Functional and biochemical data have suggested a role for the cytochrome P450 arachidonate monooxygenases in the pathophysiology of hypertension, a leading cause of cardiovascular, cerebral, and renal morbidity and mortality. We show here that disruption of the murine cytochrome P450, family 4, subfamily a, polypeptide 10 (Cyp4a10) gene causes a type of hypertension that is, like most human hypertension, dietary salt sensitive. Cyp4a10 -/-mice fed low-salt diets were normotensive but became hypertensive when fed normal or high-salt diets. Hypertensive Cyp4a10 -/-mice had a dysfunctional kidney epithelial sodium channel and became normotensive when administered amiloride, a selective inhibitor of this sodium channel. These studies (a) establish a physiological role for the arachidonate monooxygenases in renal sodium reabsorption and blood pressure regulation, (b) demonstrate that a dysfunctional Cyp4a10 gene causes alterations in the gating activity of the kidney epithelial sodium channel, and (c) identify a conceptually novel approach for studies of the molecular basis of human hypertension. It is expected that these results could lead to new strategies for the early diagnosis and clinical management of this devastating disease. IntroductionPrevalence, complexity, and multiple medical and socioeconomic consequences make hypertension a major health challenge for most of the Western world (1). While environmental factors and coexist ing conditions play a role in the development and progression of hypertension, segregation and linkage analyses indicate that mul tiple genetic factors contribute to its complex etiology (2-7). Fur thermore, clinical studies show that the cardiovascular and renal morbidity and mortality resulting from hypertension are markedly reduced by timely diagnosis and early clinical intervention (1). As the kidneys play a central role in the control of body salt and fluid balance, they are frequent targets for the treatment of hypertension, especially those forms sensitive to dietary salt (2-5). However, since the molecular basis of prevalent forms of the disease remains uncer tain, its early diagnosis and treatment are largely symptomatic. It is expected that the identification of novel pathways/genes involved in blood pressure variations (3, 6, 7) will lead to new therapeutic targets and to improved diagnosis and prevention. Indeed, early detection and treatment are urgently needed to prevent the dangerous and profound consequences of untreated chronic hypertension.The metabolism of endogenous arachidonic acid (AA) to epoxy eicosatrienoic acids (EETs) and 20hydroxyeicosatetraenoic acid

No abstract

Despite advances in diagnosis and treatment, cancer continues to pose major clinical challenges and is the focus of efforts to develop therapies that combine effectiveness with low toxicity. Among these, angiogenesis is a current target of attempts aimed to reduce tumor vascularization and growth (1, 2), because it holds a promise for more effective and better tolerated approaches for cancer treatment. The peroxisomal proliferator-activated nuclear receptors (PPARs), 2 i.e. PPAR␣, PPAR␥, and PPAR␦, control the transcription of genes mostly involved in the regulation of lipid metabolism and energy homeostasis. Although several roles for the PPAR␦ and -␥ isotypes in the pathophysiology of cancer have been proposed (3-5), recent animal studies have identified PPAR␣ ligands as effective inhibitors of tumor angiogenesis and growth (6 -8).The potential significance of these findings has been emphasized by epidemiological data (9 -12), and by studies in human cancer cell lines (13-16), suggesting that PPAR␣ ligands such as Fenofibrate and Bezafibrate may have beneficial effects in the prognosis of human cancer. A unique feature of these PPAR␣ ligands is that, through their long history of clinical use as hypolipidemic drugs, they have been shown to be well tolerated and to have limited side effects and/or toxicity, indicating that they could serve as targets for the development of novel, safer, and with low toxicity anti-cancer treatments.The PPAR␣-mediated transcriptional regulation of members of the CYP2C gene subfamily of cytochrome P450s is well established (17, 18), as is the role of these enzymes in the metabolism and bio-activation of arachidonic acid (AA) (19). The CYP2C epoxygenases metabolize AA to 5,8,11,and 14,, and these metabolites have been characterized as pro-angiogenic lipids in vitro (20 -22) and in vivo (23). The demonstration that the anti-tumorigenic effects of PPAR␣ ligand activation were associated with reductions in the endothelial expression of the murine Cyp2c44 epoxygenase and in the levels of plasma and endothelial EETs (6), suggested pro-angiogenic and pro-tumorigenic roles for this epoxygenase, and pointed to this enzyme as a target of the anti-tumorigenic effects resulting from PPAR␣ activation (6). The murine Cyp2c44 epoxygenase generates 11,12-and 14,15-EET as its major products (24), is expressed in endothelial cells (6), and is under PPAR␣ transcriptional control (6). Similarly, human CYP2C8 and CYP2C9, catalytic homologues of murine Cyp2c44 (25), have been identified as endothelial epoxygenases (21,22), and their participation in

