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Hila Roshanravan, Eun Y Kim, Stuart E Dryer
The arachidonic acid metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) regulates renal function, including changes in glomerular function evoked during tubuloglomerular feedback (TGF). This study describes the cellular actions of 20-HETE on cultured podocytes, assessed by whole-cell recordings from cultured podocytes combined with pharmacological and cell-biological manipulations of cells. Bath superfusion of 20-HETE activates cationic currents that are blocked by the pan-TRP blocker SKF-96365 and by 50 μM La(3+), and which are attenuated after siRNA knockdown of TRPC6 subunits...
2016: Frontiers in Physiology
Mohamed M Katary, Chelsey Pye, Ahmed A Elmarakby
The pro-inflammatory cyclooxygenase (COX)-derived prostaglandins and the anti-inflammatory cytochrome P450 epoxygenase-derived epoxyeicosatrienoic acids (EETs) play an important role in the regulation of renal injury. The current study examined whether COX inhibition augments the reno-protective effects of increased EETs levels via inhibiting EETs degradation by soluble epoxide hydrolase (sEH) in diabetic rats. Streptozotocin (50mg/kg, i.v) was used to induce diabetes in male Sprague Dawley rats. Rats were then divided into 5 groups (n=6-8); control non diabetic, diabetic, diabetic treated with the sEH inhibitor trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB), diabetic treated with the COX inhibitor meloxicam and diabetic treated with meloxicam plus t-AUCB for 2 months...
September 2, 2016: Prostaglandins & Other Lipid Mediators
Yidan Wei, Meijuan Xu, Yi Ren, Guo Lu, Yangmei Xu, Yangyang Song, Hui Ji
Arachidonic acid (AA) is a precursor that is metabolized by several enzymes to many biological eicosanoids. Accumulating data indicate that the ω-hydroxylation metabolite of AA, 20-hydroxyeicosatetraenoic acid (20-HETE), is considered to be involved in the myocardial ischemia-reperfusion injury (MIRI). The inhibitors of AA ω-hydroxylase, however, are demonstrated to exhibit protective effects on MIRI. Dihydrotanshinone I (DI), a bioactive constituent of danshen, is proven to be a potent inhibitor of AA ω-hydroxylase by our preliminary study in vitro...
June 24, 2016: Canadian Journal of Physiology and Pharmacology
Bijun Zhang, Guangrui Lai, Jingjing Wu, Ru Sun, Runhong Xu, Xianghong Yang, Yafei Qi, Yanyan Zhao
We previously generated cytochrome P450 4F2 (CYP4F2) transgenic mice that have high levels of 20-hydroxyeicosatetraenoic acid (20-HETE) production; these mice exhibit both hypertension and hyperglycemia without insulin resistance. Currently, it is unclear whether and how 20-HETE affects insulin secretion, thus resulting in hyperglycemia. In this study, we found that 20-HETE attenuated glucose-stimulated insulin secretion (GSIS) in CYP4F2 transgenic mice as well as in rat insulinoma INS-1E cells treated with 0...
August 27, 2016: Endocrine
Wojciech G Garbacz, Peipei Lu, Tricia M Miller, Samuel M Poloyac, Nicholas S Eyre, Graham Mayrhofer, Meishu Xu, Songrong Ren, Wen Xie
The common complications in obesity and type 2 diabetes include hepatic steatosis and disruption of glucose-glycogen homeostasis, leading to hyperglycemia. Fatty acid translocase (FAT/CD36), whose expression is inducible in obesity, is known for its function in fatty acid uptake. Previous work by us and others suggested that CD36 plays an important role in hepatic lipid homeostasis, but the results have been conflicting and the mechanisms were not well understood. In this study, by using CD36-overexpressing transgenic (CD36Tg) mice, we uncovered a surprising function of CD36 in regulating glycogen homeostasis...
