Deficient eNOS phosphorylation is a mechanism for diabetic vascular dysfunction contributing to increased stroke size.
Deficient eNOS phosphorylation is a mechanism for diabetic vascular dysfunction contributing to increased stroke size.
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DOI：
10.1161/strokeaha.113.002073
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发表时间：
2013-11
期刊：
影响因子：
8.3
通讯作者：
Huang PL
中科院分区：
文献类型：
--
作者：
Li Q;Atochin D;Kashiwagi S;Earle J;Wang A;Mandeville E;Hayakawa K;d'Uscio LV;Lo EH;Katusic Z;Sessa W;Huang PL
eNOS（其酶活性的重要翻译后调节剂）的磷酸化在糖尿病中降低。我们假设调节 eNOS 磷酸化可以克服糖尿病血管功能障碍并改善中风的预后。我们使用 2 型糖尿病的 db/db 小鼠模型。我们将 db/db 小鼠与在 S1176 磷酸化位点携带单氨基酸突变的 eNOS 敲入小鼠交配；拟磷酸化 SD 突变显示 eNOS 酶活性增加，而非磷酸化 SA 突变显示 eNOS 酶活性降低。我们描述了血管解剖结构、基线生理参数和血管反应性。我们使用中风大脑中动脉闭塞模型并测量梗塞体积和神经功能缺损。 db/db 小鼠在 S1176 处表现出 eNOS 磷酸化减弱。 eNOS SD 和 SA 突变不会改变 db/db 小鼠的威利斯环血管解剖结构、脑毛细血管密度、心率或动脉血气。 eNOS SD 突变（而非 SA 突变）可降低 db/db 小鼠的血压并改善血管对乙酰胆碱的反应性。 eNOS SD 突变可减少中风规模和大脑中动脉闭塞后的神经功能缺损。 eNOS 磷酸化减弱是 db/db 小鼠血管功能障碍的机制。我们在此表明，db/db 小鼠中 eNOS S1176 磷酸化位点的调节与血管反应性的改善以及大脑中动脉闭塞后中风结果的改善相关。
Phosphorylation of eNOS, an important post-translational modulator of its enzymatic activity, is reduced in diabetes. We hypothesized that modulation of eNOS phosphorylation could overcome diabetic vascular dysfunction and improves the outcome to stroke. We used the db/db mouse model of type 2 diabetes. We mated db/db mice with eNOS knockin mice that carry single-amino acid mutations at the S1176 phosphorylation site; the phosphomimetic SD mutation shows increased eNOS enzymatic activity, while the unphosphorylatable SA mutation shows decreased eNOS activity. We characterized the vascular anatomy, baseline physiologic parameters and vascular reactivity. We used the middle cerebral artery occlusion model of stroke and measured infarct volume and neurological deficits. db/db mice showed diminished eNOS phosphorylation at S1176. eNOS SD and SA mutations do not change the vascular anatomy at the Circle of Willis, brain capillary density, heart rate, or arterial blood gases of db/db mice. The eNOS SD mutation, but not the SA mutation, lowers blood pressure and improves vascular reactivity to acetylcholine in db/db mice. The eNOS SD mutation reduces stroke size and neurologic deficit following middle cerebral artery occlusion. Diminished eNOS phosphorylation is a mechanism of vascular dysfunction in db/db mice. We show here that modulation of the eNOS S1176 phosphorylation site in db/db mice is associated with improved vascular reactivity and improved outcome to stroke following middle cerebral artery occlusion.