leukotriene-b4 and Myocardial-Infarction

Omega-3 polyunsaturated fatty acid (ω-3 PUFA) have been reported to have beneficial cardiovascular effects, but its mechanism of protection against acute myocardial infarction (AMI) who are under guideline-based therapy is not fully understood. Here, we used a metabolomic approach to systematically analyze the eicosanoid metabolites induced by ω-3 PUFA supplementation and investigated the underlying mechanisms.. Participants with AMI after successful percutaneous coronary intervention were randomized to 3 months of 2 g daily ω-3 PUFA and guideline-adjusted therapy (n = 30, ω-3 therapy) or guideline-adjusted therapy alone (n = 30, Usual therapy). Functional PUFA-derived eicosanoids in plasma were profiled by metabolomics. Clinical and laboratory tests were obtained before and 3 months after baseline and after the study therapy.. By intent-to-treat analysis, the content of 11-HDoHE, 20-HDoHE and 16,17-EDP and that of epoxyeicosatetraenoic acids (EEQs), derived from docosahexaenoic acid and eicosapentaenoic acid, respectively, were significantly higher with ω-3 group than Usual therapy, whereas that of prostaglandin J2 (PGJ2) and leukotriene B4, derived from arachidonic acid, was significantly decreased. As compared with Usual therapy, ω-3 PUFA therapy significantly reduced levels of triglycerides (-6.3%, P < 0.05), apolipoprotein B (-4.9%, P < 0.05) and lipoprotein(a) (-37.0%, P < 0.05) and increased nitric oxide level (62.2%, P < 0.05). In addition, the levels of these variables were positively correlated with change in 16,17-EDP and EEQs content but negatively with change in PGJ2 content.. ω-3 PUFA supplementation may improve lipid metabolism and endothelial function possibly by affecting eicosanoid metabolic status at a systemic level during convalescent healing after AMI.. URL: http://www.chictr.org.cn. Unique identifier: ChiCTR1900025859.

Topics: Acute Disease; Aged; Atrial Fibrillation; Death, Sudden, Cardiac; Dietary Supplements; Eicosanoids; Endothelium, Vascular; Fatty Acids, Omega-3; Female; Humans; Intention to Treat Analysis; Leukotriene B4; Lipid Metabolism; Male; Metabolome; Metabolomics; Middle Aged; Myocardial Infarction; Nitric Oxide; Nutrition Policy; Percutaneous Coronary Intervention; Prostaglandin D2

Myocardial infarction (MI) is the leading cause of death in the world. Variants in the 5-lipoxygenase-activating protein (FLAP) gene are associated with risk of MI.. To determine the effect of an inhibitor of FLAP on levels of biomarkers associated with MI risk.. A randomized, prospective, placebo-controlled, crossover trial of an inhibitor of FLAP (DG-031) in MI patients who carry at-risk variants in the FLAP gene or in the leukotriene A4 hydrolase gene. Of 268 patients screened, 191 were carriers of at-risk variants in FLAP (87%) or leukotriene A4 hydrolase (13%). Individuals were enrolled in April 2004 and were followed up by designated cardiologists from a university hospital in Iceland until September 2004.. Patients were first randomized to receive 250 mg/d of DG-031, 500 mg/d of DG-031, 750 mg/d of DG-031, or placebo. After a 2-week washout period, patients received DG-031 if they had received placebo first or placebo if they had received DG-031 first. Treatment periods lasted for 4 weeks.. Changes in levels of biomarkers associated with risk of MI.. In response to 750 mg/d of DG-031, production of leukotriene B4 was significantly reduced by 26% (95% confidence interval [CI], 10%-39%; P = .003) and myeloperoxidase was significantly reduced by 12% (95% CI, 2%-21%; P = .02). The higher 2 doses of DG-031 produced a nonsignificant reduction in C-reactive protein (16%; 95% CI, -2% to 31%; P = .07) at 2 weeks. However, there was a more pronounced reduction (25%; 95% CI, 5%-40%; P = .02) in C-reactive protein at the end of the washout period that persisted for another 4 weeks thereafter. The FLAP inhibitor DG-031 was well tolerated and was not associated with any serious adverse events.. In patients with specific at-risk variants of 2 genes in the leukotriene pathway, DG-031 led to significant and dose-dependent suppression of biomarkers that are associated with increased risk of MI events.

Topics: 5-Lipoxygenase-Activating Proteins; Aged; Biomarkers; Carrier Proteins; Coronary Artery Disease; Cross-Over Studies; Epoxide Hydrolases; Female; Humans; Leukotriene B4; Leukotriene E4; Lipoxygenase Inhibitors; Male; Membrane Proteins; Middle Aged; Myocardial Infarction; Peroxidase; Polymorphism, Single Nucleotide; Prospective Studies; Quinolines; Risk Factors

[Figure: see text].

Topics: Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Chemokine CCL2; Chemokine CCL4; Chemokine CXCL2; Female; Leukotriene B4; Lipoxygenase; Macrophages; Male; Mice; Mice, Inbred C57BL; Myocardial Infarction; Myocardium; Protein Serine-Threonine Kinases; Receptors, Cell Surface; Receptors, Leukotriene B4; Serine-Threonine Kinase 3

Leukotriene B

Topics: Animals; Disease Models, Animal; Inflammation; Leukotriene B4; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardial Infarction; Receptors, Leukotriene B4; Signal Transduction