November 1, 2016: Molecular and Cellular Biology
C Menni, S Metrustry, G Ehret, A F Dominiczak, P Chowienczyk, T D Spector, S Padmanabhan, A M Valdes
OBJECTIVE: The dicarboxylic fatty acid hexadecanedioate is functionally associated with increased blood pressure. The aims of this study was to further characterize which pathways are related to this compound using genetic and transcriptomic data. DESIGN AND METHOD: A genome-wide association scan (GWAS) was conducted on 6447 individuals from the TwinsUK and KORA cohorts. SNPs achieving genome-wide significance were then tested in the International Consortium for Blood Pressure and in a GWAS of extremes of blood pressure...
September 2016: Journal of Hypertension
J D Imig
Endothelial and vascular smooth cells generate cytochrome P450 (CYP) arachidonic acid metabolites that can impact endothelial cell function and vascular homeostasis. The objective of this review is to focus on the physiology and pharmacology of endothelial CYP metabolites. The CYP pathway produces two types of eicosanoid products: epoxyeicosatrienoic acids (EETs), formed by CYP epoxygenases, and hydroxyeicosatetraenoic acids (HETEs), formed by CYP hydroxylases. Advances in CYP enzymes, EETs, and 20-HETE by pharmacological and genetic means have led to a more complete understanding of how these eicosanoids impact on endothelial cell function...
2016: Advances in Pharmacology
Manoocher Soleimani, Sharon Barone, Jie Xu, Saeed Alshahrani, Marybeth Brooks, Francis X McCormack, Roger D Smith, Kamyar Zahedi
Contribution of salt wasting and volume depletion to the pathogenesis of hypercalciuria and hyperphosphaturia is poorly understood. Pendrin/NCC double KO (pendrin/NCC-dKO) mice display severe salt wasting under basal conditions and develop profound volume depletion, prerenal renal failure, and metabolic alkalosis and are growth retarded. Microscopic examination of the kidneys of pendrin/NCC-dKO mice revealed the presence of calcium phosphate deposits in the medullary collecting ducts, along with increased urinary calcium and phosphate excretion...
2016: PloS One
Lingyun Zu, Ge Guo, Boda Zhou, Wei Gao
OBJECTIVE: To investigate the correlation of arachidonic acid (ARA) metabolites and prognosis in ACS patients. METHODS AND RESULTS: This is a mono-center retrospective nested case-control study. We followed up 470 ACS patients, of whom 39 patients had MACE in a mean follow up time of 1037days (identified as MACE group). Another 39 clinically matched patients without MACE were selected from the 470 ACS patients (Non-MACE group). Thirty-nine subjects without Coronary Heart Disease were enrolled as Control group...
August 2016: Thrombosis Research
Üzen Savas, Shouzou Wei, Mei-Hui Hsu, John R Falck, F Peter Guengerich, Jorge H Capdevila, Eric F Johnson
Male and female homozygous 129/Sv mice carrying four copies of the human cytochrome P450 4A11 gene (CYP4A11) under control of its native promoter (B-129/Sv-4A11(+/+)) develop hypertension (142 ± 8 versus 113 ± 7 mm Hg systolic blood pressure (BP)), and exhibit increased 20-hydroxyeicosatetraenoic acid (20-HETE) in kidney and urine. The hypertension is reversible by a low-sodium diet and by the CYP4A inhibitor HET0016. B-129/Sv-4A11(+/+) mice display an 18% increase of plasma potassium (p < 0.02), but plasma aldosterone, angiotensin II (ANGII), and renin activities are unchanged...
August 5, 2016: Journal of Biological Chemistry
Ronan M G Berg
The present paper presents a mechanistic model of cerebral autoregulation, in which the dual effects of the arachidonic acid metabolites 20-hydroxyeicosatetraenoic acid (20-HETE) and epoxyeicosatrienoic acids (EETs) on vascular smooth muscle mediate the cerebrovascular adjustments to a change in cerebral perfusion pressure (CPP). 20-HETE signalling in vascular smooth muscle mediates myogenic feedback to changes in vessel wall stretch, which may be modulated by metabolic feedback through EETs released from astrocytes and endothelial cells in response to changes in brain tissue oxygen tension...
