Background-Peroxisome proliferator-activated receptor-␣ (PPAR-␣) is expressed in the heart and regulates genes involved in myocardial fatty acid oxidation (FAO). The role of PPAR-␣ in acute ischemia/reperfusion myocardial injury remains unclear. Methods and Results-The coronary arteries of male mice were ligated for 30 minutes. After reperfusion for 24 hours, ischemic and infarct sizes were determined. A highly selective and potent PPAR-␣ agonist, GW7647, was administered by mouth for 2 days, and the third dose was given 1 hour before ischemia. GW7647 at 1 and 3 mg · kg Ϫ1 · d Ϫ1 reduced infarct size by 28% and 35%, respectively (PϽ0.01), and myocardial contractile dysfunction was also improved. Cardioprotection by GW7647 was completely abolished in PPAR-␣-null mice. Ischemia/reperfusion downregulated mRNA expression of cardiac PPAR-␣ and FAO enzyme genes, decreased myocardial FAO enzyme activity and in vivo cardiac fat oxidation, and increased serum levels of free fatty acids. All of these changes were reversed by GW7647. Moreover, GW7647 attenuated ischemia/reperfusion-induced release of multiple proinflammatory cytokines and inhibited neutrophil accumulation and myocardial expression of matrix metalloproteinases-9 and -2. Furthermore, GW7647 inhibited nuclear factor-B activation in the heart, accompanied by enhanced levels of inhibitor-B␣. Conclusions-Activation of PPAR-␣ protected the heart from reperfusion injury. This cardioprotection might be mediated through metabolic and antiinflammatory mechanisms. This novel effect of the PPAR-␣ agonist could provide an added benefit to patients treated with PPAR-␣ activators for dyslipidemia.
These results suggest that MMP-9 plays an important role in ischemia-reperfusion-induced myocardial infarction and MMP-9 could be a target for prevention or treatment of acute ischemic myocardial injury.
Epoxy-and dihydroxy-eicosatrienoic acids (EETs and DHETs) are vasoactive cytochrome P450 metabolites of arachidonic acid. Interestingly, however, the mechanism(s) by which EETs/ DHETs mediate smooth muscle relaxation remains unclear. In contrast to previous reports, where dilation was purportedly large-conductance Ca 2ϩ -activated K ϩ (BK Ca ) and/or transient receptor potential cation channel, subfamily V, member 4 (TRPV4) channel-mediated, 14,15-EET-induced vasodilation [reversal of contractile tone established with the thromboxane receptor (TP) agonist 15-hydroxy-11␣,9␣-(epoxymethano)prosta-5,13-dienoic acid (U-46619)] was unaltered in BK Ca and TRPV4 knockout mouse isolated aortae compared with wild-type controls, indicating a significant BK Ca /TRPV4-resistant mechanism. Whereas all EET and DHET regioisomers reversed U-46619 contraction in rat aortae and mouse mesenteric resistance arteries, these eicosanoids failed to alter phenylephrine-induced contraction, suggesting that they mediated dilation via a "TP-selective" mechanism. Competitive TP antagonism was also observed in nonvascular tissue, including rat fundus and tertiary bronchus, indicating that the effect is not specific to blood vessels. Such effects were TP-selective because 14,15-EET failed to inhibit "non-TP" prostanoid receptor-mediated function in multiple cell/ tissue-based assays (K b Ͼ 10 M). In accordance, 14,15-EET inhibited specific [ 3 H]7-(3-((2-((phenylamino)carbonyl)hydrazino)-methyl)-7-oxabicyclo(2.2.1)hept-2-yl)-5-heptenoic acid (SQ-29548) binding to human recombinant TP receptor, with a K i value of 3.2 M, and it showed weaker affinity for non-TP prostanoid receptors, including DP, FP, EP 1-4 , and IP receptors (K i values of 6.1, 5.3, 42.6, 19.7, 13.2, 20.2, and Ͼ25 M, respectively) and no appreciable affinity (K i values Ͼ10 M) for a diverse array of pharmacologically distinct receptors, including the leukotriene receptors Cys-LT 1/2 and BLT 1 . As such, EETs/ DHETs represent a unique class of "endogenous" G proteincoupled receptor competitive antagonists, inducing vasodilation via direct TP inhibition. Thus, EETs/DHETs represent novel autoregulatory agents, directly modulating the actions of cyclooxygenase-derived eicosanoids following arachidonic acid mobilization.Upon release from cell membranes, arachidonic acid can be converted to a range of eicosanoids by three principal classes of enzymes: cyclooxygenases (COX), lipoxygenases, and cytochrome P450 monooxygenases. The P450 epoxygenases can introduce an epoxide to any of the four double bonds (5,6, 8,9, 11,12, and 14,15) of arachidonic acid, resulting in the generation of four distinct EET regioisomers (Capdevila et al., 1990). Each EET can be further metabolized to dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolase (sEH), resulting in the generation of four corresponding DHET regioisomers.Since their discovery more than 25 years ago (Capdevila et Article, publication date, and citation information can be found at
sulphonamide (GW627368X) is a novel, potent and selective competitive antagonist of prostanoid EP 4 receptors with additional human TP receptor affinity. 2 At recombinant human prostanoid EP 4 receptors expressed in HEK293 cells, GW627368X produced parallel rightward shifts of PGE 2 concentration-effect (E/[A]) curves resulting in an affinity (pK b ) estimate of 7.970.4 and a Schild slpoe not significantly different from unity. The affinity was independent of the agonist used. 3 In rings of phenylephrine precontracted piglet saphenous vein, GW627368X (30-300 nM) produced parallel rightward displacement of PGE 2 E/[A] curves (pK b ¼ 9.270.2; slope ¼ 1). 4 GW627368X appears to bind to human prostanoid TP receptors but not the TP receptors of other species. In human washed platelets, GW627368X (10 mM) produced 100% inhibition of U-46619 (EC 100 )-induced aggregation (approximate pA 2 B7.0). However, in rings of rabbit and piglet saphenous vein and of guinea-pig aorta GW627368X (10 mM) did not displace U-46619 E/[A] curves indicating an affinity of o5.0 for rabbit and guinea-pig prostanoid TP receptors. 5 In functional assays GW627368X is devoid of both agonism and antagonist affinity for prostanoid CRTH 2 , EP 2 , EP 3 , IP and FP receptors. At prostanoid EP 1 receptors, GW627368X was an antagonist with a pA 2 of 6.0, and at prostanoid IP receptors the compound increased the maximum effect of iloprost by 55%. At rabbit prostanoid EP 2 receptors the pA 2 of GW627368X was o5.0. 6 In competition radioligand bioassays, GW627368X had affinity for human prostanoid EP 4 and TP receptors (pK i ¼ 7.070.2 (n ¼ 10) and 6.8 (n ¼ 2), respectively). Affinity for all other human prostanoid receptors was o5.3. 7 GW627368X will be a valuable tool to explore the role of the prostanoid EP 4 receptor in many physiological and pathological settings.
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