The Effects of Leukocyte-Type 12/15-Lipoxygenase on Id3-Mediated Vascular Smooth Muscle Cell Growth

Abstract

Objective-12/15-Lipoxygenase (12/15-LO) has been implicated in the pathogenesis of vascular disease. Vascular smooth muscle cell (VSMC) proliferation is a key component of the response to injury in vascular disease. -LO), highly homologous to human 15-lipoxygenase, and its products have been shown to be increased in animal models of native atherosclerosis and injury-induced restenosis. Further, pharmacological inhibition and knockout (KO) of the 12/15-LO gene in atherosclerosis and injury models result in significantly less vascular lesion formation. [1][2][3][4][5][6][7] There are several theories as to how 12/15-LO induces lesion formation. It has been shown that lipoxygenases have the ability to oxidize low-density lipoprotein (LDL), a step important in lesion initiation and progression, and KO of the lipoxygenase gene decreases oxidant stress. 6,8,9 It has also been demonstrated that 12/15-LO and its products have the ability to mediate the effects of angiotensin II (Ang II), platelet-derived growth factor, and cytokines, all important mediators of vascular injury. 10 -14 12/15-LO is expressed in macrophages, fibroblasts, endothelial cells, and vascular smooth muscle cells (VSMCs), all important contributors to vascular lesion formation and progression. 9,12,[15][16][17] Recently, its role in the VSMC has begun to be defined. Indeed, the 12/15-LO products of arachidonic and linoleic acids 12S-hydroxy-eicosatetraenoic acid (12S-HETE), 15S-HETE, and 13S-hydroperoxyoctadecadienoic acid (13S-HPODE) are produced in VSMCs. Lipoxygenase activity has been shown to be increased by and to mediate the hypertrophic effects of Ang II, the mitogenic effects of cytokines, and the chemotactic effects of platelet-derived growth factor in VSMCs, whereas 12/15-LO inhibition blocks these effects. 10,11,13,14 12/15-LO products have direct hypertrophic effects in VSMCs. 10,18 12/15-LO appears to also affect VSMC proliferation because 12/15-LO increases dramatically with arterial injury in VSMCs, and inhibition of 12/15-LO decreases smooth muscle cell proliferation and neointimal formation after balloon injury. 4 Recent studies show that VSMCs from 12/15-LO KO mice display decreased S-phase entry and growth-related responses relative to those from wildtype mice. 19 However, although much is known about the effects of 12/15-LO and its products, less is known about the specific mechanisms by which 12/15-LO regulates key nuclear transcription factors related to VSMC growth.

Physiologic and pathophysiologic roles of lipid mediators in the kidney

“…155 12-HETE also promotes vascular smooth muscle cell proliferation, [164][165][166] whereas 12/15-LO gene deletion reduces vascular smooth muscle cell growth. 167 In the kidney, 12-HETE and 15-HETE constrict renal vessels and glomerular mesangial cells. 88,149 When infused into the renal artery, 12-HETE decreases RBF and GFR.…”

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

“…Increased Id3 protein expression in VSMCs with increased expression of 12/15LO and attenuated 12/15LO- induced VSMC proliferation in VSMCs from mice null for Id3 10 provide evidence that Id3 is a downstream regulator of 12/15LO-induced VSMC proliferation in culture. In vivo, Id3 expression is induced during vascular lesion formation in response to injury.…”

“…Real-time RT-PCR, 28 immunohistochemistry, 26 cell culture, 26 chromatin immunoprecipitation, 28 and promoter-reporter analysis 10 were performed as previously described.…”

“…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. 11 Compared with uninjured carotids, 12/15LO expression is significantly increased in rat carotids on day 12 after injury.…”

“…More importantly, overexpression of 12/15LO in culture increases growth in BL-6 VSMCs but not in Id3 Ϫ/Ϫ VSMCs. 10 The goal of the current study was to determine whether the effects of increased 12/15LO on Id3 expression and proliferation in VSMCs in culture occurred in vivo and if increased expression of 12/15LO at baseline increases NIF in response to injury.…”