Angiotensin-Converting Enzyme in Smooth Muscle Cells Promotes Atherosclerosis-Brief Report.

Angiotensin-converting enzyme (ACE) is present in many cell types of atherosclerotic lesions. This study determined whether ACE activity in endothelium and smooth muscle cells (SMCs), two major resident cell types of the aorta, contributes to hypercholesterolemia-induced atherosclerosis. All study mice were in LDL receptor -/- background. To determine the contribution of ACE on endothelial cells to atherosclerosis, female ACE floxed mice were bred to male Tie2-Cre transgenic mice. Endothelial cell-specific deletion of ACE significantly decreased serum ACE activity, but had no effect on systolic blood pressure and atherosclerosis. Since ACE protein is present on SMCs, the most abundant cell type of the aorta, we then determined whether ACE on SMCs contributes to atherosclerosis. ACE was depleted from SMCs by breeding female ACE floxed mice with male SM22-Cre transgenic mice. SMC-specific deficiency of ACE did not affect ACE activity in serum, but ablated its presence and activity in the aortic media. Although SMC-specific deficiency of ACE had no effect on systolic blood pressure, it significantly attenuated hypercholesterolemia-induced atherosclerosis in both male and female mice. These studies provide direct evidence that ACE derived from endothelial cells does not play a critical role in atherosclerosis. Rather, smooth muscle cell-derived ACE contributes to atherosclerosis, independent of circulating ACE activity and blood pressure.

血管紧张素转换酶（ACE）存在于动脉粥样硬化病变的许多细胞类型中。本研究旨在确定主动脉的两种主要驻留细胞类型——内皮细胞和平滑肌细胞（SMCs）中的ACE活性是否对高胆固醇血症诱导的动脉粥样硬化有影响。 所有研究用小鼠均为低密度脂蛋白受体（LDL receptor）-/-背景。为了确定内皮细胞上的ACE对动脉粥样硬化的作用，将雌性ACE基因敲除小鼠与雄性Tie2 - Cre转基因小鼠交配。内皮细胞特异性ACE缺失显著降低了血清ACE活性，但对收缩压和动脉粥样硬化没有影响。由于ACE蛋白存在于平滑肌细胞（主动脉中最丰富的细胞类型）上，我们接着确定平滑肌细胞上的ACE是否对动脉粥样硬化有影响。通过将雌性ACE基因敲除小鼠与雄性SM22 - Cre转基因小鼠交配，使平滑肌细胞中的ACE耗竭。平滑肌细胞特异性ACE缺乏不影响血清中的ACE活性，但消除了其在主动脉中膜的存在和活性。尽管平滑肌细胞特异性ACE缺乏对收缩压没有影响，但它显著减轻了雄性和雌性小鼠高胆固醇血症诱导的动脉粥样硬化。 这些研究提供了直接证据，表明内皮细胞来源的ACE在动脉粥样硬化中不起关键作用。相反，平滑肌细胞来源的ACE对动脉粥样硬化有促进作用，且与循环ACE活性和血压无关。