Li Shu-lian, Reddy Marpadga A, Cai Qiangjun, Meng Li, Yuan Hang, Lanting Linda, Natarajan Rama
Department of Diabetes, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA.
Diabetes. 2006 Sep;55(9):2611-9. doi: 10.2337/db06-0164.
Diabetes is associated with enhanced inflammatory responses and cardiovascular complications such as atherosclerosis. However, it is unclear whether similar responses are present in cells derived from experimental animal models of diabetes. We examined our hypothesis that macrophages and short-term cultured vascular smooth muscle cells (VSMCs) derived from obese, insulin-resistant, and diabetic db/db mice would exhibit increased proatherogenic responses relative to those from control db/+ mice. We observed that macrophages from db/db mice exhibit significantly increased expression of key inflammatory cytokines and chemokines as well as arachidonic acid-metabolizing enzymes cyclooxygenase-2 and 12/15-lipoxygenase that generate inflammatory lipids. Furthermore, VSMCs derived from db/db mice also showed similar enhanced expression of inflammatory genes. Expression of inflammatory genes was also significantly increased in aortas derived from db/db mice. Both macrophages and VSMCs from db/db mice demonstrated significantly increased oxidant stress, activation of key signaling kinases, and transcription factors cAMP response element-binding protein and nuclear factor-kappaB, involved in the regulation of atherogenic and inflammatory genes. Interestingly, VSMCs from db/db mice displayed enhanced migration as well as adhesion to WEHI mouse monocytes relative to db/+. Thus, the diabetic milieu and a potential hyperglycemic memory can induce aberrant behavior of vascular cells. These new results demonstrate that monocyte/macrophages and VSMCs derived from db/db mice display a "preactivated" and proinflammatory phenotype associated with the pathogenesis of diabetic vascular dysfunction and atherosclerosis.
糖尿病与炎症反应增强以及动脉粥样硬化等心血管并发症相关。然而，目前尚不清楚在糖尿病实验动物模型来源的细胞中是否存在类似的反应。我们检验了这样一个假设：与对照db/+小鼠来源的细胞相比，肥胖、胰岛素抵抗及糖尿病db/db小鼠来源的巨噬细胞和短期培养的血管平滑肌细胞（VSMC）会表现出更强的促动脉粥样硬化反应。我们观察到，db/db小鼠的巨噬细胞中关键炎症细胞因子、趋化因子以及生成炎症脂质的花生四烯酸代谢酶环氧合酶-2和12/15-脂氧合酶的表达显著增加。此外，db/db小鼠来源的VSMC也表现出类似的炎症基因表达增强。db/db小鼠主动脉中炎症基因的表达也显著增加。db/db小鼠的巨噬细胞和VSMC均表现出明显增强的氧化应激、关键信号激酶的激活以及参与动脉粥样硬化和炎症基因调控的转录因子环磷酸腺苷反应元件结合蛋白和核因子-κB的激活。有趣的是，与db/+小鼠相比，db/db小鼠来源的VSMC对WEHI小鼠单核细胞的迁移及黏附增强。因此，糖尿病环境和潜在的高血糖记忆可诱导血管细胞的异常行为。这些新结果表明，db/db小鼠来源的单核细胞/巨噬细胞和VSMC表现出与糖尿病血管功能障碍和动脉粥样硬化发病机制相关的“预激活”和促炎表型。
