montelukast and Atherosclerosis

Obstructive sleep apnea (OSA) characterized by nocturnal intermittent hypoxia (IH) is associated with atherosclerosis and cysteinyl-leukotrienes (CysLT) pathway activation. We aimed to identify the determinants of CysLT pathway activation and the role of CysLT in OSA-related atherosclerosis.. Determinants of the urinary excretion of LTE. IH-related CysLT pathway activation contributes to OSA-induced atherogenesis. In the era of personalized medicine, U-LTE

Topics: 5-Lipoxygenase-Activating Proteins; Acetates; Adult; Animals; Arachidonate 5-Lipoxygenase; Atherosclerosis; Case-Control Studies; Cyclopropanes; Cysteine; Disease Models, Animal; Disease Progression; Female; Humans; Leukotriene Antagonists; Leukotriene E4; Leukotrienes; Male; Mice, Knockout, ApoE; Middle Aged; Plaque, Atherosclerotic; Quinolines; Receptors, Leukotriene; Risk Factors; Signal Transduction; Sleep Apnea, Obstructive; Sulfides

Recruitment of monocytes to endothelial cells is important during early stages of atherosclerosis development, which is activated in response to a number of inflammatory stimuli, including oxidized low-density lipoprotein (ox-LDL). Montelukast is a licensed drug approved by the Food and Drug Administration (FDA) and clinically used for the treatment of asthma by reducing the eosinophilic inflammation in the airway. Little information regarding the effects of Montelukast on endothelial inflammation has been reported before. In the current study, we found that Montelukast markedly reduced ox-LDL-induced monocyte adhesion to human umbilical vein endothelial cells. In addition, the inhibitory mechanism of Montelukast was associated with suppression of adhesion molecule expression, including VCAM-1 and E-selectin. Mechanistically, ERK5 mediated expression of the transcriptional factor KLF2 was found to be involved in the anti-inflammation effects of Montelukast against ox-LDL induced endothelial inflammation. Results indicate that Montelukast plays a protective role in the early stages of atherosclerosis.

Topics: Acetates; Anti-Asthmatic Agents; Atherosclerosis; Blotting, Western; Cell Adhesion; Cell Line, Tumor; Cells, Cultured; Cyclopropanes; Dose-Response Relationship, Drug; E-Selectin; Endothelium, Vascular; Gene Expression; Human Umbilical Vein Endothelial Cells; Humans; Kruppel-Like Transcription Factors; Lipoproteins, LDL; Mitogen-Activated Protein Kinase 7; Molecular Structure; Monocytes; Protective Agents; Quinolines; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Sulfides; Vascular Cell Adhesion Molecule-1

Topics: Acetates; Administration, Inhalation; Adult; Airway Obstruction; Asthma; Atherosclerosis; Bronchodilator Agents; Bronchoscopy; Child; Cyclopropanes; Glucocorticoids; Humans; Hyperthermia, Induced; Leukotriene Antagonists; Quinolines; Scopolamine Derivatives; Sulfides; Tiotropium Bromide

Atherosclerosis is characterized by inflammatory responses of the arterial wall to "injury", which is prominently driven by inflammatory mediators. Montelukast, a selective CysLT1 receptor antagonist, has potent anti-inflammatory effects in diverse animal models. However, the role of montelukast in regulating inflammatory progression of atherosclerosis has not been elucidated. Therefore, we investigated the effect of montelukast on atherosclerosis compared with that of atorvastatin. Twenty-six male New Zealand White rabbits were randomized into four groups including a negative control group. The rabbits were fed a normal diet or an atherogenic diet for 12 weeks. The rabbits, except the negative control group, received right carotid artery balloon-injury 2 weeks after initiation of the atherogenic diet. Animals were then treated with montelukast (1mg/kg/day), atorvastatin (1.5mg/kg/day) or placebo for 4 weeks, respectively. At the end of the treatment, animals were killed and carotids were dislodged and detected. The results indicated that the placebo group had significant progression of atherosclerosis compared with the negative control group. In contrast, montelukast or atorvastatin treated rabbits showed a significant reduction of neointima, decreased macrophage content, increased SMC content and inhibited expression of MCP-1. Between two drugs, there were no significant differences in reducing neointima and decreasing the level of MCP-1. However, montelukast had no influence on plasma lipids, while atorvastatin down-regulated the levels of TC, TG and LDL. These results suggest that montelukast produces anti-atherogenic effects unrelated to plasma lipid modulation but related to MCP-1 down regulation.

