br The lipoxygenase pathway in

The 12/15-lipoxygenase pathway in vascular physiology and pathology The mammalian 12- and 15-LOXs have high substrate specificity oxidizing predominantly ω−6 (arachidonic and linoleic acids) but also the ω−3 (docosahexanoic) WWL 70 [86], [87], [88]. Different LOXs oxidize fatty acids both in the free form or in complex lipid-protein assemblies like membrane phospholipids and cholesterol esters in lipoproteins [87]. While having high substrate specificity, the positional selectivity of the oxygenation varies, leading in most cases to a mix of 12- and 15HPETEs which are subsequently reduced to their corresponding hydroxyl, more stable derivatives HETEs. In contrast, oxygenation of linoleic acid leads to the uniformly predominant formation of 13HPODEs and subsequently the reduced 13HODEs. Recently, 15-LOX1 was also implicated in oxygenation of ω−3 docosahexanoic acid leading to the resolvin D1 and protectin D1 classes of eicosanoids [89], [90], [91] (described in the Introduction and in Fig. 1).
The 12/15-lipoxygenase pathway in regulation of renal function and pathology A variety of AA metabolites formed via the three major enzymatic pathways (COX, CYP450, and LOX) have significant effects on regulation of renal hemodynamics, and disturbances in any of these pathways can contribute to renal injury, progression to renal nephropathy and renal function alterations [185], [186], [187]. Generation of eicosanoids in the kidney is altered in a variety of conditions such as hypertension, diabetic nephropathy, and acute renal failure. Therefore there is evidence that altered vascular production of AA metabolites could be both cause and effect in various renal pathologic conditions. In this chapter we will focus solely on evidence for the physiologic and pathogenic role of the 12- and 15-LOX pathway in the kidney. Several studies showed key renal hemodynamic effects of 12- and 15-LOX pathway in the kidney (Fig. 6). 12(S)-HETE and 15(S)-HETE were shown to have vasoconstrictive actions on renal vessels and glomerular mesangial cells [185], [188]. 12HETE infusion in the renal artery of rats resulted in decreased renal blood flow and glomerular filtration rate (GFR) [189]. Also, 12(S)-HETE was shown to contribute to vasoconstrictive response of the renal afferent arteriole to angiotensin II [188]. Likewise, 12(S)-HETE enhanced the vasoconstrictive effect of angiotensin II in the aorta of SHR through an increase in intracellular calcium [190]. Recent studies showed that interaction between 12/15-LOX and angiotensin II is mediated in part by AT1 receptor. 12-LOX enhanced AT1R expression in diabetic glomeruli and 12-LOX inhibition could ameliorate diabetic nephropathy progression through downregulation of AT1R expression [191]. Also, valsartan reduced platelet 12-LOX in mice in adipocytes [85]. Of importance, as described under vascular actions of 12/15-LOX in this review, there is mutual interaction with the NO production and signaling. 12/15-LOX induces catalytic consumption of NO and can prevent NO-dependent soluble guanylate cyclase activation [192]. In accordance to above reported effects, 12/15 LOX knockout mice had reduced vasoconstriction responses to angiotensin II and increased eNOS expression and NO bioavailability [101]. Of importance, the 12- and 15-LOX pathways also act as mediators of the interaction between angiotensin II and aldosterone in the adrenal cortex with important implications on renal function and on cardiac hypertrophy. Angiotensin II stimulated aldosterone production in both rat and human granulosa cells [193], [194]. The major lipid mediator responsible for this effect is the 12(S)-HETE but not the 15(S)-HETE. Basal aldosterone secretion is not mediated via the 12-LOX products, however angiotensin-dependent aldosterone secretion is critically dependent on the LOX pathway metabolite. A recent report emphasizes the reciprocal effect of aldosterone on up-regulation of 12- and 15-LOX expression and LDL oxidation in human vascular smooth muscle cells [195]. Increased production of 12(S)-HETE and 15(S)-HETE induced increased smooth muscle cell contractility, hypertrophy and migration as well as enhanced LDL oxidation [195]. via these effects, 12- and 15-LOX could contribute to vascular reactivity and atherogenesis, as well as blood pressure regulation.