CYP4A1 antisense oligonucleotide reduces mesenteric vascular reactivity and blood pressure in SHR

Wang, Mong Heng; Zhang, Fan; Marji, Jackleen; Zand, Barbara A.; Nasjletti, Alberto; Laniado−Schwartzman, Michal

doi:10.1152/ajpregu.2001.280.1.r255

Cited by 101 publications

(91 citation statements)

References 27 publications

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“…This fall in MAP is consistent with previous findings in the SHR, in which inhibition of the renal formation of 20-HETE with ABT, 13 sodium 10-undecynyl sulfate (10-SUYS), 11 or antisense oligonucleotides 16 have been reported to reduce blood pressure in this strain. ABT has also been reported to lower blood pressure in deoxycorticosterone acetate (DOCA) salt-hypertensive rats 17,18 and in rats with angiotensin II-induced hypertension.…”

Section: Discussionsupporting

confidence: 93%

Inhibitors of 20-HETE Formation Promote Salt-Sensitive Hypertension in Rats

2003

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Abstract-This study examined whether chronic blockade of epoxyeicosatrienoic acids (EETs) and/or 20-hydroxyeicosatetraenoic acid (20-HETE) formation promotes development of salt-sensitive hypertension. Changes in blood pressure, renal cytochrome P450 metabolism of arachidonic acid, and 20-HETE excretion in response to a high salt diet were measured in rats chronically treated with 1-aminobenzotriazole (ABT, 50 mg/kg per day) to block EETs and 20-HETE formation or N-hydroxy-NЈ-(4-butyl-2 methylphenyl) formamidine (HET0016, 10 mg/kg per day) that selectively reduces 20-HETE formation. ABT reduced blood pressure in rats fed a low salt (0.4% NaCl) diet, but blood pressure rose by 20 mm Hg after these rats were switched to a high salt (8% NaCl) diet for 10 days. HET0016 had no effect on blood pressure in rats fed a low salt diet; however, blood pressure rose by 18 mm Hg after the rats were fed a high salt diet. 20-HETE formation in kidney homogenates rose by 30% and epoxygenase activity doubled when rats were fed a high salt diet. Chronic treatment with ABT and HET0016 inhibited the renal formation of 20-HETE by Ϸ90%. Renal epoxygenase activity decreased by 76% in ABT-treated rats and was not significantly altered in rats treated with HET0016. 20-HETE excretion rose from 470Ϯ21 to 570Ϯ41 ng/d when the rats were switched from the low to the high salt diet. 20-HETE excretion fell by 68% and 85% in rats that were chronically treated with ABT and HET0016. These results suggest that chronic blockade of the formation of 20-HETE promotes the development of salt-sensitive hypertension in rats. Key Words: rats, Dahl Ⅲ metabolism Ⅲ arachidonic acids Ⅲ blood pressure Ⅲ hypertension, sodium-dependent T he role of the cytochrome P450 (P450) metabolites of arachidonic acid (AA) in the development and maintenance of hypertension remains uncertain in part because this pathway has both prohypertensive and antihypertensive actions. 1 20-Hydroxyeicosatetraenoic acid (20-HETE) inhibits Na ϩ transport in the proximal tubule and thick ascending limb of the loop of Henle (TALH), 2-5 and compounds that induce the renal formation of 20-HETE lower blood pressure in Dahl salt-sensitive (DS) rats. 1 Similarly, epoxyeicosatrienoic acids (EETs) inhibit Na ϩ transport in the proximal tubule and collecting duct, 6,7 and increasing the renal levels of EETs with inhibitors of soluble epoxide hydrolase (sEH) reduces blood pressure in spontaneously hypertensive rats (SHRs) 8 and angiotensin II-induced hypertensive rats. 9 However, 20-HETE is also a potent vasoconstrictor, 1 and many investigators have reported that blocking the vascular effects of 20-HETE may contribute to its antihypertensive effect in SHR and other experimental models of hypertension. 10,11 Part of the problem in defining the role of the P450 metabolites of AA in the control of blood pressure has been the lack of selective inhibitors of the pathway that chronically block the formation of 20-HETE and EETs in vivo. Inhibitors that are commonly used to inhibit the formation of EETs and ...

