title: Upregulation of TRPC1 in the development of cardiac hypertrophy.
abstract: The importance of Ca(2+) entry in the cardiac hypertrophic response is well documented, but the actual Ca(2+) entry channels remain unknown. Transient receptor potential (TRP) proteins are thought to form either homo- or heteromeric Ca(2+) entry channels that are involved in the proliferation and differentiation of various cells. The purpose of this study was to explore the potential involvement of TRP channels in the development of cardiac hypertrophy. The mRNA and protein expression of several TRP channel subunits were evaluated using hearts from abdominal aortic-banded (AAB) rats. Although TRPs C1, C3, C5, and C6 were constitutively expressed, only TRPC1 expression was significantly increased in the hearts of AAB rats compared to sham-operated rats. Using primary cultures of neonatal rat cardiomyocytes, we detected increases in the expression of TRPC1, brain natriuretic peptide (BNP), and atrial natriuretic factor (ANF), as well as increases in store-operated Ca(2+) entry (SOCE) and cell surface area, following endothelin-1 (ET-1) treatment. Silencing of the TRPC1 gene via small interfering RNA (siRNA) attenuated SOCE and prevented ET-1-, angiotensin-II (AT II)-, and phenylephrine (PE)-induced cardiac hypertrophy. In HEK 293T cells, overexpression of TRPC1 augmented SOCE, leading to an increase in nuclear factor of activated T cells (NFAT) promoter activity, while co-transfection with dominant-negative forms of TRPC1 suppressed it. In conclusion, TRPC1 functions in Ca(2+) influx, and its upregulation is involved in the development of cardiac hypertrophy; moreover, it plays an important role in the regulation of the signaling pathways that govern cardiac hypertrophy. These findings establish TRPC1 as a functionally important regulator of cardiac hypertrophy.
authors.affiliation: Second Department of Internal Medicine, Akita University School of Medicine, Hondoh, Akita, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Ohba
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Watanabe
authors.forename: Manabu
authors.initials: M
authors.lastname: Murakami
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Kenji
authors.initials: K
authors.lastname: Iino
authors.forename: Sadao
authors.initials: S
authors.lastname: Kuromitsu
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Mori
authors.forename: Kyoichi
authors.initials: K
authors.lastname: Ono
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Iijima
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ito
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002460:Cell Line; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000494:pharmacology; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D050052:TRPC Cation Channels / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D019332:Endothelin-1; D034741:RNA, Small Interfering; D050052:TRPC Cation Channels; C096351:transient receptor potential cation channel, subfamily C, member 1; D002118:Calcium