leukotriene-b4 and Stroke

Leukotrienes are potent inflammatory mediators synthesized locally within the cardiovascular system through the 5-lipoxygenase pathway of arachidonic acid metabolism. The leukotrienes, consisting of dihydroxy leukotriene LTB4 and the cysteinyl leukotrienes LTC4, LTD4 and LTE4, act by targeting cell surface receptors expressed on inflammatory cells and on structural cells of vessel walls. LTB, induces leukocyte activation and chemotaxis via high- and low-affinity receptor subtypes (BLT1 and BLT2), respectively. Recently, BLT, receptors were found on human vascular smooth muscle cells, inducing their migration and proliferation. Cysteinyl leukotrienes are vasoconstrictors and induce endothelium-dependent vascular responses through the CysLT, and CysLT2 receptor subtypes. There is also pharmacological evidence for the existence of further CysLT receptor subtypes. Taken together, experimental and genetic studies suggest a major role of leukotrienes in atherosclerosis and in its ischemic complications such as acute coronary syndromes and stroke. Furthermore, the effects on vascular smooth muscle cells suggest a role in the vascular remodeling observed after coronary angioplasty, as well as in aortic aneurysm. Further experimental and clinical studies are needed to determine the potential of therapeutic strategies targeting the leukotriene pathway in cardiovascular disease.

Topics: Angioplasty, Balloon, Coronary; Animals; Aortic Aneurysm; Arachidonic Acid; Atherosclerosis; Cardiovascular Diseases; Cell Movement; Coronary Restenosis; Disease Models, Animal; Guinea Pigs; Humans; Hypertension; Leukotriene Antagonists; Leukotriene B4; Leukotriene C4; Leukotriene D4; Leukotriene E4; Leukotrienes; Mice; Muscle, Smooth, Vascular; Rats; Receptors, Leukotriene; Stroke

Neuroinflammatory response contributes to early neurological deterioration (END) and unfavorable long-term functional outcome in patients with acute ischemic stroke (AIS) who recanalized successfully by endovascular thrombectomy (EVT), but there are no reliable biomarkers for their accurate prediction. Here, we sought to determine the temporal plasma profiles of the bioactive lipid mediators lipoxin A4 (LXA4), resolvin D1 (RvD1), and leukotriene B4 (LTB4) for their associations with clinical outcome.. We quantified levels of LXA4, RvD1, and LTB4 in blood samples retrospectively and longitudinally collected from consecutive AIS patients who underwent complete angiographic recanalization by EVT at admission (pre-EVT) and 24 hrs post-EVT. The primary outcome was unfavorable long-term functional outcome, defined as a 90-day modified Rankin Scale score of 3-6. Secondary outcome was END, defined as an increase in National Institutes of Health Stroke Scale (NIHSS) score ≥4 points at 24 hrs post-EVT.. Eighty-one consecutive AIS patients and 20 healthy subjects were recruited for this study. Plasma levels of LXA4, RvD1, and LTB4 were significantly increased in post-EVT samples from AIS patients, as compared to those of healthy controls. END occurred in 17 (20.99%) patients, and 38 (46.91%) had unfavorable 90-day functional outcome. Multiple logistic regression analyses demonstrated that post-EVT levels of LXA4 (adjusted odd ratio [OR] 0.992, 95% confidence interval [CI] 0.987-0.998), ΔLXA4 (adjusted OR 0.995, 95% CI 0.991-0.999), LTB4 (adjusted OR 1.003, 95% CI 1.001-1.005), ΔLTB4 (adjusted OR 1.004, 95% CI 1.002-1.006), and post-EVT LXA4/LTB4 (adjusted OR 0.023, 95% CI 0.001-0.433) and RvD1/LTB4 (adjusted OR 0.196, 95% CI 0.057-0.682) ratios independently predicted END, and post-EVT LXA4 levels (adjusted OR 0.995, 95% CI 0.992-0.999), ΔLXA4 levels (adjusted OR 0.996, 95% CI 0.993-0.999), and post-EVT LXA4/LTB4 ratio (adjusted OR 0.285, 95% CI 0.096-0.845) independently predicted unfavorable 90-day functional outcome. These were validated using receiver operating characteristic curve analyses.. Plasma lipid mediators measured 24 hrs post-EVT were independent predictors for early and long-term outcomes. Further studies are needed to determine their causal-effect relationship, and whether the imbalance between anti-inflammatory/pro-resolving and pro-inflammatory lipid mediators could be a potential adjunct therapeutic target.

