Induction of vascular insulin resistance and endothelin-1 expression and acceleration of atherosclerosis by the overexpression of protein kinase C-β isoform in the endothelium.
Induction of vascular insulin resistance and endothelin-1 expression and acceleration of atherosclerosis by the overexpression of protein kinase C-β isoform in the endothelium.
复制标题
通过蛋白激酶C-β同工型在内皮中诱导血管胰岛素抵抗和内皮蛋白-1表达以及动脉粥样硬化的加速。
DOI：
10.1161/circresaha.113.301074
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发表时间：
2013-08-02
影响因子：
20.1
通讯作者：
King GL
中科院分区：
文献类型：
--
作者：
Li Q;Park K;Li C;Rask-Madsen C;Mima A;Qi W;Mizutani K;Huang P;King GL
失去胰岛素对内皮的作用可导致内皮功能障碍和动脉粥样硬化。糖尿病引起的高血糖和脂肪酸升高可激活蛋白激酶C (PKC) β亚型，选择性抑制磷脂酰肌醇3-激酶(PI3K)/Akt通路的胰岛素信号通路，从而抑制内皮型一氧化氮合酶（eNOS）的激活和代谢作用。证明内皮细胞中过表达PKCβ2异构体可引起选择性胰岛素抵抗，加剧主动脉动脉粥样硬化。PKCβ2异构体在血管内皮细胞钙粘蛋白（VE-Cadherin）启动子的作用下在内皮细胞中过表达。这些小鼠与ApoE-/-小鼠（Tg (Prkcb)ApoE-/-）杂交。在西方饮食中，Tg(Prkcb)ApoE-/-和ApoE-/-小鼠在全身胰岛素敏感性、葡萄糖耐量、血浆脂质或血压方面没有差异。与ApoE-/-小鼠相比，Tg(Prkcb)ApoE-/-小鼠的内皮细胞和股动脉中的胰岛素作用在Akt/eNOS激活方面受损约40%，培养的Tg(Prkcb)ApoE-/-小鼠的肺内皮细胞中白细胞-内皮细胞结合增加。与ApoE-/-小鼠相比，Tg(Prkcb)ApoE-/-小鼠的基础和血管紧张素刺激的大内皮素-1 （ET-1）水平升高。通过表面脂肪染色和平滑肌细胞、巨噬细胞和细胞外基质的斑块含量测量，Tg(Prkcb)ApoE-/-小鼠主动脉动脉粥样硬化的严重程度增加了~ 70%。内皮细胞中特异性PKCβ2的激活由于胰岛素刺激的Akt/eNOS激活的丧失和血管紧张素诱导的ET-1表达的增加而导致功能障碍和加速动脉粥样硬化。
Loss of insulin action on the endothelium can cause endothelial dysfunction and atherosclerosis. Hyperglycemia and elevated fatty acids induced by diabetes can activate protein kinase C (PKC) β isoforms and selectively inhibit insulin signaling via phosphatidylinositol 3-kinase (PI3K)/Akt pathway to inhibit the activation of endothelial nitric oxide synthase (eNOS) and metabolic actions. To demonstrate that overexpressing PKCβ2 isoform in endothelial cells can cause selective insulin resistance and exacerbate atherosclerosis in the aorta. PKCβ2 isoform was overexpressed in endothelial cells using a promoter of vascular endothelial cell-cadherin (VE-Cadherin). These mice were cross-bred with ApoE-/- mice (Tg (Prkcb)ApoE-/-). On a Western diet, Tg(Prkcb)ApoE-/- and ApoE-/- mice did not differ in systemic insulin sensitivity, glucose tolerance, plasma lipid or blood pressure. Insulin action in endothelial cells and femoral artery from Tg(Prkcb)ApoE-/- mice were impaired by ∼40% with respect to Akt/eNOS activation and leukocyte-endothelial cell binding increased in cultured lung endothelial cells from Tg(Prkcb)ApoE-/-mice compared to ApoE-/- mice. Basal and angiotensin stimulated big endothelin-1 (ET-1) levels were elevated in Tg(Prkcb)ApoE-/- mice compared to ApoE-/- mice. The severity of atherosclerosis in the aorta from Tg(Prkcb)ApoE-/- mice increased by ∼70% as measured by en face fat staining and plaque content of the number of smooth muscle cells, macrophages and extracellular matrix. Specific PKCβ2 activation in the endothelial cells caused dysfunction and accelerated atherosclerosis due to loss of insulin-stimulated Akt/eNOS activation and angiotensin induced increases in ET-1 expression.