Formation and actions of 20-hydroxyeicosatetraenoic acid in rat renal arterioles

Imig, John D.; Zou, Ai-Ping; Stec, Dave E.; Harder, David R.; Falck, John R.; Roman, Richard J.

doi:10.1152/ajpregu.1996.270.1.r217

Cited by 170 publications

(254 citation statements)

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“…All of the isoforms catalyze the ω-and ω-1 hydroxylation of arachidonic acid to produce 20-HETE [2,5,[25][26][27]. Ito et al [28] used isoform specific primers to amplify 4A isoforms individually and found that the expression of CYP4A1 mRNA was very low but that CYP 4A2 and 4A3 mRNA are constitutively expressed throughout various nephron segments and the renal vessels in male SD rats.…”

Section: Discussionmentioning

confidence: 99%

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%

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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“…The cytochrone P 450 pathway is also a route of arachidonic acid metabolism in the kidney [42], and 20-HETE generated by cytochrome P 450 has a constrictor effect on afferent arterioles [45] and thus may also contribute to the exaggerated TGF response in Ang II-dependent hypertension.…”

Section: Effects Of Angiotensin II On Juxtaglomerular Apparatusmentioning

confidence: 99%

Renal Renin-Angiotensin System

Ichihara

Kobori

Nishiyama

et al. 2004

Contributions to Nephrology

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The cardinal role of the intrarenal renin-angiotensin system (RAS) in the control of sodium excretion and the pathophysiology of hypertension continues to receive increased attention. In addition to its very powerful vasoconstrictor action, angiotensin (Ang) II exerts important actions on tubular transport function and several recent studies have emphasized the potential importance of actions of angiotensin peptides on receptors localized to the luminal membranes of both proximal and distal nephron segments. Furthermore, a strong case is being developed supporting the importance of local mechanisms regulating the activity of the RAS. This is due to the fact that all components of the RAS are strongly expressed in the kidneys.

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“…Among various existing pulmonary arterial vasodilators, such as NO, sildenafil, and cGMP (24,25), 20-hydroxyeicosatetraenoic acid (20-HETE), a cytochrome P-450 4A metabolite of arachidonic acid, consistently dilates pulmonary arteries in several species, including humans (2). 20-HETE induces a relaxation in bovine pulmonary arteries, whereas it induces a contraction in bovine renal arteries (12,15), suggesting a specific mode of action of 20-HETE according to vascular beds. Interestingly, on one hand, hypoxia blocks the conversion of arachidonic acid into 20-HETE in rabbit lung (34), whereas, on the other hand, chronic hypoxia induces sustained elevated pulmonary arterial pressure and vascular remodeling leading to PAH (26), suggesting a potential role for a lower -hydroxylase activity and a decreased production of endogenous 20-HETE in chronic hypoxia-induced PAH.…”

mentioning

confidence: 94%

Effects of ω-hydroxylase product on distal human pulmonary arteries

Morin¹,

Guibert²,

Sirois³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Morin C, Guibert C, Sirois M, Echave V, Gomes MM, Rousseau E. Effects of -hydroxylase product on distal human pulmonary arteries. Am J Physiol Heart Circ Physiol 294: H1435-H1443, 2008. First published January 18, 2008 doi:10.1152/ajpheart.01115.2007The aim of the present study was to provide a mechanistic insight into how 20-hydroxyeicosatetraenoic acid (20-HETE) relaxes distal human pulmonary arteries (HPAs). This compound is produced by -hydroxylase from free arachidonic acid. Tension measurements, performed on either fresh or 1 day-cultured pulmonary arteries, revealed that the contractile responses to 1 M 5-hydroxytryptamine were largely relaxed by 20-HETE in a concentration-dependent manner (0.01-10 M). Iberiotoxin pretreatments (10 nM) partially decreased 20-HETE-induced relaxations. However, 10 M indomethacin and 3 M SC-560 pretreatments significantly reduced the relaxations to 20-HETE in these tissues. The relaxing responses induced by the eicosanoid were likely related to a reduced Ca 2ϩ sensitivity of the myofilaments since free Ca 2ϩ concentration ([Ca 2ϩ ])-response curves performed on ␤-escin-permeabilized cultured explants were shifted toward higher [Ca 2ϩ ]. 20-HETE also abolished the tonic responses induced by phorbol-ester-dibutyrate (a PKC-sensitizing agent). Western blot analyses, using two specific primary antibodies against the PKC-potentiated inhibitory protein CPI-17 and its PKC-dependent phosphorylated isoform pCPI-17, confirmed that 20-HETE interferes with this intracellular process. We also investigated the effect of 20-HETE on the activation of Rho-kinase pathway-induced Ca 2ϩ sensitivity. The data demonstrated that 20-HETE decreased U-46619-induced Ca 2ϩ sensitivity on arteries. Hence, this observation was correlated with an increased staining of p116 Rip , a RhoA-binding protein. Together, these results strongly suggest that the 20-hydroxyarachidonic acid derivative is a potent modulator of tone in HPAs in vitro. 20-hydroxyeicosatetraenoic acid; calcium sensitivity; tension measurement PULMONARY ARTERY VASOCONSTRICTION and vascular remodeling greatly contribute to a sustained elevation of pulmonary vascular resistance and pulmonary arterial pressure in patients with pulmonary arterial hypertension (PAH), an often fatal hemodynamic abnormality (11). Pulmonary vasoconstriction is believed to be an early component of the pulmonary hypertensive process and has been attributed to an impaired production of vasodilators [nitric oxide (NO) and prostacyclin] and an increased production of vasoconstrictors (endothelin-1 and serotonin) (11). In that respect, vasodilators have some beneficial effects on PAH. Among various existing pulmonary arterial vasodilators, such as NO, sildenafil, and cGMP (24, 25), 20-hydroxyeicosatetraenoic acid (20-HETE), a cytochrome P-450 4A metabolite of arachidonic acid, consistently dilates pulmonary arteries in several species, including humans (2). 20-HETE induces a relaxation in bovine pulmonary arteries, whereas it induces a contraction in bovine renal arte...

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Formation and actions of 20-hydroxyeicosatetraenoic acid in rat renal arterioles

Cited by 170 publications

References 0 publications

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

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

Renal Renin-Angiotensin System

Effects of ω-hydroxylase product on distal human pulmonary arteries

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