Protective effect of 20-HETE analogues in experimental renal ischemia reperfusion injury

Regner, Kevin R.; Żuk, Anna; Why, Scott K. Van; Shames, Brian D.; Ryan, Robert P.; Falck, John R.; Manthati, Vijay L.; McMullen, Meghan E.; Ledbetter, Steven; Roman, Richard J.

doi:10.1038/ki.2008.600

Cited by 79 publications

(105 citation statements)

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“…As an independent measure of cardiac myocyte injury per se, we also examined eosin autofluorescence. Eosin autofluorescence of paraffin-embedded tissue sections has been used previously as an early marker of myocardial and renal ischemia-reperfusion injury that is not normally apparent upon examination under traditional light microscopy (11,22,28). In our rat model of cardiac allograft (G. M. Pieper and I.…”

Section: Discussionmentioning

confidence: 99%

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Cardiac myocyte-specific overexpression of human GTP cyclohydrolase I protects against acute cardiac allograft rejection

Ионова¹,

Vásquez‐Vivar

Cooley³

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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Alp NJ, Pieper GM. Cardiac myocyte-specific overexpression of human GTP cyclohydrolase I protects against acute cardiac allograft rejection. Am J Physiol Heart Circ Physiol 299: H88 -H96, 2010. First published April 23, 2010; doi:10.1152/ajpheart.00203.2010 is the rate-limiting enzyme for tetrahydrobiopterin (BH 4) synthesis. Decreases in GTPCH activity and expression have been shown in late stages of acute cardiac rejection, suggesting a deficit in BH4. We hypothesized that increasing intracellular levels of BH4 by cardiac myocyte-targeted overexpression of GTPCH would diminish acute cardiac allograft rejection. Transgenic mice overexpressing GTPCH in the heart were generated and crossed on C57BL6 background. Wild-type and transgenic mouse donor hearts were transplanted into BALB/c recipient mice. Left ventricular (LV) function, histological rejection, BH4 levels, and inflammatory cytokine gene expression (mRNA) were examined. Expression of human GTPCH was documented by PCR, Western analysis, and function by a significant (P Ͻ 0.001) increase in cardiac BH4 levels. GTPCH transgene decreased histological rejection (46%; P Ͻ 0.003) and cardiac myocyte injury (eosin autofluorescence; 56%; P Ͻ 0.0001) independent of changes in inflammatory cytokine expression or nitric oxide content. GTPCH transgene decreased IL-2 (88%; P Ͻ 0.002), IL-1R2 (42%; P Ͻ 0.0001), and programmed cell death-1 (67%; P Ͻ 0.0001) expression, whereas it increased fms-like tyrosine kinase 3 (156%; P Ͻ 0.0001) and stromal-derived factor-1 (2; 190%; P Ͻ 0.0001) expression. There was no difference in ejection fraction or fractional shortening; however, LV mass was significantly increased (P Ͻ 0.05) only in wild-type grafts. The decreases in LV mass, cardiac injury, and histological rejection support a protective role of cardiac GTPCH overexpression and increased BH4 synthesis in cardiac allografts. The mechanism of the decreased rejection appears related to decreased T cell proliferation and modulation of immune function by higher expression of genes involved in hematopoietic/stromal cell development and recruitment.tetrahydrobiopterin; rejection; stromal-derived factor 1; left ventricular mass; guanosine 5=-triphosphate cyclohydrolase TETRAHYDROBIOPTERIN (BH 4 ) is a cofactor for only a few known enzymes including three isoforms of nitric oxide (NO) synthases (NOS), four aromatic amino acid hydroxylases, and glyceryl ether monoxygenase (25,30). Synthesis of BH 4 is regulated by the expression of the key enzyme GTP cyclohydrolase I (GTPCH). The discovery of nuclear localization of GTPCH and other proteins involved in BH 4 synthesis (5) coupled with earlier findings that the mitogenic action of BH 4 in various cells is independent of changes in catecholamine and NO synthesis (1) suggests potentially new unknown roles of BH 4 . Thus there is new awareness of the potential regulation of GTPCH/BH 4 for a vast array of biological processes far beyond that regulating NO and catecholamine synthesis including cell proliferation, cell division, apoptosis,...

