Increased blood pressure in mice lacking cytochrome P450 2J5

Athirakul, Krairerk; Bradbury, J. Alyce; Graves, Joan P.; DeGraff, Laura M.; Ma, Jixiang; Zhao, Yun; Couse, John F.; Quigley, Raymond; Harder, David R.; Zhao, Xueying; Imig, John D.; Pedersen, Theresa L.; Newman, John W.; Hammock, Bruce D.; Conley, Alan J; Korach, Kenneth S.; Coffman, Thomas M.; Zeldin, Darryl C.

doi:10.1096/fj.08-114413

Cited by 51 publications

(60 citation statements)

References 68 publications

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“…In this context, not only -hydroxylases (20-HETE synthases), but also epoxygenases (EET synthases) merit consideration as pressure targets of vessels that depolarize/constrict to 20-HETE and hyperpolarize/dilate to EETs (42). In accordance with this concept, altered levels of renal EETs and 20-HETE have been demonstrated in various studies to be associated with changes in blood pressure (1, 54,55). In vascular endothelial cells, epoxygenase synthesizes EETs that initiate vasodilation (3,34,47,49).…”

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confidence: 68%

Soluble epoxide hydrolase-dependent regulation of myogenic response and blood pressure

Sun

Cuevas

Gotlinger

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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Sun D, Cuevas AJ, Gotlinger K, Hwang SH, Hammock BD, Schwartzman ML, Huang A. Soluble epoxide hydrolase-dependent regulation of myogenic response and blood pressure. Am J Physiol Heart Circ Physiol 306: H1146-H1153, 2014. First published February 21, 2014 doi:10.1152/ajpheart.00920.2013 are metabolites of arachidonic acid via cytochrome P450 (CYP)/epoxygenases. EETs possess cardioprotective properties and are catalyzed by soluble epoxide hydrolase (sEH) to dihydroxyeicosatrienoic acids (DHETs) that lack vasoactive property. To date, the role of sEH in the regulation of myogenic response of resistant arteries, a key player in the control of blood pressure, remains unknown. To this end, experiments were conducted on sEH-knockout (KO) mice, wild-type (WT) mice, and endothelial nitric oxide synthase (eNOS)-KO mice treated with t-TUCB, a sEH inhibitor, for 4 wk. sEH-KO and t-TUCB-treated mice displayed significantly lower blood pressure, associated with significantly increased vascular EETs and ratio of EETs/DHETs. Pressure-diameter relationships were assessed in isolated and cannulated gracilis muscle arterioles. All arterioles constricted in response to increases in transmural pressure from 60 to 140 mmHg. The myogenic constriction was significantly reduced, expressed as an upward shift of pressure-diameter curve, in arterioles of sEH-KO and t-TUCB-treated eNOS-KO mice compared with their controls. Removal of the endothelium, or treatment of the vessels with PPOH, an inhibitor of EET synthase, restored the attenuated pressure-induced constriction to the levels similar to those observed in their controls but had no effects on control vessels. No difference was observed in the myogenic index, or in the vascular expression of eNOS, CYP2C29 (EET synthase), and CYP4A (20-HETE synthase) among these groups of mice. In conclusion, the increased EET bioavailability, as a function of deficiency/inhibition of sEH, potentiates vasodilator responses that counteract pressure-induced vasoconstriction to lower blood pressure. myogenic response; soluble epoxide hydrolase; epoxyeicosatrienoic acids; arterioles; endothelium THE ISSUE OF HOW THE VASCULAR system maintains basal tone and regulates blood supply and organ perfusion, as well as capillary hydrostatic pressure, has been extensively investigated. Among the above-mentioned functions, the vascular myogenic response is a key contributor. The myogenic response is characterized by the intrinsic ability of small arteries/arterioles to contract in response to increases in transmural pressure. In physiological conditions, the myogenic response functions as an autoregulator that allows the vascular bed to maintain a constant blood flow despite wide changes in arterial pressure. In certain pathological conditions, however, augmented myogenic response initiates an increase in peripheral resistance and consequently increases the risk of hypertension. On the other hand, attenuated myogenic response may exhibit beneficial properties in the regulation of blood pressure, such as an estrogen...

