Transient receptor potential canonical-3 channel-dependent fibroblast regulation in atrial fibrillation

Masahide Harada, Xiaobin Luo, Xiao Yan Qi, Artavazd Tadevosyan, Ange Maguy, Balazs Ordog, Jonathan Ledoux, Takeshi Kato, Patrice Naud, Niels Voigt, Yanfen Shi, Kaichiro Kamiya, Toyoaki Murohara, Itsuo Kodama, Jean Claude Tardif, Ulrich Schotten, David R. Van Wagoner, Dobromir Dobrev, Stanley Nattel

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142 Citations (Scopus)

Abstract

BACKGROUND-: Fibroblast proliferation and differentiation are central in atrial fibrillation (AF)-promoting remodeling. Here, we investigated fibroblast regulation by Ca-permeable transient receptor potential canonical-3 (TRPC3) channels. METHODS AND RESULTS-: Freshly isolated rat cardiac fibroblasts abundantly expressed TRPC3 and had appreciable nonselective cation currents (INSC) sensitive to a selective TPRC3 channel blocker, pyrazole-3 (3 μmol/L). Pyrazole-3 suppressed angiotensin II-induced Ca influx, proliferation, and α-smooth muscle actin protein expression in fibroblasts. Ca removal and TRPC3 blockade suppressed extracellular signal-regulated kinase phosphorylation, and extracellular signal-regulated kinase phosphorylation inhibition reduced fibroblast proliferation. TRPC3 expression was upregulated in atria from AF patients, goats with electrically maintained AF, and dogs with tachypacing-induced heart failure. TRPC3 knockdown (based on short hairpin RNA [shRNA]) decreased canine atrial fibroblast proliferation. In left atrial fibroblasts freshly isolated from dogs kept in AF for 1 week by atrial tachypacing, TRPC3 protein expression, currents, extracellular signal-regulated kinase phosphorylation, and extracellular matrix gene expression were all significantly increased. In cultured left atrial fibroblasts from AF dogs, proliferation rates, α-smooth muscle actin expression, and extracellular signal-regulated kinase phosphorylation were increased and were suppressed by pyrazole-3. MicroRNA-26 was downregulated in canine AF atria; experimental microRNA-26 knockdown reproduced AF-induced TRPC3 upregulation and fibroblast activation. MicroRNA-26 has NFAT (nuclear factor of activated T cells) binding sites in the 5′ promoter region. NFAT activation increased in AF fibroblasts, and NFAT negatively regulated microRNA-26 transcription. In vivo pyrazole-3 administration suppressed AF while decreasing fibroblast proliferation and extracellular matrix gene expression. CONCLUSIONS-: TRPC3 channels regulate cardiac fibroblast proliferation and differentiation, likely by controlling the Ca influx that activates extracellular signal-regulated kinase signaling. AF increases TRPC3 channel expression by causing NFAT-mediated downregulation of microRNA-26 and causes TRPC3-dependent enhancement of fibroblast proliferation and differentiation. In vivo, TRPC3 blockade prevents AF substrate development in a dog model of electrically maintained AF. TRPC3 likely plays an important role in AF by promoting fibroblast pathophysiology and is a novel potential therapeutic target.

Original languageEnglish
Pages (from-to)2051-2064
Number of pages14
JournalCirculation
Volume126
Issue number17
DOIs
Publication statusPublished - 23-10-2012

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Harada, M., Luo, X., Qi, X. Y., Tadevosyan, A., Maguy, A., Ordog, B., Ledoux, J., Kato, T., Naud, P., Voigt, N., Shi, Y., Kamiya, K., Murohara, T., Kodama, I., Tardif, J. C., Schotten, U., Van Wagoner, D. R., Dobrev, D., & Nattel, S. (2012). Transient receptor potential canonical-3 channel-dependent fibroblast regulation in atrial fibrillation. Circulation, 126(17), 2051-2064. https://doi.org/10.1161/CIRCULATIONAHA.112.121830