Effects of epoxyeicosatrienoic acids on isolated hearts and ventricular myocytes

Moffat, Margaret P.; Ward, Christopher A.; Bend, John R.; Mock, Thomas; Farhangkhoee, Parviz; Karmazyn, Morris

doi:10.1152/ajpheart.1993.264.4.h1154

Cited by 44 publications

(54 citation statements)

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“…A sulfaphenazole-sensitive CYP2C9-like enzyme has been demonstrated in rat arteries and is implicated in the production of the eicosanoid 11,12-EET (9). Interestingly, 11,12-EET was shown to exacerbate contractile dysfunction after ischemia and reperfusion (28). Another metabolite, 14,15-EET, has been shown to be responsible for the negative inotropic effect of bradykinin (29).…”

Section: Discussionmentioning

confidence: 99%

Reduction of ischemia and reperfusion-induced myocardial damage by cytochrome P450 inhibitors

Granville

Tashakkor²,

Takeuchi³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

156

113

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Ischemia and reperfusion both contribute to tissue damage after myocardial infarction. Although many drugs have been shown to reduce infarct size when administered before ischemia, few have been shown to be effective when administered at reperfusion. Moreover, although it is generally accepted that a burst of reactive oxygen species (ROS) occurs at the onset of reperfusion and contributes to tissue damage, the source of ROS and the mechanism of injury is unclear. We now report the finding that chloramphenicol administered at reperfusion reduced infarct size by 60% in a Langendorff isolated perfused rat heart model, and that ROS production was also substantially reduced. Chloramphenicol is an inhibitor of mitochondrial protein synthesis and is also an inhibitor of a subset of cytochrome P450 monooxygenases (CYPs). We could not detect any effect on mitochondrial encoded proteins or mitochondrial respiration in chloramphenicol-perfused hearts, and hypothesized that the effect was caused by inhibition of CYPs. We tested additional CYP inhibitors and found that cimetidine and sulfaphenazole, two CYP inhibitors that have no effect on mitochondrial protein synthesis, were also able to reduce creatine kinase release and infarct size in the Langendorff model. We also showed that chloramphenicol reduced infarct size in an open chest rabbit model of regional ischemia. Taken together, these findings implicate CYPs in myocardial ischemia͞reperfusion injury.C urrent treatment of myocardial infarction is directed at the restoration of blood flow to the ischemic region and reduction of myocardial oxygen demand. However, during reperfusion, the heart undergoes further damage due, in large part, to the generation of reactive oxygen species (ROS) (1). It is clear that permanent ischemia results in necrotic cell death. However, it is unclear whether reperfusion itself induces apoptosis or merely permits the manifestation of cell death processes that were initiated and irreversibly committed to during ischemia. Moreover, the relative contributions to tissue injury by the ischemic phase and by reperfusion have been difficult to evaluate. Resolving this question carries important therapeutic implications, as efforts directed toward treating reperfusion injury would have limited value if most cell death were predestined during ischemia.Although we initially hypothesized that the protective effect of chloramphenicol was caused by inhibition of mitochondrial protein synthesis, we did not see down-regulation of mitochondrial-encoded proteins after chloramphenicol infusion. The energy-sparing effects of inhibition of cytosolic protein synthesis have been described (2), and our previously reported observation that mitochondrial elongation factor Tu is phosphorylated during ischemia suggests a similar process may take place in the mitochondria (3). However, because chloramphenicol also inhibits some cytochrome P450 monooxygenases (CYPs), it was important to determine whether that inhibitory effect was relevant to cardioprotection. In this re...

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Section: Discussionmentioning

confidence: 99%

Reduction of ischemia and reperfusion-induced myocardial damage by cytochrome P450 inhibitors

Granville

Tashakkor²,

Takeuchi³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

156

113

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“…There is considerable controversy regarding the role of cytochrome P450s in the heart, notably the beneficial versus the detrimental effects of arachidonic acid metabolites [31,34,35,39,40,77,78]. We have demonstrated that EETs play a significant role in the improved postischemic functional recovery in isolated mouse hearts overexpressing CYP2J2 [31,34,35,57,78].…”

Section: Cardioprotective Signaling Pathwaysmentioning

confidence: 94%

Role of epoxyeicosatrienoic acids in protecting the myocardium following ischemia/reperfusion injury

Seubert¹,

Zeldin²,

Nithipatikom³

et al. 2007

Prostaglandins & Other Lipid Mediators

133

131

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Cardiomyocyte injury following ischemia-reperfusion can lead to cell death and result in cardiac dysfunction. A wide range of cardioprotective factors have been studied to date, but only recently has the cardioprotective role of fatty acids, specifically arachidonic acid (AA), been investigated. This fatty acid can be found in the membranes of cells in an inactive state and can be released by phospholipases in response to several stimuli, such as ischemia. The metabolism of AA involves the cycloxygenase (COX) and lipoxygenase (LOX) pathways, as well as the less well characterized cytochrome P450 (CYP) monooxygenase pathway. Current research suggests important differences with respect to the cardiovascular actions of specific CYP mediated arachidonic acid metabolites. For example, CYP mediated hydroxylation of AA produces 20-hydroxyeicosatetraenoic acid (20-HETE) which has detrimental effects in the heart during ischemia, pro-inflammatory effects during reperfusion and potent vasoconstrictor effects in the coronary circulation. Conversely, epoxidation of AA by CYP enzymes generates 5,6-, 8,9-, 11,12-and 14,15-epoxyeicosatrienoic acids (EETs) that have been shown to reduce ischemia-reperfusion injury, have potent anti-inflammatory effects within the vasculature, and are potent vasodilators in the coronary circulation. This review aims to provide an overview of current data on the role of these CYP pathways in the heart with an emphasis on their involvement as mediators of ischemia-reperfusion injury. A better understanding of these relationships will facilitate identification of novel targets for the prevention and/or treatment of ischemic heart disease, a major worldwide public health problem.

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“…Moffat and colleagues showed that EETs (either 5,6-or 11,12-EET) protected against ischemia-reperfusion injury in isolated hearts and ventricular myocytes (18). Other effects of EETs include direct inhibition of cell death in culture induced by hypoxiareoxygenation, hydrogen peroxide, and serum deprivation.…”

Section: Discussionmentioning

confidence: 99%

The Role of Cytochrome P-450 in Salt-Sensitive Stroke in Stroke-Prone Spontaneously Hypertensive Rats

et al. 2008

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Effects of epoxyeicosatrienoic acids on isolated hearts and ventricular myocytes

Cited by 44 publications

References 0 publications

Reduction of ischemia and reperfusion-induced myocardial damage by cytochrome P450 inhibitors

Reduction of ischemia and reperfusion-induced myocardial damage by cytochrome P450 inhibitors

Role of epoxyeicosatrienoic acids in protecting the myocardium following ischemia/reperfusion injury

The Role of Cytochrome P-450 in Salt-Sensitive Stroke in Stroke-Prone Spontaneously Hypertensive Rats

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