Topics: Brain Ischemia; Endovascular Procedures; Humans; Ischemic Stroke; Leukotriene B4; Retrospective Studies; Stroke; Thrombectomy; Treatment Outcome

Leukotriene B

Topics: Aged; Animals; Arachidonate 5-Lipoxygenase; Cerebral Cortex; Disease Models, Animal; Female; Humans; Infarction, Middle Cerebral Artery; Leukotriene A4; Leukotriene B4; Male; Middle Aged; Rats, Wistar; Severity of Illness Index; Stroke

Despite accumulating evidence supporting the association between variants of the ALOX5AP gene and atherosclerotic vascular events, the precise mechanism is still unclear. No variants in the coding sequence that lead to amino acid substitution have been found. We investigated genetic variants in the promoter region of the ALOX5AP gene and the association with ischemic stroke in a north Chinese Han population.. 505 cases of ischemic stroke and 500 age- and gender-matched controls of the north Chinese Han population were enrolled. Genetic variants in the promoter region of the ALOX5AP gene were identified by polymerase chain reaction and DNA sequencing. 40 cases and 40 controls were randomly selected and compared for serum leukotriene B(4) (LTB(4)) concentration. The effect on ischemic stroke was evaluated by logistic regression.. Three genetic variants were identified, including a mutation (-519 G > A), an insertion and deletion polymorphisms (-581_582 Ins A) and a single nuclear polymorphisms (-946 A > G). Association study showed that the II genotype of -581_582 Ins A was significantly associated with ischemic stroke of a large artery atherosclerosis (OR = 3.50, 95% CI = 1.93-6.36, p = 0.0002) and undetermined etiology (OR = 3.66, 95% CI = 1.92-6.94, p = 0.0006). No significant association was found between the -519 GA genotype (OR = 0.35, 95% CI = 0.02-5.88, p = 0.46), -946 AG genotype (OR = 1.35, 95% CI = 0.85-2.16, p = 0.21) and ischemic stroke. There was no significant difference in serum LTB(4) concentration between cases (n = 40) and controls (n = 40) (log serum LTB(4) of cases vs. controls: 2.67 ± 0.14 vs. 2.73 ± 0.18 pg/ml, p = 0.10). However, the serum LTB(4) concentration was significantly higher in participants with the II genotype of -581_582 Ins A (n = 12) than that of participants with the DD genotype (n = 68) (log serum LTB(4) of participants with II genotype vs. DD genotype: 2.82 ± 0.18 vs. 2.68 ± 0.15 pg/ml, p = 0.01).. The -581_582 Ins A polymorphism might be a novel genetic risk factor for ischemic stroke in a north Chinese Han population. Further studies on molecular mechanism are warranted.

Topics: 5-Lipoxygenase-Activating Proteins; Aged; Analysis of Variance; Base Sequence; Biomarkers; Brain Ischemia; Case-Control Studies; Chi-Square Distribution; China; Female; Gene Frequency; Genetic Predisposition to Disease; Humans; Leukotriene B4; Linkage Disequilibrium; Logistic Models; Male; Middle Aged; Molecular Sequence Data; Odds Ratio; Phenotype; Polymorphism, Single Nucleotide; Promoter Regions, Genetic; Risk Assessment; Risk Factors; Stroke