Background: Epoxyeicosatrienoic acids (EETs) regulate sodium excretion in the distal nephron. Results: Lack of a Cyp2c44 epoxygenase blunts the ERK1/2-mediated inhibition of ENaC and causes salt-sensitive hypertension. Conclusion: Cyp2c44 is the epoxygenase responsible for the synthesis of natriuretic EETs during increased salt intake. Significance: Roles for the human CYP2C8 and CYP2C9 epoxygenases as antihypertensive therapeutic targets are proposed.

Although the mechanism underlying the effect of androgen on BP and cardiovascular disease is not well understood, recent studies suggest that 8,11,, a primary cytochrome P450 4 (Cyp4)-derived eicosanoid, may mediate androgen-induced hypertension. Here, treatment of normotensive mice with 5a-dihydrotestosterone increased BP and induced both Cyp4a12 expression and 20-HETE levels in preglomerular microvessels. Administration of a 20-HETE antagonist prevented and reversed the effects of dihydrotestosterone on BP. Cyp4a14(2/2) mice, which exhibit androgen-sensitive hypertension in the male mice, produced increased levels of vascular 20-HETE; furthermore, administration of a 20-HETE antagonist normalized BP. To examine whether androgen-independent increases in 20-HETE are sufficient to cause hypertension, we studied Cyp4a12-transgenic mice, which express the CYP4A12-20-HETE synthase under the control of a doxycycline-sensitive promoter. Administration of doxycycline increased BP by 40%, and administration of a 20-HETE antagonist prevented this increase. Levels of CYP4A12 and 20-HETE in preglomerular microvessels of doxycycline-treated transgenic mice approximately doubled, correlating with increased 20-HETE-dependent sensitivity to phenylephrine-mediated vasoconstriction and with decreased acetylcholine-mediated vasodilation in the renal microvasculature. We observed a similar contribution of 20-HETE to myogenic tone in the mesenteric microvasculature. Taken together, these results suggest that 20-HETE both mediates androgeninduced hypertension and can cause hypertension independent of androgen. 24: 128824: -129624: , 201324: . doi: 10.1681 The v-hydroxylation of arachidonic acid (AA) to 20-hydroxy-5,8,11,14-eicosatetraenoic acid (20-HETE) is catalyzed by members of the cytochrome P450 4 (CYP4) gene family and regulated by factors such as age, sex hormones, and dietary lipids. 1,2 CYP4 expression and 20-HETE synthesis have been implicated in the regulation of vascular and tubular function and the development of hypertension in experimental models. [3][4][5] Studies demonstrating that 20-HETE is a vasoconstrictor [6][7][8] suggest that increased 20-HETE synthesis and/or effects in the renal vasculature underlies its prohypertensive property. [9][10][11][12] This notion has been substantiated by several reports showing the following: (1) the synthesis of and vascular reactivity to 20-HETE are significantly higher in spontaneously hypertensive rats (SHRs), 13,14 (2) inhibition of vascular 20-HETE synthesis by CYP4A2 antisense oligonucleotides decreases BP in SHRs, 15,16 J Am Soc Nephrol