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Section: Discussionsupporting

confidence: 93%

Inhibitors of 20-HETE Formation Promote Salt-Sensitive Hypertension in Rats

2003

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“…These results suggested that CYP4A is involved in maintenance of normal blood pressure and contributes to development of hypertension [13,14]. This conclusion has been further supported by Wang and colleagues [15]. In the present study, we further explored the long-term modifications of blood pressure in normotensive and spontaneously hypertensive rats (SHR) by gene delivery of i) rAAV-mediated cytochrome P450 arachidonic acid hydroxylase to overexpress CYP4A1 protein or ii) antisense to block the expression of CYP4A.…”

Section: Construction and Preparation Of Raavmentioning

confidence: 61%

Long-term modifications of blood pressure in normotensive and spontaneously hypertensive rats by gene delivery of rAAV-mediated cytochrome P450 arachidonic acid hydroxylase

et al. 2005

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Arachidonic acid cytochrome P-450 (CYP) hydroxylase 4A isoforms, including 4A1, 4A2, 4A3 and 4A8 in the rat kidney, catalyze arachidonic acid to produce 19/20-Hydroxyeicosatetraenoic acids (20-HETE), a biologically active metabolite, which plays an important role in the regulation of blood pressure. However, controversial results have been reported regarding the exact role of 20-HETE on blood pressure. In the present study, we used recombinant adenoassociated viral vector (rAAV) to deliver CYP 4A1 cDNA and antisense 4A1 cDNA into Sprague-Dawley (SD) rats and spontaneously hypertensive rats (SHR), respectively, to investigate the effects of long-term modifications of blood pressure and the potential for gene therapy of hypertension. The mean systolic pressure increased by 14.2±2.5 mm Hg in rAAV·4A1-treated SD rats and decreased by 13.7±2.2 mm Hg in rAAV·anti4A1-treated SHR rats 5 weeks after the injection compared with controls and these changes in blood pressure were maintained until the experiments ended at 24 weeks. In 4A1 treated animals CYP4A was overexpressed in various tissues, but preferentially in the kidney at both mRNA and protein levels. In anti-4A1-treated SHR, CYP4A mRNA in various tissues was probed, especially in kidneys, but 4A1 protein expression was almost completely inhibited. These results suggest that arachidonic acid CYP hydroxylases contribute not only to the maintenance of normal blood pressure but also to the development of hypertension. rAAV-mediated anti4A administration strategy has the potential to be used as targeted gene therapy in human hypertension by blocking expression of CYP 4A in kidneys.

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Section: Discussionmentioning

confidence: 99%

“…CYP4A1 and CYP4A2 antisense oligonucleotides inhibit 20-HETE synthesis in both the vasculature and renal tubules and have an antihypertensive effect in Sprague-Dawley rats and SHRs (47,48). Antisense oligonucleotides have also been used to demonstrate that CYP4A1 plays an important role in mesenteric vascular reactivity (48). ABT is a mechanism-based inhibitor of renal -and ( -1)-hydroxylation of arachidonic acid and causes a loss of CYP4A apoprotein, a decrease in urinary 20-HETE excretion, and reduction in blood pressure in the SHR and in an ANG II model of hypertension (1,31,45).…”

Section: Discussionmentioning

confidence: 99%

“…More recently, mechanism-based CYP inhibitors and antisense oligonucleotides have been used to manipulate CYP eicosanoid production in vivo. Administration of CYP4A1 and CYP4A2 antisense oligonucleotides to SHR and Sprague-Dawley rats resulted in decreased levels of CYP4A mRNA and immunoreactive proteins and significant reduction of mean arterial blood pressure (MAP; 47,48). Studies in our laboratory demonstrated that 1-aminobenzotriazole (ABT) is a potent inhibitor of renal arachidonic acid -and ( -1)-hydroxylases with little effect on epoxygenases and that ABT has an antihypertensive effect in 7-wk-old SHRs (45).…”

