RT Journal Article
SR Electronic
T1 Calcium Channel Blockers Act Through Nuclear Factor Y to Control Transcription of Key Cardiac Genes
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.112.078253
DO 10.1124/mol.112.078253
A1 Hyunjoo Cha-Molstad
A1 Guanlan Xu
A1 Junqin Chen
A1 Gu Jing
A1 Martin E Young
A1 John C Chatham
A1 Anath Shalev
YR 2012
UL http://molpharm.aspetjournals.org/content/early/2012/06/25/mol.112.078253.abstract
AB First generation calcium channel blockers such as verapamil are a widely used class of anti-hypertensive drugs that block L-type calcium channels. Surprisingly, we recently discovered that they also reduce cardiac expression of pro-apoptotic thioredoxin-interacting protein (TXNIP) suggesting that they may have unappreciated transcriptional effects. Using 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/knock-down, luciferase and chromatin immunoprecipitation (ChIP) 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. Interestingly, the transcriptional control conferred by this newly-identified verapamil-calcineurin-NFY signaling cascade was not limited to TXNIP, suggesting 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.