Peroxisome proliferator-activated receptors gamma (PPARgamma) are nuclear receptors with essential roles as transcriptional regulators of glucose and lipid homeostasis. PPARgamma are also potent anti-inflammatory receptors, a property that contributes to the neuroprotective effects of PPARgamma agonists in experimental stroke. The mechanism of these beneficial actions, however, is not fully elucidated. Therefore, we have explored further the actions of the PPARgamma agonist rosiglitazone in experimental stroke induced by permanent middle cerebral artery occlusion (MCAO) in rodents. Rosiglitazone induced brain 5-lipoxygenase (5-LO) expression in ischemic rat brain, concomitantly with neuroprotection. Rosiglitazone also increased cerebral lipoxin A(4) (LXA(4)) levels and inhibited MCAO-induced production of leukotriene B4 (LTB(4)). Furthermore, pharmacological inhibition and/or genetic deletion of 5-LO inhibited rosiglitazone-induced neuroprotection and downregulation of inflammatory gene expression, LXA(4) synthesis and PPARgamma transcriptional activity in rodents. Finally, LXA(4) caused neuroprotection, which was partly inhibited by the PPARgamma antagonist T0070907, and increased PPARgamma transcriptional activity in isolated nuclei, showing for the first time that LXA(4) has PPARgamma agonistic actions. Altogether, our data illustrate that some effects of rosiglitazone are attributable to de novo synthesis of 5-LO, able to induce a switch from the synthesis of proinflammatory LTB(4) to the synthesis of the proresolving LXA(4). Our study suggests novel lines of study such as the interest of lipoxin-like anti-inflammatory drugs or the use of these molecules as prognostic and/or diagnostic markers for pathologies in which inflammation is involved, such as stroke.

Topics: Animals; Arachidonate 5-Lipoxygenase; Brain; Brain Infarction; Infarction, Middle Cerebral Artery; Leukotriene B4; Lipoxins; Mice; Neuroprotective Agents; PPAR gamma; Rats; Rosiglitazone; Stroke; Thiazolidinediones

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

Activated polymorphonuclear leukocytes (PMNs) have been suggested to contribute to the development of increased intracranial pressure (ICP). We recently demonstrated that human PMNs produce a novel cytochrome P450-derived arachidonic acid metabolite, 1 6(R)-hydroxyeicosatetraenoic acid [16(R)-HETE], that modulates their function. It was thus of interest to examine this novel mediator in an acute stroke model.. 16-HETE was assessed initially in a variety of human PMN and platelet in vitro assays and subsequently in an established rabbit model of thromboembolic stroke. A total of 50 rabbits completed a randomized, blinded, four-arm study, receiving 16(R)-HETE, tissue plasminogen activator, both, or neither. Experiments were completed 7 hours after autologous clot embolization. The primary end point for efficacy was the suppression of increased ICP.. In in vitro assays, 16(R)-HETE selectively inhibited human PMN adhesion and aggregation and leukotriene B4 synthesis. In the thromboembolic stroke model, animals that received 16(R)-HETE demonstrated significant suppression of increased ICP (7.7 +/- 1.2 to 13.1 +/- 2.7 mm Hg, baseline versus final 7-h time point, mean +/- standard error), compared with either the vehicle-treated group (7.7 +/- 0.9 to 15.8 +/- 2.6 mm Hg) or the tissue plasminogen activator-treated group (7.6 +/- 0.6 to 13.7 +/- 2.1 mm Hg). The group that received the combination of 16(R)-HETE plus tissue plasminogen activator demonstrated no significant change in ICP for the duration of the protocol (8.6 +/- 0.6 to 11.1 +/- 1.2 mm Hg).. 16(R)-HETE suppresses the development of increased ICP in a rabbit model of thromboembolic stroke and may serve as a novel therapeutic strategy in ischemic and inflammatory pathophysiological states.

Topics: Animals; Arachidonic Acid; Cell Adhesion; Cell Aggregation; Cytochrome P-450 Enzyme System; Drug Synergism; Fibrinolytic Agents; Humans; Hydroxyeicosatetraenoic Acids; Intracranial Embolism and Thrombosis; Intracranial Pressure; Leukotriene B4; Neutrophils; Rabbits; Single-Blind Method; Stroke; Tissue Plasminogen Activator