Genetic variation in the genes ALOX5 (arachidonate 5-lipoxygenase), ALOX5AP (arachidonate 5-lipoxygenase-activating protein) and LTA4H (leukotriene A4 hydrolase) has previously been shown to contribute to the risk of MI (myocardial infarction) in Caucasian and African American populations. All genes encode proteins playing a role in the synthesis of the pro-inflammatory leukotriene B mediators, possibly providing a link between MI and inflammation. The aim of the present study was to investigate whether these associations could be confirmed in the study of China MI patients. The study included 401 Han Chinese MI patients and 409 controls. Six tag single nucleotide polymorphisms (SNPs)-ALOX5 rs12762303 and rs12264801, ALOX5AP rs10507391, LTA4H rs2072512, rs2540487 and rs2540477-were selected. SNP genotyping was performed by an improved multiplex ligation detection reaction assay.. The rs2540487 genotype was associated with the risk of MI in overdominant model (P = 0.008). rs12762303 and rs10507391 SNPs were significantly associated with lipid levels in MI patients (P < 0.006-0.008). Several SNPs interacted with alcohol consumption, cigarette smoking, and hypertension to modify TC, TG, LDL-C and CRE levels, and the risk of MI (P < 0.0017 for all). No association between the SNPs of LT pathway and susceptibility to MI was found (P > 0.05 for all).. Taken together, this study provides additional evidence that functional genetic variation of the LT pathway can mediate atherogenic processes and the risk of MI in Chinese.

Topics: 5-Lipoxygenase-Activating Proteins; Alcohol Drinking; Arachidonate 5-Lipoxygenase; Atherosclerosis; China; Epoxide Hydrolases; Female; Genetic Association Studies; Genetic Predisposition to Disease; Genotype; Haplotypes; Humans; Inflammation; Leukotriene B4; Male; Metabolic Networks and Pathways; Middle Aged; Myocardial Infarction; Polymorphism, Single Nucleotide; Risk Factors; White People

Myocardial infarction (MI) is one of the leading causes of death worldwide. Oxidative stress and inflammation play vital role in the development of MI. The Indian basil or Tulsi (Ocimum sanctum Linn.), owing to its antioxidant potential, is used in the traditional system of Indian medicine to treat various disorders. We evaluated methanolic extract of O. sanctum (Tulsi) leaves on inflammation in isoproterenol (ISP) induced MI in rats. ISP-induced MI increased the levels of cardiac markers, phospholipases and phospholipid content. However, the same were reduced on pre-treatment with methanolic extract of O. sanctum leaves. The activities of 5-lipoxygenase and cycloxygenase-2 and levels of leukotriene B4 and thromboxane B2 were also elevated in ISP-treated rats, which were significantly decreased (P < 0.001) in extract pre-treated rats. The enhanced mRNA expressions of nuclear factor kappa-B, 5-lipoxygenase activating protein and receptor for leukotriene B4 on MI induction, were considerably reduced (P < 0.001) on extract pre-treatment. Histopathological analysis also confirmed the findings. The results also revealed the high phenolic content of methanolic extract of O. sanctum leaves. The study demonstrated that methanolic extract of Tulsi leaves can decrease inflammation in the cardiac tissue of ISP-induced MI in rats and its effect may be through downregulation of oxidative stress and arachidonic acid pathway. This cardioprotective effect may be due to the high phenolic content of methanolic extract of O. sanctum leaves.

Topics: Animals; Antioxidants; Disease Models, Animal; Inflammation; Isoproterenol; Leukotriene B4; Male; Medicine, Traditional; Methanol; Myocardial Infarction; NF-kappa B; Ocimum; Oxidative Stress; Phenols; Phospholipids; Plant Extracts; Plant Leaves; Rats; Rats, Sprague-Dawley; RNA, Messenger; Thromboxane B2

Transient receptor potential melastatin 2 (TRPM2) highly expressed in immunocytes is a Ca(2+)-permeable non-selective cation channel activated by oxidative stress. Myocardial ischaemia/reperfusion (I/R) injury is characterized by acute inflammation associated with the augmentation of oxidative stress. We hypothesized that TRPM2 is implicated in the exacerbation of myocardial I/R injury.. Wild-type (Trpm2(+/+)) and Trpm2 knockout (Trpm2(-/-)) mice were subjected to ligation of the left main coronary artery followed by reperfusion. Myocardial infarction following I/R, but not ischaemia alone, was reduced more in Trpm2(-/-)mice than in Trpm2(+/+) mice and cardiac contractile functions were also improved in Trpm2(-/-)mice. TRPM2 was highly expressed in the polymorphonuclear leucocytes (PMNs) rather than in the heart. The number of neutrophils and myeloperoxidase (MPO) activity in the reperfused area following ischaemia was lowered in Trpm2(-/-) mice. When Trpm2(+)(/+) or Trpm2(-/-) PMNs were administered to the Trpm2(-/-) heart ex vivo through the perfusate or in vivo by iv injection, Trpm2(+)(/+) PMNs produced enlargement of the infarct size. Following in vitro regional I/R, a pharmacological inhibitor of TRPM2 reduced the infarct size. The combination of H(2)O(2) and leukotriene B(4) (LTB(4)) increased intracellular Ca(2+) concentration and their adhesion to endothelial cells in Trpm2(+)(/+) but not in Trpm2(-/-)PMNs.. These findings indicate that neutrophil TRPM2 is implicated in the exacerbation of myocardial reperfusion injury. Accumulation of neutrophils in the reperfused area mediated by TRPM2 activation is likely to play a crucial role in myocardial I/R injury.

Topics: Animals; Calcium; Cell Movement; Hydrogen Peroxide; Leukotriene B4; Male; Mice; Mice, Inbred C57BL; Myocardial Infarction; Myocardial Reperfusion Injury; Neutrophils; TRPM Cation Channels; Ventricular Function, Left

