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

• Published in: American journal of physiology. Lung cellular and molecular physiology 2015-09, Vol.309 (5), p.L449-L462
• Main Authors: Shen, Tingting, Shi, Jiucheng, Wang, Na, Yu, Xiufeng, Zhang, Chen, Li, Jing, Wei, Liuping, Ma, Cui, Zhao, Xijuan, Lian, Mingming, Jiang, Chun, Zhu, Daling
• Format: Article
• Language: English
• Subjects: Animals; Arachidonate 15-Lipoxygenase - genetics; Arachidonate 15-Lipoxygenase - metabolism; Blood Platelets - pathology; Cells, Cultured; Chemokine CCL2 - antagonists & inhibitors; Coagulation; Cytokines - secretion; Heart failure; Humans; Hydroxyeicosatetraenoic Acids - metabolism; Hypertension; Hypertension, Pulmonary - drug therapy; Hypertension, Pulmonary - pathology; Hypoxia; Hypoxia - blood; Hypoxia - pathology; Indazoles - therapeutic use; Lesions; Lipoxygenase Inhibitors - therapeutic use; Male; Masoprocol - therapeutic use; Physiology; Platelet Activation - drug effects; Propionates - therapeutic use; Pulmonary Artery - pathology; Pulmonary hypertension; Random Allocation; Rats; Rats, Wistar; RNA Interference; RNA, Small Interfering; Rodents; Signal transduction; Signal Transduction - drug effects; Thromboembolism; Thrombosis; Thrombosis - drug therapy; Thrombosis - etiology; Thrombosis - metabolism; Vascular Resistance - drug effects; Vascular Resistance - physiology
• ISSN: 1040-0605; 1522-1504
• DOI: 10.1152/ajplung.00004.2015

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.