Combined TRPC3 and TRPC6 blockade by selective small-molecule or genetic deletion inhibits pathological cardiac hypertrophy

Kinya Seo, Peter P. Rainer, Virginia Shalkey Hahn, Dong Lee, Su Hyun Jo, Asger Andersen, Ting Liu, Xiaoping Xu, Robert N. Willette, John J. Lepore, Joseph P. Marino, Lutz Birnbaumer, Christine G. Schnackenberg, David A Kass

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1551-1556
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number4
DOIs
StatePublished - Jan 28 2014

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Cardiomegaly
Hypertrophy
Heart Diseases
Transient Receptor Potential Channels
Pressure
Mechanical Stress
Gene Deletion
Endothelin-1
Disease Management
Cardiac Myocytes
Protein Binding
Angiotensin II
Inhibitory Concentration 50
Pharmaceutical Preparations
Therapeutics

Keywords

  • Calcium
  • Gq-coupled protein receptors
  • Ion channels
  • Myocardial
  • Nuclear factor of activated T cells

ASJC Scopus subject areas

  • General

Cite this

Combined TRPC3 and TRPC6 blockade by selective small-molecule or genetic deletion inhibits pathological cardiac hypertrophy. / Seo, Kinya; Rainer, Peter P.; Hahn, Virginia Shalkey; Lee, Dong; Jo, Su Hyun; Andersen, Asger; Liu, Ting; Xu, Xiaoping; Willette, Robert N.; Lepore, John J.; Marino, Joseph P.; Birnbaumer, Lutz; Schnackenberg, Christine G.; Kass, David A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 4, 28.01.2014, p. 1551-1556.

Research output: Contribution to journalArticle

Seo, Kinya ; Rainer, Peter P. ; Hahn, Virginia Shalkey ; Lee, Dong ; Jo, Su Hyun ; Andersen, Asger ; Liu, Ting ; Xu, Xiaoping ; Willette, Robert N. ; Lepore, John J. ; Marino, Joseph P. ; Birnbaumer, Lutz ; Schnackenberg, Christine G. ; Kass, David A. / Combined TRPC3 and TRPC6 blockade by selective small-molecule or genetic deletion inhibits pathological cardiac hypertrophy. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 4. pp. 1551-1556.
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