Emerging role of epoxyeicosatrienoic acids in coronary vascular function

Larsen, Brandon T.; Gutterman, David D.; Hatoum, Ossama A.

doi:10.1111/j.1365-2362.2006.01634.x

Cited by 81 publications

(51 citation statements)

References 91 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This phenomenon is also seen in vessels from subjects with coronary artery disease, which exhibit elevated levels of inflammation and oxidative stress. 40,41 Increased markers of endothelial damage in sph/sph mice The presence of increased levels of soluble VCAM-1 (sVCAM-1), E-selectin (sE-sel), and P-selectin (sP-sel) in plasma is indicative of increased vascular injury. 26,27,42 As shown in Figure 3A, levels of sVCAM-1 in the plasma of sph/sph mice were approximately 3.5-fold higher than those in the plasma of normal (ϩ/ϩ, sph/ϩ) mice (P Ͻ .0001).…”

Section: Pulmonary Hypertension In Sph/sph Micementioning

confidence: 99%

Vascular dysfunction in a murine model of severe hemolysis

Frei

Guo

Jones

et al. 2008

Blood

View full text Add to dashboard Cite

Spectrin is the backbone of the erythroid cytoskeleton; sph/sph mice have severe hereditary spherocytosis (HS) because of a mutation in the murine erythroid ␣-spectrin gene. sph/sph mice have a high incidence of thrombosis and infarction in multiple tissues, suggesting significant vascular dysfunction. In the current study, we provide evidence for both pulmonary and systemic vascular dysfunction in sph/sph mice. We found increased levels of soluble cell adhesion molecules in sph/ sph mice, suggesting activation of the vascular endothelium. We hypothesized that plasma hemoglobin released by intravascular hemolysis initiates endothelial injury through nitric oxide (NO) scavenging and oxidative damage. Likewise, electron paramagnetic resonance spectroscopy showed that plasma hemoglobin is much greater in sph/sph mice. Moreover, plasma from sph/sph mice had significantly higher oxidative potential. Finally, xanthine oxidase, a potent superoxide generator, is decreased in subpopulations of liver hepatocytes and increased on liver endothelium in sph/sph mice. These results indicate that vasoregulation is abnormal, and NO-based vasoregulatory mechanisms particularly impaired, in sph/sph mice. Together, these data indicate that sph/sph mice with severe HS have increased plasma hemoglobin and NO scavenging capacity, likely contributing to aberrant vasoregulation and initiating oxidative damage. (Blood. 2008;112:398-405) IntroductionThe membrane skeleton, a multiprotein complex located just beneath the plasma membrane, provides the red blood cells (RBCs) with the mechanical strength and deformability required to withstand the high shear forces of the microcapillaries. Spectrin, a tetramer composed of ␣-and ␤-subunits, is the backbone of the erythroid membrane skeleton and is tethered to the membrane at 2 positions. Disruption of either spectrin or proteins involved in tethering spectrin to the RBC plasma membrane can result in the hemolytic anemia known as hereditary spherocytosis (HS) in both humans and mice. [1][2][3] We have shown that sph/sph mice have severe autosomal recessive HS because of a spontaneous single-base deletion in the murine erythroid ␣-spectrin gene, Spna1. 4 Although heterozygous (sph/ϩ) mice are phenotypically normal, the sph/sph RBC is extremely fragile, resulting in an RBC life span of approximately 1 day (normal is 48 days). 5 As a consequence, sph/sph mice have a very severe hemolytic anemia, with hematocrit values of 0.15 to 0.20 and compensatory reticulocytosis of 90% to 95%. 5 As a result of the severe hemolysis, sph/sph mice with severe HS develop multiorgan pathology in kidney, heart, liver, and spleen. 6,7 In addition, sph/sph mice develop thrombosis and infarction in multiple tissues, 6-8 suggesting significant vascular dysfunction.Recent studies of patients with hemolytic anemia have indicated that the incidence of pulmonary hypertension, as indicated by increased tricuspid regurgitant jet velocity (Ն 3.0 m/sec), is relatively high in patients with sickle cell disease (SCD), thalassemia,...

show abstract

Section: Pulmonary Hypertension In Sph/sph Micementioning

confidence: 99%

Vascular dysfunction in a murine model of severe hemolysis

Frei

Guo

Jones

et al. 2008

Blood

View full text Add to dashboard Cite

show abstract

“…Inhibitors of EET synthesis block functional hyperemia in brain (Alkayed et al 1997;Peng et al 2002Peng et al ,2004, suggesting that EETs may play a role in neurovascular coupling (Harder et al 1998). Besides their role as vasodilators, EETs are considered neuroprotective agents because of their anti-inflammatory, antipyretic, antithrombotic, and proangiogenic effects (Larsen et al 2006). EETs are formed from arachidonic acid through the enzymatic action of CYP-450 epoxygenases (Zeldin 2001), and all four regioisomers of EETs are found in the rodent brain: 5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET (Amruthesh et al 1992;Roman 2002).…”

Section: Introductionmentioning

confidence: 99%

Distribution and Expression of Soluble Epoxide Hydrolase in Human Brain

Sura

Enayetallah

et al. 2008

J Histochem Cytochem.

View full text Add to dashboard Cite

S U M M A R Y Epoxyeicosatrienoic acids (EETs) are cytochrome P450 metabolites of arachidonic acid, which function in the brain to regulate cerebral blood flow and protect against ischemic brain injury. EETs are converted by soluble epoxide hydrolase (sEH) to the corresponding inactive diol metabolites. Previous animal studies have indicated that sEH gene deletion or treatment with sEH inhibitors results in increased levels of EETs and protection against stroke-induced brain damage. To begin elucidating the underlying mechanism for these effects, we sought to determine the distribution, expression, and activity of sEH in human brain samples obtained from patients with no neurological changes/pathologies. Immunohistochemical analyses showed the distribution of sEH mainly in the neuronal cell bodies, oligodendrocytes, and scattered astrocytes. Surprisingly, in the choroid plexus, sEH was found to be highly expressed in ependymal cells. Vascular localization of sEH was evident in several regions, where it was highly expressed in the smooth muscles of the arterioles. Western blot analysis and enzyme assays confirmed the presence of sEH in the normal brain. Our results indicate differential localization of sEH in the human brain, thus suggestive of an essential role for this enzyme in the central nervous system. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials. (J Histochem Cytochem 56:551-559, 2008)

show abstract

“…4 It is therefore likely that these genotypes also affect metabolism of arachidonic acid, 5 and consequently could influence development of atherosclerosis in which arachidonic acid metabolites may have a major role. [6][7][8] Arachidonic acid, a fatty acid found in cell membranes, is metabolized by CYP2C9 to biologically active epoxyeicosatrienoic acids. 1 Epoxyeicosatrienoic acids are involved in vascular regulation causing relaxation of vascular smooth muscle cells and thereby vasodilatation.…”

Section: Introductionmentioning

confidence: 99%

“…Epoxyeicosatrienoic acids are also involved in neuroprotection and cardioprotection after ischemia, 9 and possess vascular antiinflammatory effects 6 important in the protection against atherosclerosis. 7,8 CYP2C9 is mainly expressed in the liver, but is also expressed in the blood vessel wall. 10 We therefore hypothesized that genetic polymorphisms in CYP2C9 with decreased enzyme activity associate with increased risk of atherosclerosis and related diseases.…”

Section: Introductionmentioning

confidence: 99%