Abstract
First-generation calcium channel blockers such as verapamil are a widely used class of antihypertensive drugs that block L-type calcium channels. We recently discovered that they also reduce cardiac expression of proapoptotic thioredoxin-interacting protein (TXNIP), suggesting that they may have unappreciated transcriptional effects. By use of TXNIP promoter deletion and mutation studies, we found that a CCAAT element was mediating verapamil-induced transcriptional repression and identified nuclear factor Y (NFY) to be the responsible transcription factor as assessed by overexpression/knockdown and luciferase and chromatin immunoprecipitation assays in cardiomyocytes and in vivo in diabetic mice receiving oral verapamil. We further discovered that increased NFY-DNA binding was associated with histone H4 deacetylation and transcriptional repression and mediated by inhibition of calcineurin signaling. It is noteworthy that the transcriptional control conferred by this newly identified verapamil-calcineurin-NFY signaling cascade was not limited to TXNIP, suggesting that it may modulate the expression of other NFY targets. Thus, verapamil induces a calcineurin-NFY signaling pathway that controls cardiac gene transcription and apoptosis and thereby may affect cardiac biology in previously unrecognized ways.
Footnotes
↵
The online version of this article (available at http://molpharm.aspetjournals.org) contains supplemental material.
This work was supported in part by the National Institutes of Health National Heart Lung and Blood Institute [Grants R21-HL089205, R21-HL089205-02S1]; the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant R01-DK078752]; the American Diabetes Association [Grant 7-07-CD-22]; and the Juvenile Diabetes Research Foundation/Johnson & Johnson Services Inc. [Grant 40-2011-1].
Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
ABBREVIATIONS:
- TXNIP
- thioredoxin-interacting protein
- NFY
- nuclear factor Y
- CyA
- cyclosporine A
- FK506
- tacrolimus
- STZ
- streptozotocin
- ChIP
- chromatin immunoprecipitation
- RT
- reverse transcriptase
- PCR
- polymerase chain reaction
- si
- small interfering
- TUNEL
- transferase-mediated dUTP nick-end labeling
- NFAT
- nuclear factor of activated T cells
- bp
- base pair(s).
- Received February 8, 2012.
- Accepted June 25, 2012.
- Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|