Effects of methylglyoxal on human cardiac fibroblast: roles of transient receptor potential ankyrin 1 (TRPA1) channels

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 307; no. 9; pp. H1339 - H1352
• Main Authors: Oguri, Gaku, Nakajima, Toshiaki, Yamamoto, Yumiko, Takano, Nami, Tanaka, Tomofumi, Kikuchi, Hironobu, Morita, Toshihiro, Nakamura, Fumitaka, Yamasoba, Tatsuya, Komuro, Issei
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.11.2014
• Subjects: Acetanilides - pharmacology; Allyl Compounds - pharmacology; Calcium - metabolism; Calcium Channel Blockers - pharmacology; Calcium Channels - genetics; Calcium Channels - metabolism; Calcium Signaling; Cardiomyopathy; Cell Cycle; Cell Line; Fibroblasts - drug effects; Fibroblasts - metabolism; Fluorescence; Guanidines - pharmacology; Heart Ventricles - cytology; Humans; Isocyanates - pharmacology; Nerve Tissue Proteins - agonists; Nerve Tissue Proteins - antagonists & inhibitors; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Pathogenesis; Proteins; Purines - pharmacology; Pyruvaldehyde - pharmacology; Ribonucleic acid; RNA; RNA, Messenger - genetics; RNA, Messenger - metabolism; Ruthenium Red - pharmacology; Smooth muscle; Transient Receptor Potential Channels - agonists; Transient Receptor Potential Channels - antagonists & inhibitors; Transient Receptor Potential Channels - genetics; Transient Receptor Potential Channels - metabolism; TRPA1 Cation Channel; human cardiac fibroblast; methylglyoxal; transient receptor potential ankyrin 1 channels
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.01021.2013

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.