Role of 12-lipoxygenase in hypoxia-induced rat pulmonary artery smooth muscle cell proliferation

Abstract

The 12-lipoxygenase (12-LO) pathway of arachidonic acid metabolism stimulates cell growth and metastasis of various cancer cells and the 12-LO metabolite, 12(S)-hydroxyeicosatetraenoic acid [12(S)-HETE], enhances proliferation of aortic smooth muscle cells (SMCs). However, pulmonary vascular effects of 12-LO have not been previously studied. We sought evidence for a role of 12-LO and 12(S)-HETE in the development of hypoxia-induced pulmonary hypertension. We found that 12-LO gene and protein expression is elevated in lung homogenates of rats exposed to chronic hypoxia. Immunohistochemical staining with a 12-LO antibody revealed intense staining in endothelial cells of large pulmonary arteries, SMCs (and possibly endothelial cells) of medium and small-size pulmonary arteries and in alveolar walls of hypoxic lungs. 12-LO protein expression was increased in hypoxic cultured rat pulmonary artery SMCs. 12(S)-HETE at concentrations as low as 10(-5) microM stimulated proliferation of pulmonary artery SMCs. 12(S)-HETE induced ERK 1/ERK 2 phosphorylation but had no effect on p38 kinase expression as assessed by Western blotting. 12(S)-HETE-stimulated SMC proliferation was blocked by the MEK inhibitor PD-98059, but not by the p38 MAPK inhibitor SB-202190. Hypoxia (3%)-stimulated pulmonary artery SMC proliferation was blocked by both U0126, a MEK inhibitor, and baicalein, an inhibitor of 12-LO. We conclude that 12-LO and its product, 12(S)-HETE, are important intermediates in hypoxia-induced pulmonary artery SMC proliferation and may participate in hypoxia-induced pulmonary hypertension.

The Amiloride Derivative Phenamil Attenuates Pulmonary Vascular Remodeling by Activating NFAT and the Bone Morphogenetic Protein Signaling Pathway

“…Phenamil (15 or 30 mg/kg of body weight/day) was administered continuously for 21 days at an infusion rate of 1 ml/h. The rats were subjected to hypobaric hypoxia (10.5% oxygen) or normoxia (room air) for 21 days as described previously (34).…”

“…The right ventricular peak pressure (RVPP) was measured by inserting a 26-gauge needle with 12 in. of P-50 tubing connected to a pressure transducer into the right ventricle (RV) as described previously (34). Continuous measurement of RV pressure was recorded on a polygraph, and RVPP was measured as the highest pressure recording over a 1-to 3-min period during which pressure recordings remained stable.…”

Interferon Regulatory Factor-1 Regulates the Autophagic Response in LPS-Stimulated Macrophages through Nitric Oxide

“…While hypoxia-induced remodeling is associated with medial hypertrophy, direct stimulation of SMC proliferation by hypoxia remains somewhat controversial (37). Although there are reports of hypoxia driven smooth muscle cell proliferation (38,39), several in vitro studies have shown that hypoxia does not directly increase SMC proliferation (40)(41)(42) or may actually decrease proliferation (43,44). However, fibroblasts that are less differentiated than the other two main vascular cell types, have a greater proliferative response to hypoxia (44)(45)(46).…”

Downregulation of Angiotensin II-Induced 12-Lipoxygenase Expression and Cell Proliferation in Vascular Smooth Muscle Cells from Spontaneously Hypertensive Rats by CCL5

“…The 12-lipoxygenase (LO) pathway of arachidonic acid metabolism has been linked to cell growth and the pathology of hypertension (Preston et al, 2006). Ang II is a potent positive regulator of 12-LO expression and proliferation in porcine and human vascular smooth muscle cells (VSMCs) (Natarajan et al, 1993;Kim et al, 1995).…”