Department of Pharmacology and Toxicology College of Pharmacy, Southwest Environmental Health Sciences Center, Steele Children's Research Center and Bio5 Institute, University of Arizona, Tucson, AZ 85721, USA.
Toxicol Appl Pharmacol. 2013 Oct 1;272(1):147-53. doi: 10.1016/j.taap.2013.04.035. Epub 2013 Jun 2.
Exposure to arsenic results in several types of cancers as well as heart disease. A major contributor to ischemic heart pathologies is coronary artery disease, however the influences by environmental arsenic in this disease process are not known. Similarly, the impact of toxicants on blood vessel formation and function during development has not been studied. During embryogenesis, the epicardium undergoes proliferation, migration, and differentiation into several cardiac cell types including smooth muscle cells which contribute to the coronary vessels. The TGFβ family of ligands and receptors is essential for developmental cardiac epithelial to mesenchymal transition (EMT) and differentiation into coronary smooth muscle cells. In this in vitro study, 18hour exposure to 1.34μM arsenite disrupted developmental EMT programming in murine epicardial cells causing a deficit in cardiac mesenchyme. The expression of EMT genes including TGFβ2, TGFβ receptor-3, Snail, and Has-2 are decreased in a dose-dependent manner following exposure to arsenite. TGFβ2 cell signaling is abrogated as detected by decreases in phosphorylated Smad2/3 when cells are exposed to 1.34μM arsenite. There is also loss of nuclear accumulation pSmad due to arsenite exposure. These observations coincide with a decrease in vimentin positive mesenchymal cells invading three-dimensional collagen gels. However, arsenite does not block TGFβ2 mediated smooth muscle cell differentiation by epicardial cells. Overall these results show that arsenic exposure blocks developmental EMT gene programming in murine coronary progenitor cells by disrupting TGFβ2 signals and Smad activation, and that smooth muscle cell differentiation is refractory to this arsenic toxicity.
砷暴露会导致多种癌症和心脏病。导致缺血性心脏病病理的一个主要因素是冠状动脉疾病，然而，环境砷对这一疾病过程的影响尚不清楚。同样，有毒物质对发育过程中血管形成和功能的影响也尚未研究过。在胚胎发生过程中，心外膜经历增殖、迁移，并分化为几种心脏细胞类型，包括平滑肌细胞，这些细胞有助于冠状动脉的形成。TGFβ 配体和受体家族对于心脏上皮细胞向间充质转化 (EMT) 和分化为冠状动脉平滑肌细胞的发育至关重要。在这项体外研究中，18 小时暴露于 1.34μM 的亚砷酸盐破坏了鼠心外膜细胞的发育 EMT 编程，导致心脏间充质减少。暴露于亚砷酸盐后，EMT 基因（包括 TGFβ2、TGFβ 受体-3、Snail 和 Has-2）的表达呈剂量依赖性下降。TGFβ2 细胞信号转导被阻断，因为当细胞暴露于 1.34μM 亚砷酸盐时，磷酸化 Smad2/3 减少。由于砷暴露，核积累的 pSmad 也会丢失。这些观察结果与侵袭三维胶原凝胶的间充质细胞中波形蛋白阳性的间充质细胞减少相一致。然而，亚砷酸盐并没有阻止 TGFβ2 介导的心外膜细胞向平滑肌细胞的分化。总的来说，这些结果表明，砷暴露通过破坏 TGFβ2 信号和 Smad 激活，阻断了鼠冠状动脉祖细胞发育性 EMT 基因编程，而平滑肌细胞分化对这种砷毒性具有抗性。
