Rationale: Activation of monocytes/macrophages by hyperlipidemia associated with diabetes mellitus and obesity contributes to the development of atherosclerosis. PKCδ (protein kinase C δ) expression and activity in monocytes were increased by hyperlipidemia and diabetes mellitus 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 high-fat diet (HFD). Mice fed AD and HFD exhibited hyperlipidemia, but only HFD-fed mice had insulin resistance and mild diabetes mellitus. Surprisingly, MPKCδKO/ApoE^−/− mice exhibited accelerated aortic atherosclerotic lesions by 2-fold versus 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 number in aortic plaques and spleen by 1.7- and 2-fold, respectively, in MPKCδKO/ApoE^−/− versus ApoE^−/− mice because of decreased apoptosis (62%) and increased proliferation (1.9-fold), and not because of uptake, with parallel increased expressions of inflammatory cytokines. Mechanisms for the increased macrophages in MPKCδKO/ApoE^−/− were associated with elevated phosphorylation levels of prosurvival cell-signaling proteins, Akt and FoxO3a, with reduction of proapoptotic 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激活单核细胞/巨噬细胞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（蛋白激酶Cδ）的表达和活性，对动脉粥样硬化的后果尚不清楚。

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）繁殖PKCδflox / flox小鼠，产生巨噬细胞中PKCδ选择性缺失的小鼠，并在动脉粥样硬化（AD）和高脂饮食（HFD）中进行研究）。用AD和HFD喂养的小鼠表现出高脂血症，但是只有HFD喂养的小鼠具有胰岛素抵抗和轻度糖尿病。出人意料的是，与AD或HFD上的ApoE ^-/-小鼠相比，MPKCδKO/ ApoE ^-/-小鼠表现出2倍的加速主动脉粥样硬化病变。在MPKCδKO/ ApoE ^-/-中观察到脾肿大在AD和HFD上的老鼠，而不是定期吃东西的老鼠。无论是AD或HFD增加主动脉斑块和脾的巨噬细胞数目由1.7-和2倍，分别在MPKCδKO/的ApoE ^{- / -}与的ApoE ^{- / -}的，因为降低的细胞凋亡（62％）和增加的增殖的小鼠（1.9〜倍），而不是因为摄取，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生存细胞信号蛋白Akt和FoxO3a磷酸化水平升高有关，而与PKCδ诱导的P85 / PI3K抑制有关的凋亡前蛋白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。