title: Effects of methylglyoxal on human cardiac fibroblast: roles of transient receptor potential ankyrin 1 (TRPA1) channels.
abstract: Cardiac fibroblasts contribute to the pathogenesis of cardiac remodeling. Methylglyoxal (MG) is an endogenous carbonyl compound produced under hyperglycemic conditions, which may play a role in the development of pathophysiological conditions including diabetic cardiomyopathy. However, the mechanism by which this occurs and the molecular targets of MG are unclear. We investigated the effects of MG on Ca(2+) signals, its underlying mechanism, and cell cycle progression/cell differentiation in human cardiac fibroblasts. The conventional and quantitative real-time RT-PCR, Western blot, immunocytochemical analysis, and intracellular Ca(2+) concentration [Ca(2+)]i measurement were applied. Cell cycle progression was assessed using the fluorescence activated cell sorting. MG induced Ca(2+) entry concentration dependently. Ruthenium red (RR), a general cation channel blocker, and HC030031, a selective transient receptor potential ankyrin 1 (TRPA1) antagonist, inhibited MG-induced Ca(2+) entry. Treatment with aminoguanidine, a MG scavenger, also inhibited it. Allyl isothiocyanate, a selective TRPA1 agonist, increased Ca(2+) entry. The use of small interfering RNA to knock down TRPA1 reduced the MG-induced Ca(2+) entry as well as TRPA1 mRNA expression. The quantitative real-time RT-PCR analysis showed the prominent existence of TRPA1 mRNA. Expression of TRPA1 protein was confirmed by Western blotting and immunocytochemical analyses. MG promoted cell cycle progression from G0/G1 to S/G2/M, which was suppressed by HC030031 or RR. MG also enhanced α-smooth muscle actin expression. The present results suggest that methylglyoxal activates TRPA1 and promotes cell cycle progression and differentiation in human cardiac fibroblasts. MG might participate the development of pathophysiological conditions including diabetic cardiomyopathy via activation of TRPA1.
authors.affiliation: Department of Cardiovascular Medicine, University of Tokyo, Tokyo, Japan;
authors.forename: Gaku
authors.initials: G
authors.lastname: Oguri
authors.affiliation: Department of Ischemic Circulatory Physiology, University of Tokyo, Tokyo, Japan; nakajima-2im@h.u-tokyo.ac.jp.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Nakajima
authors.affiliation: Department of Cardiovascular Medicine, University of Tokyo, Tokyo, Japan;
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Department of Cardiovascular Medicine, University of Tokyo, Tokyo, Japan;
authors.forename: Nami
authors.initials: N
authors.lastname: Takano
authors.affiliation: Department of Cardiovascular Medicine, University of Tokyo, Tokyo, Japan;
authors.forename: Tomofumi
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Department of Cardiovascular Medicine, University of Tokyo, Tokyo, Japan;
authors.forename: Hironobu
authors.initials: H
authors.lastname: Kikuchi
authors.affiliation: Department of Ischemic Circulatory Physiology, University of Tokyo, Tokyo, Japan;
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Morita
authors.affiliation: Teikyo University Chiba Medical Center, Ichihara, Chiba, Japan.
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Nakamura
authors.affiliation: Department of Otolaryngology, University of Tokyo, Tokyo, Japan; and.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Yamasoba
authors.affiliation: Department of Cardiovascular Medicine, University of Tokyo, Tokyo, Japan;
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
mesh_terms: D000083:Acetanilides / Q000494:pharmacology; D000498:Allyl Compounds / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000235:genetics / Q000378:metabolism*; D020013:Calcium Signaling; D002453:Cell Cycle; D002460:Cell Line; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D006146:Guanidines / Q000494:pharmacology; D006352:Heart Ventricles / Q000166:cytology; D006801:Humans; D017953:Isocyanates / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011687:Purines / Q000494:pharmacology; D011765:Pyruvaldehyde / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012430:Ruthenium Red / Q000494:pharmacology; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: C552888:2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopropylphenyl)acetamide; D000083:Acetanilides; D000498:Allyl Compounds; D002121:Calcium Channel Blockers; D015220:Calcium Channels; D006146:Guanidines; D017953:Isocyanates; D009419:Nerve Tissue Proteins; D011687:Purines; D012333:RNA, Messenger; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D050051:Transient Receptor Potential Channels; C491149:allyl isocyanate; D012430:Ruthenium Red; D011765:Pyruvaldehyde; C004479:pimagedine; D002118:Calcium
keywords: human cardiac fibroblast; methylglyoxal; transient receptor potential ankyrin 1 channels