Selenium (Se), an essential micronutrient, exerts its biological functions through selenoproteins. There are evidences that show Se to have an impact on the course and outcome of a number of etiologically inflammatory diseases. Leukotriene B(4) (LTB(4)) is an inflammatory mediator, and its production is mediated through two specific enzymes--lipooxygenase (LOX) and leukotriene A(4) hydrolase (LTA(4)H). We examined the effect of Se on LTB(4) synthesis during isoproterenol (ISP)-induced myocardial infarction (MI) in rats. Rats were divided as: control, ISP, Se, and Se + ISP. Sodium selenite was administered at dose of 8 μg/100 g/day. ISP was injected subcutaneously twice (10 mg/100 g body weight). The rats pretreated with Se had increased concentration of phospholipids and enhanced biosynthetic enzymes compared with that of ISP. The activities of phospholipases decreased on Se treatment. The level of calcium was increased in ISP group whereas, on Se treatment, it was near normal levels. Activities of LOX and expression of LTA(4)H were down-regulated in the case of Se-pretreated rats. Our study shows the anti-inflammatory mechanism of selenium during MI.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Calcium; Calcium-Transporting ATPases; Epoxide Hydrolases; Fatty Acids, Nonesterified; Female; Isoproterenol; Leukotriene B4; Lipoxygenase; Myocardial Infarction; Myocardium; Phospholipases; Phospholipids; Random Allocation; Rats; Rats, Sprague-Dawley; Selenium

Group IVA cytosolic phospholipase A(2) (cPLA(2)α), which preferentially cleaves arachidonic acid from phospholipids, plays a role in apoptosis and tissue injury. Downstream signals in response to tumor necrosis factor (TNF)-α, a mediator of myocardial ischemia-reperfusion (I/R) injury, involve cPLA(2)α activation. This study examined the potential role of cPLA(2)α and its mechanistic link with TNF-α in myocardial I/R injury using cPLA(2)α knockout (cPLA(2)α(-/-)) mice. Myocardial I/R was created with 10-wk-old male mice by 1 h ligation of the left anterior descending coronary artery, followed by 24 h of reperfusion. As a result, compared with wild-type (cPLA(2)α(+/+)) mice, cPLA(2)α(-/-) mice had a 47% decrease in myocardial infarct size, preservation of echocardiographic left ventricle (LV) function (%fractional shortening: 14 vs. 21%, respectively), and lower content of leukotriene B(4) and thromboxane B(2) (62 and 50% lower, respectively) in the ischemic myocardium after I/R. Treatment with the TNF-α inhibitor (soluble TNF receptor II/IgG1 Fc fusion protein, sTNFR:Fc) decreased myocardial I/R injury and LV dysfunction in cPLA(2)α(+/+) mice but not cPLA(2)α(-/-) mice. sTNFR:Fc also suppressed cPLA(2)α phosphorylation in the ischemic myocardium after I/R of cPLA(2)α(+/+) mice. Similarly, sTNFR:Fc exerted protective effects against hypoxia-reoxygenation (H/R)-induced injury in the cultured cardiomyocytes from cPLA(2)α(+/+) mice but not cPLA(2)α(-/-) cardiomyocytes. H/R and TNF-α induced cPLA(2)α phosphorylation in cPLA(2)α(+/+) cardiomyocytes, which was reversible by sTNFR:Fc. In cPLA(2)α(-/-) cardiomyocytes, TNF-α induced apoptosis and release of arachidonic acid to a lesser extent than in cPLA(2)α(+/+) cardiomyocytes. In conclusion, disruption of cPLA(2)α attenuates myocardial I/R injury partly through inhibition of TNF-α-mediated pathways.

Topics: Animals; Cells, Cultured; Etanercept; Group IV Phospholipases A2; Immunoglobulin G; Leukotriene B4; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Models, Animal; Myocardial Infarction; Myocardial Reperfusion Injury; Myocytes, Cardiac; Receptors, Tumor Necrosis Factor; Signal Transduction; Thromboxane B2; Tumor Necrosis Factor-alpha; Ventricular Dysfunction, Left

Group V secretory phospholipase A(2) (sPLA(2)-V) is highly expressed in the heart. This study examined (i) the role of sPLA(2)-V in myocardial ischaemia-reperfusion (I/R) injury and (ii) the cooperative action of sPLA(2)-V and cytosolic PLA(2) (cPLA(2)) in myocardial I/R injury, using sPLA(2)-V knockout (sPLA(2)V(-/-)) mice.. Myocardial I/R injury was created by 1 h ligation of the left anterior descending coronary artery, followed by 24 h of reperfusion. The sPLA(2)V(-/-) mice had a 44% decrease in myocardial infarct size, a preservation of echocardiographic LV function (%fractional shortening: 40 ± 3.5 vs. 21 ± 4.6, respectively), and lower content of leucotriene B(4) (LTB(4)) and thromboxane B(2) (TXB(2)) (40 and 37% lower, respectively) in the ischaemic myocardium after I/R compared with wild-type (WT) mice. Intraperitoneal administration of AACOCF3 or MAFP, inhibitors of cPLA(2) activity, decreased myocardial infarct size and myocardial content of LTB(4) and TXB(2) in both genotyped mice. The decrease in myocardial infarct size and content of LTB(4) and TXB(2) after cPLA(2) inhibitor administration was greater in WT mice than in sPLA(2)V(-/-) mice. I/R increased phosphorylation of extracellular signal-related kinase 1/2, c-Jun N-terminal kinase, and p38 mitogen-activated protein kinases in the ischaemic myocardium in association with cPLA(2) phosphorylation. The I/R-induced increase in the phosphorylation of p38 and cPLA(2) was less in sPLA(2)-V(-/-) mice than in WT mice. Pretreatment with the p38 inhibitor SB202190 suppressed an increase in cPLA(2) phosphorylation after I/R in WT mice.. sPLA(2)-V plays an important role in the pathogenesis of myocardial I/R injury partly in concert with the activation of cPLA(2).

