Department of Pharmacology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
Department of Physiological Sciences, Biological Sciences Center, State University of Londrina, Paraná, Brazil.
Life Sci. 2019 Jan 1;216:279-286. doi: 10.1016/j.lfs.2018.11.030. Epub 2018 Nov 14.
Inflammation is involved in diabetes-related vascular dysfunction. Estrogen receptor ESR2/ERβ induces the expression of inducible nitric oxide (NO) synthase (iNOS) and inflammation. The present study investigated the effect of alloxan-induced type 1 diabetes on the iNOS and ESR2 expression and the effect of the chronic iNOS inhibition on the vascular smooth muscle dysfunction in diabetic female rats. In addition, we evaluated the involvement of ESR2 in iNOS expression.
Alloxan-induced diabetic female rats were treated or not with iNOS inhibitor (L-NIL). iNOS and ESR2 immunostaining, S-nitrosylated proteins and IL-1β protein expression in aorta and plasmatic NO levels were analyzed. Contractile response to noradrenaline was analyzed in endothelium-denuded aorta. iNOS mRNA expression was analyzed in isolated aortic smooth muscle cells (ASMCs) of female rats, incubated with 22 mM glucose and an ESR2 antagonist.
Aortic iNOS and ESR2 immunostaining, S-nitrosylated proteins, IL-1β protein expression and plasmatic NO levels were all increased, whereas noradrenaline-induced contraction was reduced in aorta of diabetic female rats. With the exception of iNOS and ESR2 immunostaining, all these parameters were corrected by L-NIL treatment. High glucose increased iNOS mRNA expression in ASMCs, which was reduced by an ESR2 antagonist.
We demonstrated that increased iNOS-NO contributed to the impairment of the contractile response of aortic smooth muscle cells in female type 1 diabetic rats and that increased expression of iNOS may involve the participation of ESR2/ERβ.
炎症参与了与糖尿病相关的血管功能障碍。雌激素受体 ESR2/ERβ可诱导诱导型一氧化氮合酶（iNOS）和炎症的表达。本研究旨在探讨 1 型糖尿病对雌性大鼠诱导型一氧化氮合酶（iNOS）和 ESR2 表达的影响，以及慢性 iNOS 抑制对糖尿病雌性大鼠血管平滑肌功能障碍的影响。此外，我们还评估了 ESR2 在 iNOS 表达中的作用。
采用链脲佐菌素（alloxan）诱导雌性糖尿病大鼠，并给予或不给予 iNOS 抑制剂（L-NIL）治疗。分析主动脉中 iNOS 和 ESR2 的免疫染色、S-亚硝基化蛋白和白细胞介素-1β（IL-1β）蛋白的表达以及血浆中一氧化氮（NO）的水平。还分析了去内皮主动脉对去甲肾上腺素的收缩反应。用 22mM 葡萄糖和 ESR2 拮抗剂孵育雌性大鼠的主动脉平滑肌细胞（ASMCs），分析 iNOS mRNA 的表达。
与正常雌性大鼠相比，糖尿病雌性大鼠主动脉中 iNOS 和 ESR2 的免疫染色、S-亚硝基化蛋白、IL-1β 蛋白的表达以及血浆中 NO 的水平均升高，去甲肾上腺素诱导的收缩反应减弱。除了 iNOS 和 ESR2 的免疫染色外，L-NIL 治疗均纠正了这些参数的变化。高葡萄糖增加了 ASMCs 中 iNOS mRNA 的表达，而 ESR2 拮抗剂则降低了其表达。
我们证明了增加的 iNOS-NO 导致了 1 型糖尿病雌性大鼠主动脉平滑肌细胞收缩反应受损，而 iNOS 的表达增加可能涉及 ESR2/ERβ 的参与。
