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Updated: May 3, 2026
Isolation, Culture, and Functional Characterization of Adult Mouse Cardiomyoctyes
Published on: September 24, 2013
Combined TRPC3 and TRPC6 blockade by selective small-molecule or genetic deletion inhibits pathological cardiac
Kinya Seo1, Peter P Rainer, Virginia Shalkey Hahn
1Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21205.
Insights
Dual inhibition of TRPC3 and TRPC6 channels shows promise for treating heart disease. Combined genetic deletion protected against pressure overload, suggesting therapeutic potential for dual TRPC3/6 antagonists.
Area of Science:
- Cardiovascular Biology
- Ion Channel Physiology
- Pharmacology
Background:
- Chronic stress in heart disease involves neurohormonal and mechanical factors.
- Transient receptor potential canonical (TRPC) channels TRPC3 and TRPC6 are implicated in heart pathophysiology.
- Increased TRPC3/TRPC6 expression correlates with cardiac hypertrophy and dysfunction.
Purpose of the Study:
- To investigate the therapeutic potential of dual TRPC3/6 inhibition for heart disease.
- To evaluate selective TRPC3/6 antagonists (GSK2332255B and GSK2833503A) in cellular and in vivo models.
- To assess the impact of combined TRPC3 and TRPC6 genetic deletion on cardiac function.
Main Methods:
- Tested selective TRPC3/6 antagonists (GSK2332255B, GSK2833503A) in HEK293T cells, neonatal and adult cardiac myocytes.
- Administered antagonists to mice and rats subjected to pressure overload.
- Utilized gene deletion models for TRPC3 and TRPC6, both individually and in combination.
Main Results:
- Antagonists dose-dependently blocked angiotensin II- or endothelin-1-triggered hypertrophy signaling in cardiac cells.
- In vivo efficacy was limited by rapid metabolism and high protein binding, but antifibrotic effects were observed.
- Combined TRPC3/TRPC6 gene deletion, but not single deletion, protected against pressure overload-induced hypertrophy and dysfunction.
Conclusions:
- Dual inhibition of TRPC3 and TRPC6 channels is a viable strategy for managing heart disease.
- Selective TRPC3/6 antagonists demonstrated cellular efficacy but faced pharmacokinetic challenges in vivo.
- Combined genetic deletion supports the therapeutic value of targeting both TRPC3 and TRPC6 channels concurrently.
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 as well 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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