Dianne Nunnally Hoppes Laboratory for Diabetes Complications, Section of Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Circ Res. 2013 Aug 2;113(4):418-27. doi: 10.1161/CIRCRESAHA.113.301074. Epub 2013 Jun 11.
Loss of insulin action in the endothelium can cause endothelial dysfunction and atherosclerosis. Hyperglycemia and elevated fatty acids induced by diabetes mellitus can activate protein kinase C-β isoforms and selectively inhibit insulin signaling via phosphatidylinositol 3-kinase/Akt pathway to inhibit the activation of endothelial nitric oxide synthase and metabolic actions.
To demonstrate that overexpressing protein kinase C-β2 isoform in endothelial cells can cause selective insulin resistance and exacerbate atherosclerosis in the aorta.
Protein kinase C-β2 isoform was overexpressed in endothelial cells using a promoter of vascular endothelial cell 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 was impaired by ≈40% with respect to Akt/endothelial nitric oxide synthase activation, and leukocyte-endothelial cell binding increased in cultured lung endothelial cells from Tg(Prkcb)apoE-/- mice compared with that from apoE-/- mice. Basal and angiotensin-stimulated big endothelin-1 levels were elevated in Tg(Prkcb)apoE-/- mice compared with 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 protein kinase C-β2 activation in the endothelial cells caused dysfunction and accelerated atherosclerosis because of loss of insulin-stimulated Akt/endothelial nitric oxide synthase activation and angiotensin-induced increases in endothelin-1 expression.
胰岛素作用于内皮细胞的缺失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-β 同工型,并通过磷酸肌醇 3-激酶/ Akt 途径选择性抑制胰岛素信号转导,从而抑制内皮型一氧化氮合酶的激活和代谢作用。
证明在内皮细胞中过表达蛋白激酶 C-β2 同工型可导致选择性胰岛素抵抗,并加重主动脉粥样硬化。
利用血管内皮细胞钙黏蛋白启动子在内皮细胞中过表达蛋白激酶 C-β2 同工型。这些小鼠与载脂蛋白 E 基因缺失(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-/-小鼠内皮细胞和股动脉的胰岛素作用,在 Akt/内皮型一氧化氮合酶激活方面降低了约 40%,并且培养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水平升高。主动脉粥样硬化的严重程度在 Tg(Prkcb)apoE-/-小鼠中增加了约 70%,通过正面脂肪染色和斑块平滑肌细胞、巨噬细胞和细胞外基质的数量来衡量。
内皮细胞中特定的蛋白激酶 C-β2 激活导致功能障碍和加速动脉粥样硬化,原因是胰岛素刺激的 Akt/内皮型一氧化氮合酶激活和血管紧张素诱导的内皮素-1表达增加而丧失。