Protective effects of epoxyeicosatrienoic acids on human endothelial cells from the pulmonary and coronary vasculature

Dhanasekaran, Anuradha; Al-Saghir, Rula; López, Bernardo; Zhu, Daling; Gutterman, David D.; Jacobs, Elizabeth R.; Medhora, Meetha

doi:10.1152/ajpheart.00953.2005

Cited by 62 publications

(75 citation statements)

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“…Thus, GPR40 mediated gap junction disassembly by 11,12-EET would be expected to reduce apoptosis, promote cell growth and maintain barrier function. Consistent with this conclusion, EETs inhibit apoptosis and promote proliferation in ECs (15)(16)(17).…”

Section: Discussionsupporting

confidence: 75%

“…Additionally, 11,12-and 14,15-EETs inhibit smooth muscle cell migration and aromatase expression (8,9). On endothelial cells, 11,12-EET promotes cell growth, decrease apoptosis, migration, tube formation and angiogenesis, increases tissue plasminogen activator (tPA) release, increases cyclooxygenase-2 (COX-2) expression and alters connexin-43 (Cx43) expression and gap junctions (10)(11)(12)(13)(14)(15)(16)(17). EET isomers also inhibit platelet adhesion to the endothelium, and 11,12-and 8,9-EETs inhibit inflammation by decreasing leukocyte adhesion to the endothelium (18,19).…”

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confidence: 99%

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GPR40 is a low-affinity epoxyeicosatrienoic acid receptor in vascular cells

Park

Herrnreiter

Pfister

et al. 2018

Journal of Biological Chemistry

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Endothelium-derived epoxyeicosatrienoic acids (EETs) have numerous vascular activities mediated by G protein-coupled receptors. Long-chain free fatty acids and EETs activate GPR40, prompting us to investigate the role of GPR40 in some vascular EET activities. 14,15-EET, 11,12-EET, arachidonic acid, and the GPR40 agonist GW9508 increase intracellular calcium concentrations in human GPR40-overexpressing HEK293 cells (EC 50 = 0.58 ± 0.08 µM, 0.91 ± 0.08 µM, 3.9 ± 0.06 µM and 19 ± 0.37 nM, respectively). EETs with cisand trans-epoxides had similar activities, whereas substitution of a thiirane sulfur for the epoxide oxygen decreased the activities. 8,9-EET, 5,6-EET, and the epoxide hydrolysis products 11,12-and 14,15-vicdihydroxyeicosatrienoic acids were less active than 11,12-EET. The GPR40 antagonist GW1100 and siRNA-mediated GPR40 silencing blocked the EET-and GW9508-induced calcium increases. EETs are weak GPR120 agonists. GPR40 expression was detected in human and bovine endothelial cells (ECs), smooth muscle cells, and arteries. 11,12-EET concentration-dependently relaxed preconstricted coronary arteries; however, these relaxations were not altered by GW1100. In human ECs, 11,12-EET increased MAP kinase-mediated ERK phosphorylation, phosphorylation and levels of connexin-43 (Cx43), and expression of cyclooxygenase-2 (COX-2), all of which were inhibited by GW1100 and the MAP kinase inhibitor U0126. Moreover, siRNA-mediated GPR40 silencing decreased 11,12-EETinduced ERK phosphorylation. These results indicated that GPR40 is a low-affinity EET receptor in vascular cells and arteries. We conclude that epoxidation of arachidonic acid to EETs enhances GPR40 agonist activity and that 11,12-EET stimulation of GPR40 increases Cx43 and COX-2 expression in ECs via ERK phosphorylation. INTRODUCTIONhttp://www.jbc.org/cgi

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Section: Discussionsupporting

confidence: 75%

mentioning

confidence: 99%

GPR40 is a low-affinity epoxyeicosatrienoic acid receptor in vascular cells

Park

Herrnreiter

Pfister

et al. 2018

Journal of Biological Chemistry

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“…A recent finding in a renal proximal tubular epithelial cell line demonstrated that EETs inhibit apoptosis induced by serum withdrawal and etoposide (6,41). We have reported that EETs inhibit apoptosis induced by the engagement of the death receptor Fas or by serum withdrawal in human vascular endothelial cells cultured from the heart or lung (17,36). Hence, we were interested to see whether EETs have the same antiapoptotic effect in cardiomyocytes after I/R since myocardial cell death caused by apoptosis is a main feature of this condition.…”

mentioning

confidence: 75%

“…Cells (neonatal myocytes and HL-1 cells) were cultured in 60-mm dishes to 70% confluency and subjected to normoxia or H/R with or without pretreatment with EET as described in Treatment of Cells. The cells were washed with PBS and treated with FITC-labeled annexin V (0.2 g/ml) for 20 min at room temperature (17). Labeling with FITCcoupled annexin V was performed according to the manufacturer's protocol (BD Biosciences, San Diego, CA) as previously described (17).…”