Topics: Animals; Arachidonic Acid; Caspase 3; Caspase 8; Cells, Cultured; Echocardiography; Enzyme Inhibitors; Group IV Phospholipases A2; Group V Phospholipases A2; In Situ Nick-End Labeling; Leukotriene B4; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Myocytes, Cardiac; Thromboxane B2

Several types of secretory phospholipase A2 (sPLA2) are expressed in lung tissue, yielding various eicosanoids that might cause pulmonary edema. This study examined whether inhibition of sPLA2 activity attenuates acute cardiogenic pulmonary edema in mice. Acute cardiogenic pulmonary edema was induced in C57BL/6J male mice by an increase in heart rate with continuous intravenous infusion of isoproterenol (ISP) (10 mg/kg/h) at 2 weeks after the creation of myocardial infarction by left coronary artery ligation. Just before ISP infusion, a single intraperitoneal injection of 100 mg/kg LY374388, a prodrug of LY329722 that inhibits sPLA2 activity, or vehicle was administered. The ISP infusion after myocardial infarction induced interstitial and alveolar edema on lung histology. Furthermore, it increased the lung-to-body weight ratio, pulmonary vascular permeability evaluated by the Evans blue extravasation method, lung activity of sPLA2, and lung content of thromboxane A2 and leukotriene B4. These changes were significantly attenuated by LY374388 treatment. In Kaplan-Meier analysis, the survival rate during the ISP infusion after myocardial infarction was significantly higher in LY374388- than in vehicle-treated mice. Similar results were obtained with another inhibitor of sPLA2 activity, para-bromophenacyl bromide. In conclusion, inhibition of sPLA2 activity suppressed acute cardiogenic pulmonary edema.

Topics: Animals; Indoleacetic Acids; Infusions, Intravenous; Isoproterenol; Leukotriene B4; Lung; Male; Mice; Mice, Inbred C57BL; Myocardial Infarction; Phospholipases A2, Secretory; Pulmonary Edema; Thromboxane B2

Leukotrienes are implicated in the pathogenesis of coronary artery disease. Recently two haplotypes (HapA and HapB) in the gene encoding ALOX5AP (arachidonate 5-lipoxygenase-activating protein), the main regulator of 5-lipoxygenase, have been associated with a doubling of the risk of myocardial infarction. Studies have also shown that treatment with a leukotriene inhibitor reduces biomarkers of coronary risk in patients carrying HapA, raising the possibility of developing genotype-specific therapy. In the present study, we examined whether carriage of HapA or HapB is associated with increased LTB(4) (leukotriene B(4)) production in healthy subjects. Age- and gender-matched healthy HapA carriers (n=21), HapB carriers (n=20) and non-A/non-B carriers (n=18), with no reported history of cardiovascular disease, were recruited following DNA screening of 1268 subjects from a population-based study. Blood neutrophils were isolated, and LTB(4) production was measured in response to stimulation with 1 mumol/l of the calcium ionophore A23187. There was no difference in the mean level for LTB(4) production in the three groups (non-A/non-B, 24.9+/-8.3 ng/10(6) cells; HapA, 22.2+/-11.9 ng/10(6) cells; HapB, 19.8+/-4.8 ng/10(6); P=0.14). The findings indicate that if either the HapA or the HapB haplotype of ALOX5AP indeed increases cardiovascular risk, then the mechanism is not simply due to a systematically observable effect of the haplotype on LTB(4) production in response to stimulation. The results suggest that knowledge of a patient's haplotype may not provide useful information on the probable clinical response to ALOX5AP inhibitors.

Topics: 5-Lipoxygenase-Activating Proteins; Analysis of Variance; Arachidonate 5-Lipoxygenase; Calcimycin; Carrier Proteins; Cells, Cultured; Female; Genetic Predisposition to Disease; Haplotypes; Heterozygote; Humans; Ionophores; Leukotriene B4; Male; Membrane Proteins; Middle Aged; Myocardial Infarction; Neutrophils; Polymorphism, Single Nucleotide; Risk Factors; Stimulation, Chemical

The total burden of infection at various sites may affect the progression of atherosclerosis and Alzheimer's disease (AD), the risk being modulated by host genotype. The role of lipopolysaccharide (LPS) receptor TLR4 is paradigmatic. It initiates the innate immune response against gram-negative bacteria, and TLR4 single nucleotide polymorphisms (SNPs), such as +896A/G, known to attenuate receptor signaling, have been described. This SNP shows a significantly lower frequency in patients affected by myocardial infarction or AD. Thus, people genetically predisposed to developing lower inflammatory activity seem to have less chance of developing cardiovascular disease (CVD) or AD. In the present report, to validate this hypothesis, the levels of the eicosanoids, leukotriene B4 (LTB4) and prostaglandin E2 (PGE2), known to be involved as mediators in age-related diseases, were determined by an enzyme-linked immunosorbent assay in supernatants from a whole blood assay, after stimulation with subliminal doses of LPS from Escherichia coli. The samples, genotyped for the +896A/G SNP, were challenged with LPS for 4, 24, and 48 h. Both LTB4 and PGE2 values were significantly lower in carriers bearing the TLR4 mutation. Therefore, the pathogen burden, by interacting with the host genotype, determines the type and intensity of the inflammatory responses accountable for proinflammatory status, CVD, AD, and unsuccessful aging (i.e., age-related inflammatory diseases).

Topics: Adult; Aging; Alzheimer Disease; Blood Cells; Cells, Cultured; Dinoprostone; Escherichia coli; Escherichia coli Infections; Female; Genotype; Humans; Immunity, Innate; Inflammation; Leukotriene B4; Lipopolysaccharides; Male; Middle Aged; Myocardial Infarction; Polymorphism, Single Nucleotide; Time Factors; Toll-Like Receptor 4

Following preliminary in-vitro experiments, platelet-leukocyte conjugates and their determinants were evaluated in citrated whole blood from 349 subjects (209 women, age 16-92 years) randomly recruited from the general population. Platelet activation by ADP/collagen but not leukocyte stimulation by fMLP or LTB4 resulted in formation of platelet conjugates with PMN or monocytes. In the population study, mixed cell conjugates, platelet P-selectin and leukocyte CD11b were measured by flow cytometry both at baseline and after in-vitro stimulation with ADP/collagen. The latter significantly increased platelet conjugates with either PMN or monocytes, platelet P-selectin and leukocyte CD11b expression. Platelet count significantly correlated with platelet-PMN, platelet-monocyte conjugates and P-selectin both at baseline and upon stimulation. In all conditions, both conjugate levels correlated with each other, when adjusted for gender, age and platelet count. Age correlated with platelet-PMN conjugate numbers in basal and stimulated conditions and with basal P-selectin. ADP/collagen stimulation resulted in higher P-selectin and conjugates values in women. Among risk factors, a significant correlation was found between conjugate and glucose levels. In conclusion, the presence and formation in whole blood from a large population of platelet-leukocyte conjugates reflects primary platelet - but not leukocyte - activation and varies with gender, age, platelet count and blood glucose.