Topics: Acetates; Animals; Atherosclerosis; Atorvastatin; Carotid Arteries; Catheterization; Chemokine CCL2; Cyclopropanes; Diet, Atherogenic; Disease Progression; Heptanoic Acids; Immunohistochemistry; Leukotriene Antagonists; Lipids; Male; Pyrroles; Quinolines; Rabbits; Random Allocation; Sulfides

Matrix metalloproteinases (MMPs) play important roles in the development and destabilization of atherosclerotic plaques. It is known that montelukast inhibits neointimal hyperplasia. However, the underlying mechanisms for the inhibitory effects of montelukast on neointimal formation have been poorly defined.. Thirty-six male New Zealand White rabbits were randomized as normal control, placebo (0.9% NaCl, 1.5 ml/kg/day, via intraperitoneal injection), atorvastatin (atorvastatin, 1.5 mg/kg/day, orally) and montelukast groups (montelukast, 1.5 mg/kg/day, via intraperitoneal injection). Atherosclerosis was induced by balloon-injury and high-cholesterol (HC) diet. Serum lipids were measured at 0, 8 and 12 weeks. After 12 weeks, the rabbits were sacrificed and histopathological changes examined. Immunohistochemistry and reverse transcription-polymerase chain reaction were used to measure the expression of MMP-2 and MMP-9 in the plaques.. It was found that montelukast reduced neointimal formation, decreased macrophage accumulation, and increased smooth muscle cells. It also attenuated the expression of MMP-2 and MMP-9 in atherosclerotic plaques, but it had no effect on plasma lipid levels.. These data indicate that montelukast inhibits neointimal hyperplasia in association with decreased expression of MMP-2 and MMP-9 independent of plasma lipid levels in atherosclerotic plaques after vascular injury in hyperlipidemic rabbits.

Topics: Acetates; Animals; Atherosclerosis; Atorvastatin; Cyclopropanes; Heptanoic Acids; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Leukotriene Antagonists; Lipids; Macrophages; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Myocytes, Smooth Muscle; Pyrroles; Quinolines; Rabbits; Random Allocation; Reverse Transcriptase Polymerase Chain Reaction; Sulfides

We have shown that inhibitors of five lipoxygenase activating protein (FLAP)--MK-886 and BAYx1005 inhibit atherosclerosis in apolipoprotein E/LDL receptor-double knockout mice. We, therefore, investigated whether cysteinyl leukotrienes receptor inhibitor--montelukast, given at a dose of 0.125 microg per 100 mg of body weight per day during 16 weeks, could also attenuate atherogenesis. In apoE/LDLR-DKO mouse model montelukast significantly decreased atherogenesis, measured both by "en face" method (25.5+/-2.% vs. 17.23 +/- 1.8%) and "cross-section" method (455,494 +/- 26,477 microm(2) vs. 299,201 +/- 20,373 microm(2)). The results were, however, less pronounced, comparing to FLAP inhibitors. This is the first report showing the effect of montelukast on atherogenesis in gene-targeted mice.

Topics: Acetates; Animals; Aorta; Apolipoproteins E; Atherosclerosis; Cholesterol; Cyclopropanes; Female; Leukotriene Antagonists; Lipids; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardium; Quinolines; Receptors, LDL; Sulfides; Triglycerides