Cardiovascular Center and Drug Discovery Center, Medical College of Wisconsin, Milwaukee, WI, U.S.A.
Clin Sci (Lond). 2020 Oct 30;134(20):2707-2727. doi: 10.1042/CS20191209.
Arachidonic acid can be metabolized in blood vessels by three primary enzymatic pathways; cyclooxygenase (COX), lipoxygenase (LO), and cytochrome P450 (CYP). These eicosanoid metabolites can influence endothelial and vascular smooth muscle cell function. COX metabolites can cause endothelium-dependent dilation or constriction. Prostaglandin I2 (PGI2) and thromboxane (TXA2) act on their respective receptors exerting opposing actions with regard to vascular tone and platelet aggregation. LO metabolites also influence vascular tone. The 12-LO metabolite 12S-hydroxyeicosatrienoic acid (12S-HETE) is a vasoconstrictor whereas the 15-LO metabolite 11,12,15-trihydroxyeicosatrienoic acid (11,12,15-THETA) is an endothelial-dependent hyperpolarizing factor (EDHF). CYP enzymes produce two types of eicosanoid products: EDHF vasodilator epoxyeicosatrienoic acids (EETs) and the vasoconstrictor 20-HETE. The less-studied cross-metabolites generated from arachidonic acid metabolism by multiple pathways can also impact vascular function. Likewise, COX, LO, and CYP vascular eicosanoids interact with paracrine and hormonal factors such as the renin-angiotensin system and endothelin-1 (ET-1) to maintain vascular homeostasis. Imbalances in endothelial and vascular smooth muscle cell COX, LO, and CYP metabolites in metabolic and cardiovascular diseases result in vascular dysfunction. Restoring the vascular balance of eicosanoids by genetic or pharmacological means can improve vascular function in metabolic and cardiovascular diseases. Nevertheless, future research is necessary to achieve a more complete understanding of how COX, LO, CYP, and cross-metabolites regulate vascular function in physiological and pathological states.
环加氧酶（COX）、脂加氧酶（LO）和细胞色素 P450（CYP）。这些类二十烷酸代谢物可以影响内皮细胞和血管平滑肌细胞的功能。COX 代谢物可引起内皮依赖性舒张或收缩。前列腺素 I2（PGI2）和血栓烷（TXA2）作用于各自的受体，对血管张力和血小板聚集产生相反的作用。LO 代谢物也影响血管张力。12-LO 代谢物 12S-羟基二十碳三烯酸（12S-HETE）是血管收缩剂，而 15-LO 代谢物 11,12,15-三羟基二十碳三烯酸（11,12,15-THETA）是内皮依赖性超极化因子（EDHF）。CYP 酶产生两种类型的类二十烷酸产物：EDHF 血管舒张环氧二十碳三烯酸（EETs）和血管收缩 20-HETE。由多种途径代谢花生四烯酸生成的研究较少的交叉代谢物也会影响血管功能。同样，COX、LO 和 CYP 血管类二十烷酸与旁分泌和激素因子（如肾素-血管紧张素系统和内皮素-1（ET-1））相互作用，以维持血管内稳态。代谢和心血管疾病中内皮细胞和血管平滑肌细胞 COX、LO 和 CYP 代谢物的失衡导致血管功能障碍。通过遗传或药理学手段恢复类二十烷酸的血管平衡可以改善代谢和心血管疾病中的血管功能。然而，未来的研究仍然需要更全面地了解 COX、LO、CYP 和交叉代谢物如何在生理和病理状态下调节血管功能。