Topics: Adenosine Diphosphate; Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Aging; Blood Glucose; Blood Platelets; CD11b Antigen; Collagen; Female; Flow Cytometry; Humans; Leukotriene B4; Male; Middle Aged; Monocytes; Myocardial Infarction; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; P-Selectin; Platelet Activation; Platelet Adhesiveness; Platelet Count; Population Surveillance; Sex Factors

We mapped a gene predisposing to myocardial infarction to a locus on chromosome 13q12-13. A four-marker single-nucleotide polymorphism (SNP) haplotype in this locus spanning the gene ALOX5AP encoding 5-lipoxygenase activating protein (FLAP) is associated with a two times greater risk of myocardial infarction in Iceland. This haplotype also confers almost two times greater risk of stroke. Another ALOX5AP haplotype is associated with myocardial infarction in individuals from the UK. Stimulated neutrophils from individuals with myocardial infarction produce more leukotriene B4, a key product in the 5-lipoxygenase pathway, than do neutrophils from controls, and this difference is largely attributed to cells from males who carry the at-risk haplotype. We conclude that variants of ALOX5AP are involved in the pathogenesis of both myocardial infarction and stroke by increasing leukotriene production and inflammation in the arterial wall.

Topics: 5-Lipoxygenase-Activating Proteins; Carrier Proteins; Chromosome Mapping; Chromosomes, Human, Pair 13; Genetic Predisposition to Disease; Humans; Leukotriene B4; Membrane Proteins; Microsatellite Repeats; Myocardial Infarction; Polymorphism, Single Nucleotide; Stroke

This study compared the effect of a nitric oxide donor on limiting the size of infarct resulting from myocardial ischemia-reperfusion between atherosclerotic and nonatherosclerotic models.. Endothelial-derived relaxation in coronary arteries affected by ischemia is substantially impaired after reperfusion, and this impairment may exacerbate the myocardial ischemia-reperfusion injury. In animals with experimental atherosclerosis, release of endothelial-derived relaxing factor is also decreased, and the propagation of myocardial infarction could be exacerbated.. We examined the extent of myocardial injury induced by ischemia (30 min) and reperfusion (48 hr) in rabbits fed a cholesterol-rich (1%) or normal diet for 10 weeks. We also evaluated the effect of a nitric oxide donor (S-nitroso-N-acetylpenicillamine [SNAP], a nitric oxide precursor (L-arginine) or a degradation product of SNAP (N-acetylpenicillamine) on infarct size in these models.. Severity of myocardial injury was significantly exacerbated in cholesterol-fed rabbits (75.2 +/- 4.4% [mean +/- SEM]) compared with that in non-cholesterol-fed rabbits (53.2 +/- 5.2%). This exacerbation was prevented by treatment with SNAP (50.2 +/- 6.4%) but not with L-arginine (70.5 +/- 6.0%) or N-acetylpenicillamine (70.4 +/- 4.8%) in cholesterol-fed-rabbits. However, SNAP did not limit infarct size in non-cholesterol-fed rabbits (60.8 +/- 4.2%). The rate-pressure product was similar during the course of the experiment in all the groups.. Myocardial damage induced by ischemia-reperfusion was significantly exacerbated in rabbits fed a long-term cholesterol-rich diet but was effectively reversed by treatment with a nitric oxide donor. However, this agent did not limit infarct size in normal rabbits. Thus, a nitric oxide donor reduces myocardial infarct size in atherosclerotic but not in nonatherosclerotic rabbits.

Topics: Analysis of Variance; Animals; Cholesterol, Dietary; Coronary Artery Disease; Leukocytes; Leukotriene B4; Linear Models; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Nitric Oxide; Penicillamine; Peroxidase; Rabbits; S-Nitroso-N-Acetylpenicillamine; Vasodilator Agents

Abnormalities of arachidonic acid metabolism are implicated in spasm and thrombosis in coronary arteries. Therefore, arachidonic acid metabolites were examined in patients with acute myocardial infarction (AMI). Plasma levels of thromboxane B2 (TXB2), 6-keto-prostaglandin F1 alpha (6KPGF1 alpha), leukotriene B4 (LTB4), and slow reacting substance of anaphylaxis (SRS-A) composed of leukotriene C4 (LTC4), leukotriene D4 (LTD4) and leukotriene E4 (LTE4), were measured in 19 AMI patients. Plasma levels of TXB2, LTB4, and SRS-A in systemic artery blood were significantly elevated during the acute stage (within twenty-four hours after the onset of chest pain) of AMI (TXB2, 0.36 ng/mL; LTB4, 0.75 ng/mL; and SRS-A [LTC4+LTD4+LTE4], 0.96 ng/mL compared with those of normal controls (TXB2, 0.18 ng/mL; LTB4, 0.44 ng/mL; and SRS-A (LTC4+LTD4+LTE4], 0.31 ng/mL). These values decreased to near-normal control levels by one month after the AMI attack. The findings in this study suggest that abnormalities of arachidonic acid metabolism accompany, and may play a role in the pathogenesis of, AMI.