July 2016: Medical Hypotheses
Ana C Dordea, Sara Vandenwijngaert, Victor Garcia, Robert E T Tainsh, Daniel I Nathan, Kaitlin Allen, Michael J Raher, Laurel T Tainsh, Fan Zhang, Wolfgang S Lieb, Sarah Mikelman, Andrew Kirby, Christine Stevens, Robrecht Thoonen, Allyson G Hindle, Patrick Y Sips, John R Falck, Mark J Daly, Peter Brouckaert, Kenneth D Bloch, Donald B Bloch, Rajeev Malhotra, Michal L Schwartzman, Emmanuel S Buys
Dysregulated nitric oxide (NO) signaling contributes to the pathogenesis of hypertension, a prevalent and often sex-specific risk factor for cardiovascular disease. We previously reported that mice deficient in the α1-subunit of the NO receptor soluble guanylate cyclase (sGCα1 (-/-) mice) display sex- and strain-specific hypertension: male but not female sGCα1 (-/-) mice are hypertensive on an 129S6 (S6) but not a C57BL6/J (B6) background. We aimed to uncover the genetic and molecular basis of the observed sex- and strain-specific blood pressure phenotype...
June 1, 2016: American Journal of Physiology. Heart and Circulatory Physiology
Carolina Dalmasso, Rodrigo Maranon, Chetan Patil, Mohadetheh Moulana, Damian G Romero, Jane F Reckelhoff
In male rats, androgen supplements increase 20-hydroxyeicosatetraenoic acid (20-HETE) via cytochrome P-450 (CYP)4A ω-hydroxylase and cause an increase in blood pressure (BP). In the present study, we determined the roles of 20-HETE and CYP4A2 on the elevated BP in hyperandrogenemic female rats. Chronic dihydrotestosterone (DHT) increased mean arterial pressure (MAP) in female Sprague-Dawley rats (96 ± 2 vs. 108 ± 2 mmHg, P < 0.05) and was associated with increased renal microvascular CYP4A2 mRNA expression (15-fold), endogenous renal 20-HETE (5-fold), and ω-hydroxylase activity (3-fold)...
July 1, 2016: American Journal of Physiology. Renal Physiology
Stephen J Peterson, Luca Vanella, Katherine Gotlinger, Houli Jiang, Shailendra P Singh, Komal Sodhi, Eamonn Maher, Kathleen O'Hanlon, Joseph I Shapiro, Nader G Abraham
BACKGROUND: Oxidized-HDL (OX-HDL) has been reported to increase coronary events in obese patients; however, OX-HDL has not been studied in subjects with the metabolic syndrome. A high body mass index (BMI) correlates positively with higher levels of metabolic syndrome biomarkers including vasoconstrictors and adipokines. We hypothesize that a subject with a high BMI would present with higher levels of OX-HDL, 20-HETE and Angiotensin II (Ang II) with a reciprocal reduction in serum adiponectin...
March 2016: Prostaglandins & Other Lipid Mediators
Debebe Gebremedhin, David X Zhang, Koryn A Carver, Nicole Rau, Kevin R Rarick, Richard J Roman, David R Harder
Astrocytes secrete vasodilator and vasoconstrictor factors via end feet processes, altering blood flow to meet neuronal metabolic demand. Compared to what is known about the ability of astrocytes to release factors that dilate local cerebral vasculature, very little is known regarding the source and identity of astrocyte derived constricting factors. The present study investigated if astrocytes express CYP 4A ω-hydroxylase and metabolize arachidonic acid (AA) to 20-hydroxyeicotetraenoic acid (20-HETE) that regulates KCa channel activity in astrocytes and cerebral arterial myocyte contractility...
