Abstract
Leukotriene B4 (LTB4)-mediated leukocyte recruitment and inflammatory cytokine production make crucial contributions to chronic inflammation and sepsis; however, the role of LTB4 in lipopolysaccharide (LPS)-induced cardiac dysfunction remains unclear. Therefore, the present study addressed this issue using an LTB4 receptor 1 (BLT1) inhibitor. Administration of LPS to mice resulted in decreased cardiovascular function. Inhibition of LTB4/BLT1 with the BLT1 inhibitor U75302 significantly improved survival and attenuated the LPS-induced acute cardiac dysfunction. During LPS challenge, the phosphorylated AMPK/ACC signaling pathway was slightly activated, and this effect was enhanced by U75302. Additionally, pNF-κB, Bax and cleaved caspase-3 were upregulated by LPS, and Bcl-2, IκB-α, mitochondrial complex I, complex II, and OPA1 were downregulated; however, these effects were reversed by U75302. The results indicated that the BLT1 antagonist suppressed cardiac apoptosis, inflammation, and mitochondrial impairment. Furthermore, the protection provided by the BLT1 inhibitor against LPS-induced cardiac dysfunction was significantly reversed by the AMPK inhibitor Compound C. In conclusion, inhibiting the LTB4/BLT1 signaling pathway via AMPK activation is a potential treatment strategy for septic cardiac dysfunction because it efficiently attenuates cardiac apoptosis, which may occur via the inhibition of inflammation and mitochondrial dysfunction.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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AMP-Activated Protein Kinases / antagonists & inhibitors
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AMP-Activated Protein Kinases / genetics*
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AMP-Activated Protein Kinases / metabolism
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Acetyl-CoA Carboxylase / genetics
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Acetyl-CoA Carboxylase / metabolism
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Animals
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Anti-Inflammatory Agents / pharmacology*
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Cardiomyopathies / chemically induced
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Cardiomyopathies / drug therapy*
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Cardiomyopathies / genetics
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Cardiomyopathies / pathology
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Cardiotonic Agents / pharmacology*
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Caspase 3 / genetics
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Caspase 3 / metabolism
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Fatty Alcohols / pharmacology*
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Gene Expression Regulation
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Glycols / pharmacology*
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I-kappa B Proteins / genetics
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I-kappa B Proteins / metabolism
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Inflammation
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Leukotriene B4 / metabolism*
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Lipopolysaccharides / pharmacology
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Male
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Mice
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Mice, Inbred C57BL
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Mitochondria / drug effects
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Mitochondria / metabolism
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Mitochondria / pathology
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NF-kappa B / genetics
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NF-kappa B / metabolism
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Oxazines / pharmacology
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Receptors, Leukotriene B4 / antagonists & inhibitors
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Receptors, Leukotriene B4 / genetics*
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Receptors, Leukotriene B4 / metabolism
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Signal Transduction
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Survival Analysis
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bcl-2-Associated X Protein / genetics
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bcl-2-Associated X Protein / metabolism
Substances
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Anti-Inflammatory Agents
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Bax protein, mouse
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Cardiotonic Agents
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Fatty Alcohols
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Glycols
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I-kappa B Proteins
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Lipopolysaccharides
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Ltb4r1 protein, mouse
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NF-kappa B
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Oxazines
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Proto-Oncogene Proteins c-bcl-2
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Receptors, Leukotriene B4
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bcl-2-Associated X Protein
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Bcl2 protein, mouse
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U 75302
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Leukotriene B4
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oxadin
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AMP-Activated Protein Kinases
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Casp3 protein, mouse
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Caspase 3
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Acetyl-CoA Carboxylase