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confidence: 68%

Soluble epoxide hydrolase-dependent regulation of myogenic response and blood pressure

Sun

Cuevas

Gotlinger

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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“…Mouse CYP2J5 is abundant in the convoluted and straight portions of the proximal tubules in the kidney and is active in the metabolism of AA to EETs (Ma et al, 1999). CYP2J5 expression appears to be beneficial, as CYP2J5-deficient mice develop spontaneous hypertension (Athirakul et al, 2008). CYP2J11, like CYP2J5, is expressed in the kidney, is localized to the renal proximal convoluted tubules, and is active in the metabolism of AA to EETs, primarily 14,15-EET.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Four New Mouse Cytochrome P450 Enzymes of the CYP2J Subfamily

et al. 2013

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The cytochrome P450 superfamily encompasses a diverse group of enzymes that catalyze the oxidation of various substrates. The mouse CYP2J subfamily includes members that have wide tissue distribution and are active in the metabolism of arachidonic acid (AA), linoleic acid (LA), and other lipids and xenobiotics. The mouse Cyp2j locus contains seven genes and three pseudogenes located in a contiguous 0.62 megabase cluster on chromosome 4. We describe four new mouse CYP2J isoforms (designated CYP2J8, CYP2J11, CYP2J12, and CYP2J13). The four cDNAs contain open reading frames that encode polypeptides with 62-84% identity with the three previously identified mouse CYP2Js. All four new CYP2J proteins were expressed in Sf21 insect cells. Each recombinant protein metabolized AA and LA to epoxides and hydroxy derivatives. Specific antibodies, mRNA probes, and polymerase chain reaction primer sets were developed for each mouse CYP2J to examine their tissue distribution. CYP2J8 transcripts were found in the kidney, liver, and brain, and protein expression was confirmed in the kidney and brain (neuropil). CYP2J11 transcripts were most abundant in the kidney and heart, with protein detected primarily in the kidney (proximal convoluted tubules), liver, and heart (cardiomyocytes). CYP2J12 transcripts were prominently present in the brain, and CYP2J13 transcripts were detected in multiple tissues, with the highest expression in the kidney. CYP2J12 and CYP2J13 protein expression could not be determined because the antibodies developed were not immunospecific. We conclude that the four new CYP2J isoforms might be involved in the metabolism of AA and LA to bioactive lipids in mouse hepatic and extrahepatic tissues.

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“…Deletion of the cyp4a10 gene, which leads to a marked decrease in renal EETs, results in increased blood pressure (Nakagawa et al, 2006). Increase in blood pressure was also observed in cyp2j5 null mice (Athirakul et al, 2008). In contrast, disruption of the sEH gene leads to a decrease in blood pressure (Sinal et al, 2000), although a recent study by (Luria et al, 2007) reported no change in blood pressure in the sEH null mice.…”

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Epoxyeicosatrienoic Acid Agonist Rescues the Metabolic Syndrome Phenotype of HO-2-Null Mice

Sodhi

Inoue

Gotlinger

et al. 2009

J Pharmacol Exp Ther

130

158

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Heme oxygenase (HO) and cytochrome P450 (P450)-derived epoxyeicosatrienoic acids (EETs) participate in vascular protection, and recent studies suggest these two systems are functionally linked. We examined the consequences of HO deficiency on P450-derived EETs with regard to body weight, adiposity, insulin resistance, blood pressure, and vascular function in HO-2-null mice. The HO-2-null mice were obese, displayed insulin resistance, and had high blood pressure. HO-2 deficiency was associated with decreases in cyp2c expression, EET levels, HO-1 expression, and HO activity and with an increase in superoxide production and an impairment in the relaxing response to acetylcholine. In addition, HO-2-null mice exhibited increases in serum levels of tumor necrosis factor (TNF)-␣ and macrophage chemoattractant protein (MCP)-1 and a decrease in serum adiponectin levels. Treatment of HO-2-null mice with a dual-activity EET agonist/soluble epoxide hydrolase inhibitor increased renal and vascular EET levels and HO-1 expression, lowered blood pressure, prevented body weight gain, increased insulin sensitivity, reduced subcutaneous and visceral fat, and decreased serum TNF-␣ and MCP-1, while increasing adiponectin and restoring the relaxing responses to acetylcholine. The decrease in cyp2c expression and EETs levels in HO-2-null mice underscores the importance of the HO system in the regulation of epoxygenase levels and suggests that protection against obesityinduced cardiovascular complications requires interplay between these two systems. A deficiency in one of these protective systems may contribute to the adverse manifestations associated with the clinical progression of the metabolic syndrome.

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Increased blood pressure in mice lacking cytochrome P450 2J5

Cited by 51 publications

References 68 publications

Soluble epoxide hydrolase-dependent regulation of myogenic response and blood pressure

Soluble epoxide hydrolase-dependent regulation of myogenic response and blood pressure

Characterization of Four New Mouse Cytochrome P450 Enzymes of the CYP2J Subfamily

Epoxyeicosatrienoic Acid Agonist Rescues the Metabolic Syndrome Phenotype of HO-2-Null Mice

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