Rationale: Activation of monocytes/macrophages by hyperlipidemia associated with diabetes and obesity contributes to the development of atherosclerosis. PKCδ expression and activity in monocytes were increased by hyperlipidemia and diabetes with unknown consequences to atherosclerosis.Objective: To investigate the effect of PKCδ activation in macrophages on the severity of atherosclerosis.Methods and Results: PKCδ expression and activity were increased in Zucker diabetic rats. Mice with selective deletion of PKCδ in macrophages were generated by breeding PKCδ flox/flox mice with LyzM-Cre and ApoE^-/- mice (MPKCδKO/ApoE^-/- mice) and studied in atherogenic (AD) and very high fat diet (HFD). Mice fed AD and HFD exhibited hyperlipidemia, but only HFD fed mice had insulin resistance and mild diabetes. Surprisingly, MPKCδKO/ApoE^-/- mice exhibited accelerated aortic atherosclerotic lesions by 2-fold vs. ApoE^-/- mice on AD or HFD. Splenomegaly was observed in MPKCδKO/ApoE^-/- mice on AD and HFD, but not on regular chow. Both the AD or HFD increased macrophage numbers in aortic plaques and spleen by 1.7 and 2-fold, respectively, in MPKCδKO/ApoE^-/- vs. ApoE-^-/- mice due to decreased apoptosis (62%) and increased proliferation (1.9 fold), and not due to uptake, with parallel increased expressions of inflammatory cytokines. Mechanisms for the increased macrophages in MPKCδKO/ApoE^-/- were associated with elevated phosphorylation levels of pro-survival cell signaling proteins, Akt and FoxO3a, with reduction of pro-apoptotic protein Bim associated with PKCδ induced inhibition of P85/PI3K.Conclusions: Accelerated development of atherosclerosis induced by insulin resistance and hyperlipidemia may be partially limited by PKCδ isoform activation in the monocytes, which decreased its number and inflammatory responses in the arterial wall.

理由：与糖尿病和肥胖症相关的高脂血症对单核细胞/巨噬细胞的激活有助于动脉粥样硬化的发展。高脂血症和糖尿病会增加单核细胞中PKCδ的表达和活性，对动脉粥样硬化的后果未知。目的：探讨巨噬细胞中PKCδ活化对动脉粥样硬化严重程度的影响。方法和结果：在Zucker糖尿病大鼠中PKCδ的表达和活性增加。通过用LyzM-Cre和ApoE^-/-小鼠（MPKCδKO/ ApoE^-/-小鼠），并在致动脉粥样硬化（AD）和超高脂肪饮食（HFD）中进行了研究。用AD和HFD喂养的小鼠表现出高脂血症，但是只有用HFD喂养的小鼠具有胰岛素抵抗和轻度糖尿病。令人惊讶地，MPKCδKO/的ApoE ^{- / -}小鼠表现出通过加速主动脉粥样硬化病变的2倍对的ApoE ^{- / -}对AD或HFD小鼠。在ADK和HFD的MPKCδKO/ ApoE ^-/-小鼠中观察到脾肿大，而在普通食物中则没有。无论是AD或HFD 1.7和增加的在主动脉斑块和脾巨噬细胞数目的2倍，分别在MPKCδKO/的ApoE ^{- / -}与ApoE- ^{- / -}小鼠由于减少的凋亡（62％）和增加的增殖（1.9倍），而不是由于摄取而引起的，同时炎症细胞因子的表达平行增加。MPKCδKO/ ApoE ^-/-中巨噬细胞增加的机制与存活细胞信号蛋白Akt和FoxO3a的磷酸化水平升高有关，而与PKCδ诱导的对P85 / PI3K抑制相关的促凋亡蛋白Bim减少则与之相关。结论：由胰岛素抵抗和高脂血症引起的动脉粥样硬化的加速发展可能部分受到单核细胞中PKCδ同工型激活的限制，从而降低了其在动脉壁的数量和炎性反应。