Chen Xiaofeng, Howatt Deborah A, Balakrishnan Anju, Moorleghen Jessica J, Wu Congqing, Cassis Lisa A, Daugherty Alan, Lu Hong
From the Laboratory of Cardiovascular Disease, Department of Cardiology, Taizhou Hospital, Wenzhou Medical University, Zhejiang, China (X.C.); Saha Cardiovascular Research Center (X.C., D.A.H., A.B., J.J.M., C.W., A.D., H.L.), Department of Pharmacology and Nutritional Sciences (L.A.C., A.D.), and Department of Physiology, University of Kentucky, Lexington (A.D., H.L.).
Arterioscler Thromb Vasc Biol. 2016 Jun;36(6):1085-9. doi: 10.1161/ATVBAHA.115.307038. Epub 2016 Apr 7.
Angiotensin-converting enzyme (ACE) is present in many cell types of atherosclerotic lesions. This study determined whether ACE activity in endothelial and smooth muscle cells (SMCs), 2 major resident cell types of the aorta, contributes to hypercholesterolemia-induced atherosclerosis.
All study mice were in low-density lipoprotein 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. Because 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, SMC-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多种细胞类型中。本研究旨在确定主动脉的两种主要驻留细胞类型，即内皮细胞和平滑肌细胞（SMC）中的ACE活性是否会导致高胆固醇血症诱导的动脉粥样硬化。
所有研究小鼠均为低密度脂蛋白受体基因敲除（-/-）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基因条件性敲除小鼠与雄性Tie2-Cre转基因小鼠进行杂交。内皮细胞特异性缺失ACE可显著降低血清ACE活性，但对收缩压和动脉粥样硬化没有影响。由于ACE蛋白存在于主动脉中最丰富的细胞类型SMC上，因此我们接着确定SMC上的ACE是否会导致动脉粥样硬化。通过将雌性ACE基因条件性敲除小鼠与雄性SM22-Cre转基因小鼠杂交，使SMC中的ACE缺失。SMC特异性缺失ACE对血清中的ACE活性没有影响，但消除了其在主动脉中层的存在和活性。尽管SMC特异性缺失ACE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发挥关键作用。相反，SMC来源的ACE对动脉粥样硬化有影响，且独立于循环中的ACE活性和血压。