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Section: Discussionmentioning

confidence: 99%

“…We used this technique to determine the extent of myocyte injury in acute rejection of wild-type and GTPCH transgenic allografts. Fluorescence was detected as described (11,22). A total of 4 to 5 independent 400ϫ fields were captured for each allograft.…”

Section: Methodsmentioning

confidence: 99%

Cardiac myocyte-specific overexpression of human GTP cyclohydrolase I protects against acute cardiac allograft rejection

Ионова¹,

Vásquez‐Vivar

Cooley³

et al. 2010

American Journal of Physiology-Heart and Circulatory Physiology

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“…Study participants received one capsule OMACOR® (Abbott GmbH, Germany) per day (containing 460 mg EPA and 380 mg DHA as ethyl esters) from weeks 1 to 4, and two capsules OMA-COR® per day (980 mg EPA and 760 mg DHA as ethyl esters) from weeks 5 to 8. Afterwards, omega-3 supplementation was stopped and the participants were followed-up for another 8 weeks (weeks [9][10][11][12][13][14][15][16]. Study visits and assessment of clinical and biochemical parameters were done before (basal), after week 1, week 4, week 8, week 9, and week 16 .…”

Section: Methodsmentioning

confidence: 99%

“…The contribution of EETs to cardiovascular function is infl uenced by the soluble epoxide hydrolase (sEH) that metabolizes EETs to less potent dihydroxyeicosatrienoic acids (DHETs) ( 10 ). Imbalances in CYP-eicosanoid formation are linked to the development of endothelial dysfunction and hypertension; ischemia-induced injury of the heart, kidney and brain; infl ammatory disorders; and atherosclerosis (11)(12)(13)(14)(15)(16)(17).…”

mentioning

confidence: 99%

Dietary omega-3 fatty acids modulate the eicosanoid profile in man primarily via the CYP-epoxygenase pathway

Fischer

Konkel

Mehling³

et al. 2014

Journal of Lipid Research

195

168

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This article is available online at http://www.jlr.org Cytochrome P450 (CYP) enzymes catalyze the formation of biologically active epoxy-and hydroxy-metabolites of long-chain PUFAs ( 1 ). Traditionally, and in line with the prevalence of n-6 PUFAs in the "Western diet", arachidonic acid (AA) (20:4 n-6) has been considered as the main precursor and the corresponding metabolites were categorized as a subclass of eicosanoids ( 2 ). CYP-eicosanoid formation is also known as the "third branch of the AA cascade," complementary to the previously discovered cyclooxygenase (COX)-and lipoxygenase (LOX)-initiated pathways of prostanoid and leukotriene formation ( 3, 4 ).Physiologically important AA-derived CYP-eicosanoids include a set of regio-and stereoisomeric epoxyeicosatrienoic acids (EETs) and 20-HETE ( 2, 5 ). EETs and 20-HETE play partially opposing roles in the regulation of vascular, renal, and cardiac function ( 6-9 ). The contribution of EETs to cardiovascular function is infl uenced by the soluble epoxide hydrolase (sEH) that metabolizes EETs to less potent dihydroxyeicosatrienoic acids (DHETs) ( 10 ). Imbalances in CYP-eicosanoid formation are linked to the development of endothelial dysfunction and hypertension; ischemia-induced injury of the heart, kidney and brain; infl ammatory disorders; and atherosclerosis (11)(12)(13)(14)(15)(16)(17).Recent studies demonstrated that the same CYP isoforms that epoxidize or hydroxylate AA, also effi ciently metabolize

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“…There has been renewed interest in 20-HETE because of its potential as a novel therapeutic target in the treatment of acute kidney injury (32), cancer (8 -10), and polycystic kidney disease (PKD) (28,29). Regner et al (32) showed that acute administration of a 20-HETE mimetic resulted in increased renal protection following ischemia-reperfusion injury.…”

mentioning

confidence: 99%

20-HETE activates the Raf/MEK/ERK pathway in renal epithelial cells through an EGFR- and c-Src-dependent mechanism

