American Journal of Physiology - Lung Cellular and Molecular Physiology 2015-09-01

15-Lipoxygenase and 15-hydroxyeicosatetraenoic acid regulate intravascular thrombosis in pulmonary hypertension.

Tingting Shen, Jiucheng Shi, Na Wang, Xiufeng Yu, Chen Zhang, Jing Li, Liuping Wei, Cui Ma, Xijuan Zhao, Mingming Lian, Chun Jiang, Daling Zhu

文献索引：Am. J. Physiol. Lung Cell. Mol. Physiol. 309 , L449-62, (2015)

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摘要

Pulmonary arterial hypertension (PAH) is a disease characterized by thickening of pulmonary artery walls, elevated pulmonary vascular resistance, pulmonary vascular thrombotic lesions, and right heart failure. Recent studies suggest that 15-lipoxygenase (15-LO)/15-hydroxyeicosatetraenoic acid (15-HETE) play an important role in PAH, acting on arterial walls. Here, we show evidence for the action of the 15-LO/15-HETE signaling in the pulmonary vascular thrombotic lesions in the experimental PAH models. Platelet deposition was augmented in rats exposed to hypoxia and Sugen 5416, which were both prevented by nordihydroguaiaretic acid (NDGA), a 15-LO inhibitor. Chronic hypoxic resulted in the platelet deposition specifically in pulmonary vasculature, which was reversed by 15-LO inhibitor. The 15-LO pathway mediated in the endothelial dysfunction induced by hypoxia in vivo. Meanwhile, 15-HETE positively regulated the generation of IL-6 and monocyte chemoattractant protein-1 (MCP-1). The coagulation and platelet activation induced by hypoxia were reversed by 15-LO inhibitor NDGA or the MCP-1 inhibitor synthesis inhibitor bindarit in rats. The 15-LO/15-HETE signaling promoted the coagulation and platelet activation, which was suppressed by MCP-1 inhibition. These results therefore suggest that 15-LO/15-HETE signaling plays a role in platelet activation and pulmonary vascular thrombosis in PAH, involving MCP-1. Copyright © 2015 the American Physiological Society.