Role of the lipoxygenase pathway in angiotensin II-induced vascular smooth muscle cell hypertrophy.

Abstract

The 12-lipoxygenase pathway is a key mediator of angiotensin II (Ang II)-induced effects in the adrenal cortex. We also recently demonstrated that Ang II increases 12-and 15-lipoxygenase product levels in vascular smooth muscle cells. However, the relation between lipoxygenase activation and Ang II-induced vascular smooth muscle cell hypertrophy is not known. We studied the effects of Ang II and 12-lipoxygenase products on both total cell protein content and the levels of the matrix protein fibronectin in quiescent porcine aortic smooth muscle cells. Ang II-induced increases in cellular protein content were attenuated by the specific 12-lipoxygenase inhibitor baicalein; in contrast, the cycloxygenase inhibitor ibuprofen had no effect. Direct addition of the 12-lipoxygenase product 12-S-hydroxyeicosatetraenoic acid increased total cell protein content. We have recently shown that porcine vascular smooth muscle cell growth is potentiated in high glucose (25 mmol/L) culture conditions. We observed that both Ang II and 12-5-hydroxyeicosatetraenoic acid induced a greater increase in protein content in cells cultured for two passages in high glucose. Furthermore, Ang II and 12-5-hydroxyeicosatetraenoic acid also markedly increased fibronectin levels in cells cultured in high glucose. These results suggest that 12-lipoxygenase activation plays a key role in Ang II-induced vascular smooth muscle cell hypertrophy.

Increased 12/15-Lipoxygenase Enhances Cell Growth, Fibronectin Deposition, and Neointimal Formation in Response to Carotid Injury

“…12/15LO promotes VSMC migration, and 12/15LO products of arachidonic acid have hypertrophic effects and increase the expression of the fibronectin gene in VSMCs in culture. 5,7,8 Herein, results extend these in vitro data, demonstrating a significant increase in fibronectin deposition in the neointima in response to injury in the 12/15LO-tg mice compared with the BL-6 controls.…”

“…12/15LO products of arachidonic acid, such as 12S-hydroxyeicosatetrenoic acid (HETE), 15S-HETE, and 13S-hydroperoxyoctadecadienoic acid (HPODE), are produced in VSMCs and have hypertrophic effects. 5,6 In vitro, 12/15LO inhibition attenuates hypertrophic effects of angiotensin II in VSMCs, mitogenic effects of cytokines, and chemotactic effects of platelet-derived growth factor. 5,7,8 Compared with VSMCs from C57BL/6 (BL-6) mice, VSMCs from 12/15LO-overexpressing transgenic (12/15LO-tg) mice grow faster, and VSMCs from 12/15LO Ϫ/Ϫ mice grow slower and display decreased S-phase entry in culture.…”

“…5,6 In vitro, 12/15LO inhibition attenuates hypertrophic effects of angiotensin II in VSMCs, mitogenic effects of cytokines, and chemotactic effects of platelet-derived growth factor. 5,7,8 Compared with VSMCs from C57BL/6 (BL-6) mice, VSMCs from 12/15LO-overexpressing transgenic (12/15LO-tg) mice grow faster, and VSMCs from 12/15LO Ϫ/Ϫ mice grow slower and display decreased S-phase entry in culture. 9,10 12/15LO and its products are increased in the vascular wall of animal models of atherosclerosis and injury-induced restenosis.…”

Catalytic consumption of nitric oxide by 12/15- lipoxygenase: Inhibition of monocyte soluble guanylate cyclase activation

“…Also, ang II up-regulates 12͞15-LOX in mouse macrophages and porcine smooth muscle in vitro via the AT 1 receptor (31,32). Inhibition of 12͞15-LOX by nonspecific inhibitors reduces blood pressure in hypertensive rats, and ang II-induced smooth muscle hypertrophy (33)(34)(35)(36). The mechanism(s) by which 12͞15-LOX contributes to vascular tone and smooth muscle proliferation is unclear.…”

Lipoxygenase Products Regulate Nitric Oxide and Inducible Nitric Oxide Synthase Production in Interleukin-1.BETA. Stimulated Vascular Smooth Muscle Cells.

“…LOX products, such as 12(S)-hydroxyeicosatetraenoic acid (HETE), stimulate the proliferation of VSMCs and fibronectin gene expression (15) and mediate oxidative modification of low density lipoprotein (LDL) (16). In addition, LOX enzymes have been shown to be expressed in macrophage-rich areas of atherosclerotic lesions (17).…”