Faculty of Medicine and Dentistry, Department of Physiology, Cardiovascular Research Center, University of Alberta, Edmonton, Alberta, Canada.
Department of Dermatology, Osaka Metropolitan University Graduate School of Medicine, Osaka, Japan.
Am J Physiol Heart Circ Physiol. 2022 Sep 1;323(3):H528-H534. doi: 10.1152/ajpheart.00325.2022. Epub 2022 Aug 5.
Genetically modified mice are widely used to recapitulate human diseases. Atherosclerosis can be induced in mice with low-density lipoprotein receptor ()-deficiency and a high-fat diet (HFD). Disintegrin and metalloproteinase-17 (ADAM17) in the smooth muscle cell (SMC) contribute to vascular pathologies, and hence its role in atherosclerosis was investigated. deletion in SMCs by -Cre driver (/) and HFD resulted in severe skin lesions in >70% of mice, associated with skin inflammation, which was not observed in -HFD, nor in mice with SMC deficiency of by a different Cre driver (/). We found that is highly expressed in keratinocytes (compared with SMCs), which could underlie the observed skin lesion in /-HFD. Although expression of in non-SMCs has been reported, this is the first study demonstrating a severe side effect resulting from the off-target expression of -Cre, resulting in ADAM17 loss in keratinocytes that led to a moribund state. Although -Cre is commonly used to target gene deletion in smooth muscle cells, -derived deletion resulted in unexpected severe skin lesions following high-fat diet feeding in a model of atherosclerosis. deletion by a different SMC driver, -Cre, did not result in skin lesions in the same atherosclerosis model. is highly expressed in keratinocytes, causing ectopic loss of ADAM17 in keratinocytes that caused significant epidermal lesions when combined with a high-fat diet.
基因修饰小鼠被广泛用于模拟人类疾病。通过低密度脂蛋白受体（）缺陷和高脂肪饮食（HFD）可以在小鼠中诱导动脉粥样硬化。在平滑肌细胞（SMC）中的分裂素和金属蛋白酶-17（ADAM17）有助于血管病理学，因此研究了其在动脉粥样硬化中的作用。SMC 中的缺失通过 -Cre 驱动子（/）和 HFD 导致超过 70%的小鼠出现严重的皮肤损伤，伴有皮肤炎症，这在 -HFD 中或使用不同的 Cre 驱动子（/）的 SMC 缺失的小鼠中均未观察到。我们发现在角质细胞（与 SMC 相比）中高度表达，这可能是在 /-HFD 中观察到的皮肤损伤的基础。尽管已经报道了非 SMC 中 的表达，但这是第一项研究表明由于 -Cre 的脱靶表达导致的严重副作用，导致角质细胞中 ADAM17 的缺失导致濒死状态。尽管 -Cre 通常用于靶向平滑肌细胞中的基因缺失，但在动脉粥样硬化模型中，高脂肪饮食喂养后， -Cre 导致的缺失导致出乎意料的严重皮肤损伤。使用不同的 SMC 驱动子，-Cre，在相同的动脉粥样硬化模型中不会导致皮肤损伤。在角质细胞中高度表达，导致 ADAM17 在角质细胞中的异位缺失，当与高脂肪饮食结合时会导致明显的表皮损伤。