Topics: 6-Ketoprostaglandin F1 alpha; Adult; Aged; Arachidonic Acid; Female; Humans; Leukotriene B4; Male; Middle Aged; Myocardial Infarction; SRS-A; Thromboxane B2

Arthritis is a frequent complication of pustular psoriasis. However, the mechanism of onset of this arthritis still remains unclear.. The present study was conducted to determine whether leukotriene (LT) B4 or LTC4 is one of the proinflammatory mediators that possibly enhance exacerbation of the arthritis lesions.. We investigated the condition of the arthritis and autopsy findings of two cases of generalized pustular psoriasis with the severe complication of aseptic purulent arthritis. We also measured the synovial fluid levels of LTB4 and LTC4 by radioimmunoassay.. The collected synovial fluid was purulent, but nonbacterial, and the synovium of the knee joint showed histopathologic evidence of polymorphonuclear leukocyte (PMN) invasion, edema and dilatation of small vessels showing similarity to a histologic reaction in the skin lesions. The immunoreactive (i-) LTB4 and i-LTC4 in the samples significantly exceeded the amount measured in osteoarthritis patients used as the controls.. Thus, i-LTB4 and i-LTC4 appear to be generated in the arthritis lesions of pustular psoriasis, the former attracting PMNs to the joints and the latter causing exudation of synovial fluid.

Topics: Aged; Arthritis; Female; Humans; Leukotriene B4; Leukotriene C4; Leukotrienes; Male; Middle Aged; Myocardial Infarction; Neutrophils; Psoriasis; Radioimmunoassay; Synovial Fluid; Synovitis

Interventions that inhibit neutrophil infiltration into myocardial tissue after ischaemia and reperfusion are reported to reduce the size of the infarct. We examined whether administration of trimetazidine, which is reported to reduce myocardial infarct size, affects this process. [111In]Neutrophils and [125I]albumin were administered intravenously (i.v.) to anaesthetized rabbits to allow measurement of cell accumulation and changes in microvascular plasma protein leakage. A 30-min period of coronary artery occlusion followed by 3-h reperfusion was used, and the area at risk (AR) myocardium was defined by dye exclusion. Twelve rabbits received 2.5 mg/kg trimetazidine i.v., 10 min before coronary artery occlusion; the 13 controls received saline. In the control group, the number of [111In]neutrophils/g tissue in the AR (30,591 +/- 6,725) was significantly greater than in the normal zone (NZ, 11,519 +/- 1,605, p < 0.01). In the trimetazidine-treated group, the number of [111In]neutrophils in the AR was significantly lower than in the control group (12,717 +/- 1,958 [111In]neutrophils/g, p < 0.01). There was no significant difference in neutrophil content of the NZ (7,832 +/- 1,117 [111In]neutrophils/g) in treated animals as compared with that in control. Accumulation of [111In]neutrophils in response to intradermal administration of leukotriene B4, interleukin-8 (IL-8), or zymosan-activated plasma was not affected by the drug. The effect of trimetazidine on neutrophil accumulation into post-ischaemic reperfused myocardium therefore does not appear to result from a direct action on the neutrophil.

Topics: Animals; Blood Pressure; Capillary Permeability; Disease Models, Animal; Heart Rate; Interleukin-8; Leukotriene B4; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Neutrophils; Rabbits; Trimetazidine; Zymosan

A chemically stable prostacyclin analog, KP-10614 [(4Z,16S)-4, 5, 18, 18, 19, 19-hexadehydro-16,20-dimethyl-delta 6(9 alpha)-9(O)-methano-prostaglandin I1], was synthesized to increase the cytoprotective activity and to decrease the hypotensive activity. We have reported that KP-10614, infused i.v. at a dose of 3 ng/kg/min for 4 hr, inhibited platelet functions and reduced the experimental cardiac infarct size significantly, but did not change hemodynamic parameters and the ischemic area of the heart induced by ligation of the left descending coronary artery in rats. Accordingly, we thought that myocardial protective effects of KP-10614 might be based on the inhibition of platelet functions and cellular metabolism produced by platelets at the site of tissue injury. KP-10614 suppressed leukotriene B4 synthesis by N-formyl-methionyl-leucyl-phenylalanine-stimulated polymorphonuclear leukocytes, which was enhanced by thrombin-treated platelets in a concentration-dependent manner, even though KP-10614 did not suppress leukotriene B4 synthesis by N-formyl-methionyl-leucyl-phenylalanine-stimulated polymorphonuclear leukocytes separately in vitro. Moreover in in vivo studies, KP-10614, which was infused at a dose of 3 ng/kg/min for 4 hr, suppressed leukotriene B4 content, myeroperoxidase activity and polymorphonuclear leukocyte counts in myocardial tissues that were infarcted by ligation of the left descending coronary artery for 4 hr in rats. These data supported the hypothesis that KP-10614, a new prostacyclin analog, had protective effects on myocardial infarction in rats by suppressing the platelet-polymorphonuclear leukocyte interaction at the site of tissue injury in vivo.

Topics: Animals; Blood Platelets; Cell Communication; Cells, Cultured; Disease Models, Animal; Epoprostenol; Fibrinolytic Agents; Iloprost; Leukotriene B4; Male; Myocardial Infarction; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Peroxidase; Rabbits; Rats; Rats, Sprague-Dawley

