Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 4, Pages 1551-1556Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1308963111
Keywords
ion channels; calcium; nuclear factor of activated T cells; myocardial; Gq-coupled protein receptors
Categories
Funding
- GlaxoSmithKline
- American Heart Association
- Sarnoff Cardiovascular Research Foundation
- Austrian Academy of Sciences
- National Research Foundation of Korea [2011-0013171]
- Danish Council for Independent Research [11-108410]
- National Institutes of Health [Z01-ES-101864, HL089297, HL059408]
- Muscular Dystrophy Association [186454]
- Abraham and Virginia Weiss Professorship
- Peter Belfer Endowment
- National Research Foundation of Korea [2011-0013171] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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Chronic neurohormonal and mechanical stresses are central features of heart disease. Increasing evidence supports a role for the transient receptor potential canonical channels TRPC3 and TRPC6 in this pathophysiology. Channel expression for both is normally very low but is increased by cardiac disease, and genetic gain-or loss-of-function studies support contributions to hypertrophy and dysfunction. Selective small-molecule inhibitors remain scarce, and none target both channels, which may be useful given the high homology among them and evidence of redundant signaling. Here we tested selective TRPC3/6 antagonists (GSK2332255B and GSK2833503A; IC50, 3-21 nM against TRPC3 and TRPC6) and found dose-dependent blockade of cell hypertrophy signaling triggered by angiotensin II or endothelin-1 in HEK293T cells aswell as in neonatal and adult cardiac myocytes. In vivo efficacy in mice and rats was greatly limited by rapid metabolism and high protein binding, although antifibrotic effects with pressure overload were observed. Intriguingly, although gene deletion of TRPC3 or TRPC6 alone did not protect against hypertrophy or dysfunction from pressure overload, combined deletion was protective, supporting the value of dual inhibition. Further development of this pharmaceutical class may yield a useful therapeutic agent for heart disease management.
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