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confidence: 99%

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Antihypertensive effect of mechanism-based inhibition of renal arachidonic acid ω-hydroxylase activity

Xu¹,

Straub

Pak³

et al. 2002

American Journal of Physiology-Regulatory, Integrative and Comp

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is a potent vasoconstrictor that is implicated in the regulation of blood pressure. The identification of selective inhibitors of renal 20-HETE formation for use in vivo would facilitate studies to determine the systemic effects of this eicosanoid. We characterized the acetylenic fatty acid sodium 10-undecynyl sulfate (10-SUYS) as a potent and selective mechanism-based inhibitor of renal 20-HETE formation. A single dose of 10-SUYS caused an acute reduction in mean arterial blood pressure in 8-wk-old spontaneously hypertensive rats. The decrease in mean arterial pressure was maximal 6 h after 10-SUYS treatment (17.9 Ϯ 3.2 mmHg; P Ͻ 0.05), and blood pressure returned to baseline levels within 24 h after treatment. Treatment with 10-SUYS was associated with a decrease in urinary 20-HETE formation in vivo and attenuation of the vasoconstrictor response of renal interlobar arteries to ANG II in vitro. These results provide further evidence that 20-HETE plays an important role in the regulation of blood pressure in the spontaneously hypertensive rat.spontaneously hypertensive rat; cytochrome P-450; sodium 10-undecynyl sulfate; 20-hydroxyeicosatetraenoic acid CYTOCHROMES P-450 (CYPs) are major catalysts of renal arachidonic acid metabolism, and CYP-derived eicosanoids have been implicated in the regulation of vascular tone and renal function (9, 41). The major products of CYP-catalyzed arachidonic acid metabolism are the -hydroxylated metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) and four regio-and stereoisomeric epoxyeicosatrienoic acids (EETs). EETs are further hydrated to the corresponding dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (sEH) (53). The major CYP eicosanoid formed in rat and human renal microsomes is 20-HETE (8, 28). 20-HETE depolarizes vascular smooth muscle cells by inhibiting Ca 2ϩ -activated K ϩ channels and increases the conductance of L-type Ca 2ϩ channels, both effects leading to Ca 2ϩ entry and potent vasoconstriction (14,56). Additional roles for 20-HETE include mediation of the myogenic response of small cerebral and renal arteries to elevations in transmural pressure, and the autoregulation of cerebral and renal blood flow, glomerular filtration rate, and tubular glomerular feedback (13,22,58). In renal tubules 20-HETE inhibits Na ϩ -K ϩ -ATPase, a Na ϩ -K ϩ -2Cl Ϫ cotransporter, and 70-pS K ϩ channels, leading to natriuresis and diuresis (3,30,38). EETs and DHETs are generally considered vasodilatory, although they exhibit both vasodilatory and vasoconstrictive properties in vitro, depending on the vascular bed and species that are studied (20,55,57). A number of studies suggest that EETs are endothelium-derived hyperpolarizing factors that mediate vasodilation by activation of Ca 2ϩ -dependent K ϩ channels in vascular smooth muscle cells (6,7,10). Both EETs and DHETs can also mediate natriuresis and diuresis by inhibition of Na ϩ -K ϩ -ATPase in rat proximal tubules (38).The effects of CYP eicosanoids in the regulation of vascular tone and renal function have pr...

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CYP4A1 antisense oligonucleotide reduces mesenteric vascular reactivity and blood pressure in SHR

Cited by 101 publications

References 27 publications

Inhibitors of 20-HETE Formation Promote Salt-Sensitive Hypertension in Rats

Inhibitors of 20-HETE Formation Promote Salt-Sensitive Hypertension in Rats

Long-term modifications of blood pressure in normotensive and spontaneously hypertensive rats by gene delivery of rAAV-mediated cytochrome P450 arachidonic acid hydroxylase

Antihypertensive effect of mechanism-based inhibition of renal arachidonic acid ω-hydroxylase activity

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