The purpose of this study was to assess the effect of the dual cyclooxygenase-lipoxygenase blocking agent BW755C on the extent of myocardial infarction in the pig and to identify the mechanisms of any cardioprotective action of this drug.. Activated neutrophils contribute to reperfusion injury after myocardial infarction and inhibition of neutrophil function can limit infarct size.. In 9 control and 10 study pigs pretreated with intravenous BW755C (10 mg/kg body weight) 30 min before coronary occlusion, ischemia was induced by a 50-min occlusion of the mid-left anterior descending coronary artery, followed by 3 h of reperfusion. Heart rate, arterial pressure, left ventricular end-diastolic pressure, the first derivative of left ventricular pressure (dP/dt) and regional myocardial blood flow were measured during control, occlusion and reperfusion periods. Infarct size was determined by histochemical staining; and myeloperoxidase activity, a marker for tissue neutrophil content, was assessed in normal and infarcted myocardium. The effect of BW755C on the function of isolated neutrophils stimulated with zymosan-activated serum was evaluated by measuring neutrophil degranulation, leukotriene B4 production, superoxide generation and chemotaxis.. Hemodynamic function and regional myocardial blood flow were similar in control and BW755C-treated animals. BW755C significantly reduced myocardial infarct size compared with that in control animals, as measured by infarct/risk areas by histochemical staining (39 +/- 5% vs. 63 +/- 7%, p < 0.05). Myocardial myeloperoxidase activity was similar in normal, salvaged and infarcted areas in the control and treated groups, indicating that neutrophil accumulation in injured myocardium was unaltered by BW755C. However, this agent attenuated function of isolated, stimulated (zymosan-activated serum) neutrophils. At a concentration of 0.03 mg/ml, BW755C inhibited degranulation (-46%), leukotriene B4 production (-48%) and superoxide generation (-74%), but there was minimal inhibition of chemotaxis in vitro.. These findings demonstrate that myocardial infarct size can be reduced by selective inhibition of neutrophil cytotoxic activity without affecting neutrophil migration into injured myocardium.

Topics: 4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; Analysis of Variance; Animals; Cell Movement; Coronary Circulation; Female; Hemodynamics; Leukotriene B4; Male; Myocardial Infarction; Neutrophils; Peroxidase; Superoxides; Swine

Injection of leukotriene (LT)B4 (0.1-3 micrograms/kg i.v.) in normal anesthetized dogs produced dose-related leukopenia that was accompanied by arterial hypotension and tachycardia at higher tested doses. LTD4 (0.1-3 micrograms/kg i.v.), in contrast, increased arterial blood pressure, lowered cardiac rate and produced little change in arterial blood leukocyte count. Continuous infusion of LY255283 [(1-(5-ethyl-2-hydroxy-4-(6-methyl-6-(1H-tetrazol-5-yl)- heptyloxy)phenyl)ethanone] (0.33 mg/kg/min i.v.), a selective LTB4 receptor antagonist, resulted in near complete inhibition of leukopenic, hypotensive and tachycardic responses to LTB4 (3 micrograms/kg i.v.) challenge over a 6-hr test period. Persistent antagonism of canine LTB4 receptors was associated with high circulating levels of LY255283 that were bound extensively to plasma proteins. In subsequent experiments, myocardial infarct size was measured following 1 hr of occlusion of the circumflex coronary artery and 5 hr of reperfusion in control dogs infused with vehicle, and in dogs receiving LY255283 (0.33 mg/kg/min i.v.). Drug and vehicle were infused continuously beginning 15 min before coronary artery occlusion. LY255283 treatment essentially did not alter base-line cardiovascular parameters or myocardial oxygen demand when alterations were compared to time-related changes observed in control dogs. LY255283 infusion also did not alter the degree of myocardial ischemia or the intensity and duration of cardiac arrhythmias associated with coronary artery occlusion and reperfusion. Resultant infarct sizes were 43 +/- 5% of the left ventricle placed at risk in control dogs and 32 +/- 5% in dogs given LY255283; this difference was not statistically significant. The extent of left ventricle placed at risk was similar between groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Azoles; Blood Pressure; Coronary Circulation; Dogs; Heart Rate; Leukopenia; Leukotriene B4; Male; Myocardial Infarction; Neutrophils; Receptors, Immunologic; Receptors, Leukotriene B4; SRS-A; Tetrazoles

Essential fatty acid (EFA) deficiency, induced by elimination of the dietary (n-6) fatty acids, has been shown to limit inflammatory cell influx and consequent enhanced eicosanoid production in experimental glomerulonephritis and hydronephrosis. To determine whether EFA-deficiency exerts anti-inflammatory effects following left ventricular myocardial infarction (LVMI), male weanling rabbits were fed EFA-deficient diet for 3 months prior to 60 minutes of distal left circumflex coronary artery occlusion followed by reperfusion. One and 4 days later, corresponding to infiltration of cardiac tissue with polymorphonuclear (PMN) and mononuclear leukocytes respectively, infarcted hearts were buffer perfused and stimulated to produce eicosanoids with f-met-leu-phe or bradykinin. One day following LVMI, the hearts of EFA-deficient rabbits demonstrated a marked suppression of PMN infiltration and eicosanoid production relative to controls. Four days following myocardial infarction, no differences were observed in mononuclear cell invasion, collagen deposition, or eicosanoid production between EFA-deficient and normal hearts. Our data show that EFA-deficiency inhibits PMN influx and consequent enhanced eicosanoid production without affecting the later appearance of mononuclear cells, collagen deposition, or eicosanoid production. Recent studies have shown that suppression of PMN invasion limits the extent of tissue damage following LVMI. Selective inhibition of PMN infiltration is possible and may be useful in the management of acute myocardial infarction.

Topics: 6-Ketoprostaglandin F1 alpha; Acute-Phase Reaction; Animals; Cell Migration Inhibition; Collagen; Dinoprostone; Fatty Acids, Essential; Inflammation; Leukotriene B4; Male; Myocardial Infarction; Myocardium; Neutrophils; Rabbits; Thromboxane B2

An initial increase (3-12 hr) in the polymorphonuclear leukocytes (PMN) counts after ligation of the rat left main coronary artery was reduced by 49.4% (at 12 hr) by a 5-lipoxygenase inhibitor, AA-861 (80 mg/kg, p.o., 1 hr before ligation). Depletion of the complement components induced by cobra venoma factor (CVF) (i.v.), given one day before, resulted in significant reduction in the PMN accumulation after 12 hr (by 63.6% at 24 hr). The combined treatment (CVF+AA-861) suppressed the PMN accumulation by 69.7% (24 hr). The infarct size at 48 hr was also reduced by approximately 36% by either AA-861, CVF or combined treatments.

