigated whether ASM could regulate leptin resistance in vascular endothelial cells. We induced endothelial leptin resistance in rat aortic endothelial cells through treatment with palmitic acid (0.3 mM) or knockdown of leptin receptor (Ob-Rb), which resulted in the increase of suppressor of cytokine signaling 3 expression, the decrease of Ob-Rb expression, and signal transducer and activator of transcription 3 (STAT3) phosphorylation at Tyr705. We found that these indicators of leptin resistance were reversed by knockdown of ASM or by the selective ASM inhibitors amitriptyline (AMI) and imipramine (IMI). Supplementation of ceramide inhibited Ob-Rb expression and STAT3 phosphorylation by inhibiting extracellular signal-regulated kinase 1/2 activation. Furthermore, we found that knockdown of ASM enhanced endothelial nitric oxide (NO) synthase activity and NO production, as well as the Akt phosphorylation at ser473, which was regulated by STAT3. High-fat diet (HFD) feeding-induced leptin resistance in rats in vivo; administration of AMI and IMI (10 mg· kg-1 per day, intraperitoneally, for 2 weeks) increased the release of endothelial NO to relieve the vasodilatory response and improved the endothelial leptin resistance in the aorta of HFD-fed rats. These results suggest that ASM downregulation reverses endothelial leptin resistance, and consequently improves vascular endothelial dysfunction. This study highlighted ASM as a potential therapeutic target for endothelial leptin resistance.
中文翻译：
酸性鞘磷脂酶下调减轻了大鼠血管内皮瘦素的抵抗力。
内皮细胞中的瘦素抗性导致血管内皮功能障碍，这是动脉粥样硬化的开始和关键环节。但是，瘦素抵抗的机制仍然不清楚。酸性鞘磷脂酶（ASM）催化鞘磷脂水解产生神经酰胺，神经酰胺在代谢和心血管疾病的进展中起重要作用。在这项研究中，我们调查了ASM是否可以调节血管内皮细胞中的瘦素抵抗。我们通过棕榈酸（0.3 mM）处理或敲除瘦素受体（Ob-Rb）诱导大鼠主动脉内皮细胞的内皮瘦素抵抗，导致细胞因子信号3表达的抑制子增加，Ob-Rb表达减少，以及Tyr705处的信号转导和转录激活因子3（STAT3）磷酸化。我们发现瘦素抵抗的这些指标被ASM的抑制或选择性ASM抑制剂阿米替林（AMI）和丙咪嗪（IMI）所逆转。补充神经酰胺可通过抑制细胞外信号调节激酶1/2激活来抑制Ob-Rb表达和STAT3磷酸化。此外，我们发现敲低ASM可以增强内皮一氧化氮（NO）合酶的活性和NO的产生，以及ser3的Akt磷酸化，这受STAT3的调节。高脂饮食（HFD）喂养诱导的大鼠体内瘦素抵抗；每天服用AMI和IMI（每天10 mg·kg-1，腹膜内，持续2周）可增加内皮NO的释放，从而减轻血管舒张反应，并改善HFD喂养大鼠主动脉中的内皮瘦素抵抗力。这些结果表明，ASM下调逆转了内皮瘦素的抵抗力，因此改善了血管内皮功能障碍。这项研究突出了ASM作为内皮瘦素抵抗的潜在治疗靶点。
更新日期：2019-12-18
中文翻译：
酸性鞘磷脂酶下调减轻了大鼠血管内皮瘦素的抵抗力。
内皮细胞中的瘦素抗性导致血管内皮功能障碍，这是动脉粥样硬化的开始和关键环节。但是，瘦素抵抗的机制仍然不清楚。酸性鞘磷脂酶（ASM）催化鞘磷脂水解产生神经酰胺，神经酰胺在代谢和心血管疾病的进展中起重要作用。在这项研究中，我们调查了ASM是否可以调节血管内皮细胞中的瘦素抵抗。我们通过棕榈酸（0.3 mM）处理或敲除瘦素受体（Ob-Rb）诱导大鼠主动脉内皮细胞的内皮瘦素抵抗，导致细胞因子信号3表达的抑制子增加，Ob-Rb表达减少，以及Tyr705处的信号转导和转录激活因子3（STAT3）磷酸化。我们发现瘦素抵抗的这些指标被ASM的抑制或选择性ASM抑制剂阿米替林（AMI）和丙咪嗪（IMI）所逆转。补充神经酰胺可通过抑制细胞外信号调节激酶1/2激活来抑制Ob-Rb表达和STAT3磷酸化。此外，我们发现敲低ASM可以增强内皮一氧化氮（NO）合酶的活性和NO的产生，以及ser3的Akt磷酸化，这受STAT3的调节。高脂饮食（HFD）喂养诱导的大鼠体内瘦素抵抗；每天服用AMI和IMI（每天10 mg·kg-1，腹膜内，持续2周）可增加内皮NO的释放，从而减轻血管舒张反应，并改善HFD喂养大鼠主动脉中的内皮瘦素抵抗力。这些结果表明，ASM下调逆转了内皮瘦素的抵抗力，因此改善了血管内皮功能障碍。这项研究突出了ASM作为内皮瘦素抵抗的潜在治疗靶点。
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