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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Willette, Robert N. Lepore, John J. Rainer, Peter P. Lee, Dong-ik Andersen, Asger Schnackenberg, Christine G. Birnbaumer, Lutz Marino, Joseph P. Jo, Su-hyun Xu, Xiaoping Shalkey Hahn, Virginia Seo, Kinya Kass, David A. Liu, Ting |
| Description | Author Affiliation: Seo K ( Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions, Baltimore, MD 21205.); |
| 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. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 4 |
| Volume Number | 111 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2014-01-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Cardiomegaly Genetics TRPC Cation Channels Antagonists & Inhibitors Animals HEK293 Cells Mice Mice, Inbred C57BL Mice, Knockout Phosphorylation Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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