Combined TRPC3 and TRPC6 blockade by selective small-molecule or genetic deletion inhibits pathological cardiac hypertrophy.
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.
Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21205.
Kinya
K
Seo
Peter P
PP
Rainer
Virginia
V
Shalkey Hahn
Dong-Ik
DI
Lee
Su-Hyun
SH
Jo
Asger
A
Andersen
Ting
T
Liu
Xiaoping
X
Xu
Robert N
RN
Willette
John J
JJ
Lepore
Joseph P
JP
Marino
Lutz
L
Birnbaumer
Christine G
CG
Schnackenberg
David A
DA
Kass
D000818:Animals; D006332:Cardiomegaly / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D051381:Rats; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors* / Q000235:genetics; D000074287:TRPC6 Cation Channel
D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; D000074287:TRPC6 Cation Channel; C117032:TRPC6 protein, human
Gq-coupled protein receptors; calcium; ion channels; myocardial; nuclear factor of activated T cells