Zhang Xin, Gschwind Johannes, Erben Vanessa, Bennewitz Katrin, Li Xiaogang, Sticht Carsten, Poschet Gernot, Hausser Ingrid, Fleming Thomas, Szendroedi Julia, Nawroth Peter Paul, Kroll Jens
Department of Vascular Biology, ECAS, Medical Faculty Mannheim, Heidelberg University, Mannheim, 68167, Germany.
NGS Core Facility, Medical Faculty Mannheim, Heidelberg University, Mannheim, 68167, Germany.
Redox Biol. 2025 Jun;83:103639. doi: 10.1016/j.redox.2025.103639. Epub 2025 Apr 17.
Acrolein (ACR) is an endogenous reactive unsaturated aldehyde that can be detoxified by the aldo-keto reductase (AKR) enzyme system. While it has been shown that accumulation of ACR is associated with several health problems, including inflammation, oxidative stress, and cardiovascular disease the study aimed to analyze whether an endogenous accumulation of ACR is causal for vascular dysfunction in an akr7a3 mutant zebrafish model. Enlargement of the hyaloid and retinal vasculature, as well as alterations in the larval pronephros and thickening of the glomerular basement membrane in the adult kidney were found upon ACR accumulation. Transcriptomic and metabolomic analyses, followed by functional validation, revealed that the up-regulation of genes controlling the arachidonic acid metabolism and activation of the leukotriene pathway are responsible for the observed microvascular changes. In conclusion, the data have identified an intrinsic function of ACR in akr7a3 mutants that activates the arachidonic acid metabolism and subsequently disrupts vascular integrity by promoting an inflammatory response. Thus, ACR is causal in the development of vascular disease.
丙烯醛（ACR）是一种内源性反应性不饱和醛，可通过醛酮还原酶（AKR）酶系统进行解毒。虽然已有研究表明ACR的积累与多种健康问题相关，包括炎症、氧化应激和心血管疾病，但该研究旨在分析ACR的内源性积累是否是akr7a3突变斑马鱼模型中血管功能障碍的病因。在ACR积累后，发现晶状体血管和视网膜血管增大，以及幼虫前肾的改变和成年肾脏中肾小球基底膜增厚。转录组学和代谢组学分析，随后进行功能验证，结果表明，控制花生四烯酸代谢的基因上调和白三烯途径的激活是观察到微血管变化的原因。总之，这些数据确定了ACR在akr7a3突变体中的内在功能，即激活花生四烯酸代谢，随后通过促进炎症反应破坏血管完整性。因此，ACR是血管疾病发展的病因。
