title: Inhibition of leukotriene B4 receptor 1 attenuates lipopolysaccharide-induced cardiac dysfunction: role of AMPK-regulated mitochondrial function.
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.
authors.affiliation: Department of Cardiology, The First Hospital of Shanxi Medical University, 85 Jiefang South Road, Taiyuan 030001, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Sun
authors.affiliation: Department of Cardiology, The First Hospital of Shanxi Medical University, 85 Jiefang South Road, Taiyuan 030001, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Cardiology, The First Hospital of Shanxi Medical University, 85 Jiefang South Road, Taiyuan 030001, China.
authors.forename: Qinghua
authors.initials: Q
authors.lastname: Han
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000103:Acetyl-CoA Carboxylase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D009202:Cardiomyopathies / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D005233:Fatty Alcohols / Q000494:pharmacology*; D005786:Gene Expression Regulation; D006018:Glycols / Q000494:pharmacology*; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D007249:Inflammation; D007975:Leukotriene B4 / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010078:Oxazines / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D018102:Receptors, Leukotriene B4 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; C494827:Bax protein, mouse; D002316:Cardiotonic Agents; D005233:Fatty Alcohols; D006018:Glycols; D020672:I-kappa B Proteins; D008070:Lipopolysaccharides; C503704:Ltb4r1 protein, mouse; D016328:NF-kappa B; D010078:Oxazines; D019253:Proto-Oncogene Proteins c-bcl-2; D018102:Receptors, Leukotriene B4; D051028:bcl-2-Associated X Protein; C052617:Bcl2 protein, mouse; C062137:U 75302; D007975:Leukotriene B4; C085142:oxadin; D055372:AMP-Activated Protein Kinases; C505409:Casp3 protein, mouse; D053148:Caspase 3; D000103:Acetyl-CoA Carboxylase