Topics: Animals; Complement System Proteins; Leukocyte Count; Leukocytes; Leukotriene B4; Male; Myocardial Infarction; Rats; Rats, Inbred Strains

The main left coronary artery of rats was ligated near its origin under light ether anaesthesia and the infarction observed for 48 h. The ischaemic area was determined after an intravenous injection of pontamine sky blue dye 1 h before induction of cardiac arrest with potassium chloride. The unstained area (true ischaemic area) decreased with time to 27.1% of the left ventricle at 48 h, whereas the intensely stained area between the normal and the true ischaemic areas increased with time, suggesting that blood was flowing to the border from the normal surrounding tissue. The infarcted area, identified by its lack of triphenyltetrazolium chloride staining, became evident after 3 h and stabilised at 12 h (42% of left ventricle). The polymorphonuclear leucocyte counts in the hearts, differentiated by staining of their chloroacetate esterase, increased gradually up to 5500 cells per section at 24 h. The leukotriene B4 concentration, determined by radioimmunoassay after freezing of the beating heart in liquid nitrogen, increased to eight times that of the sham operated hearts and peaked at 8 h (9.4(0.6) ng per heart, mean(SEM) n = 5) before the leucocyte counts reached their maximum. A single oral dose of a selective 5-lipoxygenase inhibitor (AA-861, 80 mg.kg-1, 1 h before ligation) lowered the leukotriene B4 concentration to that of the sham operated hearts and decreased the leucocyte count by 49.4% and 41.2% at 12 and 24 h respectively. The inhibitor also reduced the infarct size at 48 h by 34.4%. It was concluded that leukotriene B4, generated in ischaemic cardiac tissue, may increase infarct size through migration of polymorphonuclear leucocytes.

Topics: Animals; Cell Movement; Leukocyte Count; Leukotriene B4; Male; Myocardial Infarction; Myocardium; Neutrophils; Rats; Rats, Inbred Strains; Time Factors

Polymorphonuclear leukocyte activity was compared with the incidence and severity of ventricular arrhythmia evaluated by Holter electrocardiographic monitoring in 21 patients with acute myocardial infarction. A positive correlation (r = 0.706) was seen between peripheral polymorphonuclear leukocyte count and the amount of leukotriene B4 produced by A23187 (20 microM)-stimulated polymorphonuclear leukocytes on the first hospital day (p less than 0.01). Patients were divided into 3 groups according to the severity of ventricular arrhythmia: no or mild (unifocal, maximal hourly ventricular premature complex rate less than 30, n = 6), moderate (maximal hourly ventricular premature complex rate greater than or equal to 30 or multifocal, n = 6) or severe (R on T, greater than or equal to 2 consecutive ventricular premature complexes or ventricular fibrillation, n = 9). Polymorphonuclear leukocyte count and its leukotriene B4 production were increased with the increase in severity of ventricular arrhythmia among 3 groups. Polymorphonuclear leukocyte count (13,300 +/- 900/microliter, mean +/- standard error of the mean) and its leukotriene B4 production (194 +/- 24 ng/10(7) cells) in patients exhibiting severe ventricular arrhythmia were significantly increased compared with those in patients exhibiting no or mild ventricular arrhythmia (10,300 +/- 1,000/microliter, p less than 0.05 and 120 +/- 21 ng/10(7) cells, p less than 0.05, respectively). Enzymatically estimated infarct size in the latter patient group was significantly smaller than those of the other 2 groups, between which there was no difference in infarct size. These results suggest that polymorphonuclear leukocyte activity is closely related to the incidence and severity of ventricular arrhythmia during the early phase of myocardial infarction.

Topics: Arrhythmias, Cardiac; Electrocardiography; Female; Humans; Leukocyte Count; Leukotriene B4; Male; Middle Aged; Monitoring, Physiologic; Myocardial Infarction; Neutrophils

Lipoxygenase metabolites of arachidonic acid have been implicated in myocardial injury induced by coronary artery occlusion and reperfusion, as dual inhibitors of the lipoxygenase and cyclooxygenase enzymes, but not selective cyclooxygenase inhibitors, reduce infarct size. However, interpretation of these studies has been clouded by the lack of specificity of the drugs previously used. A specific 5-lipoxygenase inhibitor, REV-5901, has recently been developed. This drug inhibits A23187-induced immunoreactive leukotriene B4 generation by canine neutrophils (IC50 approximately 2.5 microM), and when given intravenously, attenuates the formation of a leukotriene D4-like material in blood ex vivo. The release of bioassayable leukotriene-like material from rabbit hearts infarcted in vivo and subsequently perfused in vitro is prevented by REV-5901. Moreover, the inhibitor also acts as an end-organ antagonist to prevent the spasmogenic effects of the peptide-containing leukotrienes in vitro with an IC50 approximately 0.1 microM. REV-5901 (10 + 2 mg/kg i.v.) reduces infarct size produced by coronary artery occlusion and reperfusion in the anesthetized dog from 56.6 +/- 2 to 28.6 +/- 3.7% of the hypoperfused zone. Salvage of the ischemic myocardium occurs independently of any apparent hemodynamic effect of the drug, but is accompanied by a diminution in neutrophil accumulation in the ischemic heart. It is proposed that inhibition of leukotriene B4 formation by REV-5901 suppresses the accumulation of neutrophils, thereby attenuating neutrophil-mediated cardiac damage.

Topics: Animals; Arachidonate Lipoxygenases; Dogs; Hydroxyquinolines; Leukotriene B4; Lipoxygenase Inhibitors; Male; Myocardial Infarction; Neutrophils; Quinolines; Rabbits; SRS-A

Topics: Animals; Benzoquinones; Leukotriene B4; Lipoxygenase Inhibitors; Male; Myocardial Infarction; Neutrophils; Quinones; Rats; Rats, Inbred Strains

Topics: Dietary Fats; Eicosapentaenoic Acid; Epoprostenol; Humans; Inflammation; Leukocytes; Leukotriene B4; Myocardial Infarction; Thrombosis; Thromboxane A2