Section: Annexin V Bindingmentioning

confidence: 99%

Multiple antiapoptotic targets of the PI3K/Akt survival pathway are activated by epoxyeicosatrienoic acids to protect cardiomyocytes from hypoxia/anoxia

Dhanasekaran

Gruenloh

Buonaccorsi³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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148

130

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“…EETs and CYPs reportedly inhibit apoptosis induced by Fas ligand, 30 TNF-␣ induced, 31,32 serum deprivation, 30 etoposide, arachidonic acid, ceramide production, inhibition of reactive oxygen species, 33 and hypoxic reperfusion possibly by antagonizing reactive oxygen species. 34 Our data are also in agreement with a previous report that MAPK and PI3/Akt signaling pathways protect endothelial cells from TNF-␣ induced apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Soluble Epoxide Inhibition Is Protective Against Cerebral Ischemia via Vascular and Neural Protection

Simpkins

Rudic

Schreihofer

et al. 2009

The American Journal of Pathology

100

118

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Inhibition of soluble epoxide hydrolase (SEH), the enzyme responsible for degradation of vasoactive epoxides, protects against cerebral ischemia in rats. However, the molecular and biological mechanisms that confer protection in normotension and hypertension remain unclear. Here we show that 6 weeks of SEH inhibition via 2 mg/day of 12-(3-adamantan-1-ylureido) dodecanoic acid (AUDA) in spontaneously hypertensive stroke-prone (SHRSP) rats protects against cerebral ischemia induced by middle cerebral artery occlusion, reducing percent hemispheric infarct and neurodeficit score without decreasing blood pressure. This level of cerebral protection was similar to that of the angiotensin-converting enzyme inhibitor, enalapril, which significantly lowered blood pressure. SEH inhibition is also protective in normotensive WistarKyoto (WKY) rats, reducing both hemispheric infarct and neurodeficit score. In SHRSP rats, SEH inhibition reduced wall-to-lumen ratio and collagen deposition and increased cerebral microvessel density, although AUDA did not alter middle cerebral artery structure or microvessel density in WKY rats. An apoptosis mRNA expression microarray of brain tissues from AUDAtreated rats revealed that AUDA modulates gene expression of mediators involved in the regulation of apoptosis in neural tissues of both WKY and SHRSP rats. Hence, we conclude that chronic SEH inhibition protects against cerebral ischemia via vascular protection in SHRSP rats and neural protection in both the SHRSP and WKY rats, indicating that SEH inhibition has broad pharmacological potential for treating ischemic stroke. Epoxyeicosatrienoic acids (EETs), lipid metabolites produced from arachidonic acid by CYP450 enzymes, are novel mediators that antagonize the sequela of hypertension, 1 match cerebral blood flow to increased neural activity and metabolic demand, promotes angiogenesis, 2 and protect against ischemia.3,4 Because ischemic stroke occurs with loss of cerebral blood flow and is strongly associated with hypertension, modulation of epoxide degradation has potential in managing ischemic stroke. Unfortunately, pharmacological utility of exogenous EETs is impractical because the epoxides are rapidly degraded by the soluble epoxide hydrolase (SEH) into their less active diol, dihydroxyeicosatrienoic acids. 5In fact, human SEH polymorphisms are linked to the incidence of ischemic stroke, 6 and this association could be related to modifications in SEH activity, and thus epoxide catabolism. 7 An alternative strategy that has been used to increase EETs systemically is SEH inhibition. 1 We previously showed that the SEH inhibitor 12-(3-adamantan-1-yl-ureido) dodecanoic acid (AUDA) protects against cerebral ischemia in spontaneously hypertensive stroke-prone (SHRSP) rats, an animal model of essential hypertension.8 Interestingly, chronic AUDA treatment in SHRSP rats effectively decreased infarct size induced by middle cerebral artery occlusion (MCAO)

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Protective effects of epoxyeicosatrienoic acids on human endothelial cells from the pulmonary and coronary vasculature

Abstract: Protective effects of epoxyeicosatrienoic acids on human endothelial cells from the pulmonary and coronary vasculature.

Cited by 62 publications

References 57 publications

GPR40 is a low-affinity epoxyeicosatrienoic acid receptor in vascular cells

GPR40 is a low-affinity epoxyeicosatrienoic acid receptor in vascular cells

Multiple antiapoptotic targets of the PI3K/Akt survival pathway are activated by epoxyeicosatrienoic acids to protect cardiomyocytes from hypoxia/anoxia

Soluble Epoxide Inhibition Is Protective Against Cerebral Ischemia via Vascular and Neural Protection

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