title: Lercanidipine and labedipinedilol--A attenuate lipopolysaccharide/interferon-γ-induced inflammation in rat vascular smooth muscle cells through inhibition of HMGB1 release and MMP-2, 9 activities.
abstract: OBJECTIVE
  Inflammation is an important molecular basis of atherosclerosis. Recent studies have shown that dihydropyridine calcium channel blockers (CCBs) can exert potent anti-inflammatory effects in models of vascular dysfunction. The purpose of the present study was to evaluate anti-inflammatory effects and mechanisms of lercanidipine and labedipinedilol-A, new generation dihydropyridine CCBs, in rat vascular smooth muscle cells (VSMCs) exposed to lipopolysaccharide (LPS) and interferon-γ (IFN-γ).
  
  
  RESULTS
  MTT, Griess reagent, RT-PCR, ELISA, gelatin zymography, immunocytochemistry and Western blotting were employed. We found that lercanidipine and labedipinedilol-A attenuated production of NO, ROS and TNF-α from LPS/IFN-γ-stimulated VSMCs. In addition, they both diminished the LPS/IFN-γ-induced expression of iNOS protein and mRNA, with attenuation of HMGB1 cytosolic translocation and subsequent extracellular release. Furthermore, they down-regulated MMP-2/MMP-9 activities, whereas expression of tissue inhibitor of matrix metalloproteinase-1 (TIMP-1), an inhibitor of MMP-9, was up-regulated. Finally, we found that lercanidipine and labedipinedilol-A inhibited the nuclear translocation of NF-κB and suppressed the phosphorylation of JNK, p38 MAPK and Akt.
  
  
  CONCLUSIONS
  Lercanidipine and labedipinedilol-A can exert their anti-inflammatory effects through suppression of NO, ROS and TNF-α through down-regulation of iNOS, MMP-2/MMP-9, and HMGB1, with inhibition of signaling transduction of MAPKs, Akt/IkB-α and NF-κB pathways. These findings implicate a valuable role of new generation dihydropyridine CCBs lercanidipine and labedipinedilol-A for the treatment of inflammatory vascular diseases.
authors.affiliation: Department and Graduate Institute of Pharmacology, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Jwu-Lai
authors.initials: JL
authors.lastname: Yeh
authors.forename: Jong-Hau
authors.initials: JH
authors.lastname: Hsu
authors.forename: Jyh-Chong
authors.initials: JC
authors.lastname: Liang
authors.forename: Ing-Jun
authors.initials: IJ
authors.lastname: Chen
authors.forename: Shu-Fen
authors.initials: SF
authors.lastname: Liou
mesh_terms: D000818:Animals; D000840:Anisoles / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D004095:Dihydropyridines / Q000494:pharmacology*; D024243:HMGB1 Protein / Q000378:metabolism*; D007249:Inflammation / Q000139:chemically induced / Q000188:drug therapy*; D007371:Interferon-gamma; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis*; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D051381:Rats; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000096:biosynthesis
chemical_list: D000840:Anisoles; D000893:Anti-Inflammatory Agents; D004095:Dihydropyridines; D024243:HMGB1 Protein; D008070:Lipopolysaccharides; D019715:Tissue Inhibitor of Metalloproteinase-1; C500368:labedipinedilol A; D007371:Interferon-gamma; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; C060343:lercanidipine