Akbulut¹,

Regner²,

Roman³

et al. 2009

American Journal of Physiology-Renal Physiology

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Hydroxyeicosatetraenoic acid (20-HETE) has been reported to promote mitogenicity in a variety of cell types, including renal epithelial cells. However, the signal transduction pathways activated by 20-HETE have not been fully defined. The present study evaluated the effects of 20-HETE and its more stable agonist analogs 20-hydroxyeicosa-5(Z),14(Z)-dienoic acid (5, and N- [20-hydroxyeicosa-5(Z),14(Z)-dienoyl]glycine (5,14-20-HEDGE) on the Raf/MEK/ERK and phosphatidylinositol 3-kinase (PI3K)-Akt pathway in LLC-PK1 renal epithelial cells. 20-HETE (20 M) increased phosphorylation of Raf-1 (2.5 Ϯ 0.2-fold), MEK1/2 (6.3 Ϯ 1.6-fold), and ERK1/2 (5.8 Ϯ 0.3-fold) compared with vehicle-treated cells. Similarly, the 20-HETE analogs also strongly activated ERK1/2 in a Raf-1-and MEK1/2-dependent manner. Moreover, 5,14-20-HEDE increased Akt phosphorylation by 2.2 Ϯ 0.3-fold. 20-HETE and 5,14-20-HEDE also promoted activation (Y1086) of epidermal growth factor receptor (EGFR; Y1086) by 1.9 Ϯ 0.2-and 2.5 Ϯ 0.2-fold, respectively. These effects were completely blocked by the EGFR inhibitor EKB-569 (0.1 M). Moreover, EKB-569 (0.1 M), as well as a c-Src inhibitor, SKI-606 (0.05 M), completely abolished the 20-HETE-mediated activation of the Raf/MEK/ERK and PI3K-Akt pathways. Blockade of PKC with bisindolylmaleimide I had no effect on 20-HETE-induced ERK1/2 activation. This study demonstrated that 20-HETE activated the Raf/ MEK/ERK and Akt pathways in renal epithelial cells secondary to the activation of c-Src and EGFR. epithelial cell proliferation; epidermal growth factor receptor; cell signaling 20-HYDROXYEICOSATETRAENOIC acid (20-HETE) is a lipid metabolite of arachidonic acid that is produced by -hydroxylase enzymes of the cytochrome P-450 4A (CYP4A) and 4F families (21). 20-HETE has long been known to play an integral role in the regulation of renal function, including renal vascular tone (14), tubuloglomerular feedback (49), autoregulation of renal blood flow (12,13,48), tubular transport (6,30,38,45), and mitogenesis (4,18,23,44).There has been renewed interest in 20-HETE because of its potential as a novel therapeutic target in the treatment of acute kidney injury (32), cancer (8 -10), and polycystic kidney disease (PKD) (28,29). Regner et al. (32) showed that acute administration of a 20-HETE mimetic resulted in increased renal protection following ischemia-reperfusion injury. In other studies, 20-HETE was found to play an important role as a mitogen to promote aberrant growth and proliferation in cancer cell lines in vitro (8, 9) and cystic epithelial collecting duct cells in animal models of PKD in vitro and in vivo (28,29).The mitogenic role of 20-HETE was initially documented in proximal tubular cells (18) One candidate pathway involved in cellular proliferation and survival is Raf/MEK/ERK (31). We and others found that inhibition of 20-HETE synthesis reduced ERK1/2 activation (9,10,28,29), but the mechanism by which 20-HETE stimulated this protein complex remains to be established. Studies have implicated an interac...

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Protective effect of 20-HETE analogues in experimental renal ischemia reperfusion injury

Cited by 79 publications

References 32 publications

Cardiac myocyte-specific overexpression of human GTP cyclohydrolase I protects against acute cardiac allograft rejection

Cardiac myocyte-specific overexpression of human GTP cyclohydrolase I protects against acute cardiac allograft rejection

Dietary omega-3 fatty acids modulate the eicosanoid profile in man primarily via the CYP-epoxygenase pathway

20-HETE activates the Raf/MEK/ERK pathway in renal epithelial cells through an EGFR- and c-Src-dependent mechanism

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