July 2016: Prostaglandins & Other Lipid Mediators
Meijuan Xu, Haiping Hao, Lifeng Jiang, Yidan Wei, Fang Zhou, Jianguo Sun, Jingwei Zhang, Hui Ji, Guangji Wang, Wenzheng Ju, Ping Li
Accumulating data suggest that epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acid, both cytochrome P450 (P450) enzyme metabolites of arachidonic acid (AA), play important roles in cardiovascular diseases. For many years, the cardiotonic pill (CP), an herbal preparation derived from Salviae Miltiorrhizae Radix et Rhizoma, Notoginseng Radix et Rhizoma, and Borneolum Syntheticum, has been widely used in China for the treatment of coronary artery disease. However, its pharmacological mechanism has not been well elucidated...
July 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Fan Fan, Ying Ge, Wenshan Lv, Matthew R Elliott, Yoshikazu Muroya, Takashi Hirata, George W Booz, Richard J Roman
Cytochrome P450s enzymes catalyze the metabolism of arachidonic acid to epoxyeicosatrienoic acids (EETs), dihydroxyeicosatetraenoic acid and hydroxyeicosatetraeonic acid (HETEs). 20-HETE is a vasoconstrictor that depolarizes vascular smooth muscle cells by blocking K+ channels. EETs serve as endothelial derived hyperpolarizing factors. Inhibition of the formation of 20-HETE impairs the myogenic response and autoregulation of renal and cerebral blood flow. Changes in the formation of EETs and 20-HETE have been reported in hypertension and drugs that target these pathways alter blood pressure in animal models...
2016: Frontiers in Bioscience (Landmark Edition)
Xingyang Yi, Lang Wu, Duanxiu Liao, Chun Wang, Biao Zhang
AIM: To better understand the relationship between the interactions among rs17110453, rs751141, and rs9333025 variants and plasma levels of cytochrome P450 (CYP) metabolites, i.e.,20-hydroxyeicosatetraenoic acid (20-HETE), epoxyeicosatrienoic acids (EETs), and dihydroxyeicosatrienoic acids (DiHETEs) in ischemia stroke (IS). METHODS: We measured plasma CYP metabolite levels in 218 acute IS cases and 126 controls, and a subset of samples were assessed to further understand the association between relevant variants and IS risk in our previous study...
April 16, 2016: Journal of Atherosclerosis and Thrombosis
Li Chen, Gregory Joseph, Frank F Zhang, Huyen Nguyen, Houli Jiang, Katherine H Gotlinger, John R Falck, Jing Yang, Michal L Schwartzman, Austin M Guo
Angiogenesis is an important adaptation for recovery from peripheral ischemia. Here, we determined whether 20-hydroxyeicosatetraenoic acid (20-HETE) contributes to ischemia-induced angiogenesis and assessed its underlying molecular and cellular mechanisms using a mouse hindlimb-ischemia angiogenesis model. Hindlimb blood flow was measured by Laser Doppler Perfusion Imaging and microvessel density was determined by CD31 and tomato lectin staining. We found that systemic and local administration of a 20-HETE synthesis inhibitor, DDMS, or a 20-HETE antagonist, 6,15-20-HEDGE significantly reduced blood flow recovery and microvessel formation in response to ischemia...
August 2016: Vascular Pharmacology
Adarsh Shankar, Thaiz F Borin, Asm Iskander, Nadimpalli Rs Varma, Bhagelu R Achyut, Meenu Jain, Tom Mikkelsen, Austin M Guo, Wilson B Chwang, James R Ewing, Hassan Bagher-Ebadian, Ali S Arbab
BACKGROUND: Due to the hypervascular nature of glioblastoma (GBM), antiangiogenic treatments, such as vatalanib, have been added as an adjuvant to control angiogenesis and tumor growth. However, evidence of progressive tumor growth and resistance to antiangiogenic treatment has been observed. To counter the unwanted effect of vatalanib on GBM growth, we have added a new agent known as N-hydroxy-N'-(4-butyl-2 methylphenyl)formamidine (HET0016), which is a selective inhibitor of 20-hydroxyeicosatetraenoic acid (20-HETE) synthesis...
2016: OncoTargets and Therapy
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