Abstract 129: Inhibition of MEF2 By Atenolol Modifies the Transcriptome During Cardiac Hypertrophy to Improve Heart Function
Cardiac hypertrophy is a growth response of the adult heart that often results from increased mechanical loading due to high blood pressure and myocardial damage caused by ischemic heart disease. The β1 selective β-adrenergic antagonist, atenolol, is historically one of the most frequently prescribed of all medicines used to preserve heart function following myocardial damage. Transcription factor, myocyte enhancer factor 2 (MEF2), is required for early cardiac development and has also been implicated in cardiac hypertrophy. The effect of β-blockade on the gene program that is activated following cardiac hypertrophy as heart failure progresses is not fully understood. Here we show that treatment with atenolol leads to in vivo changes within the murine heart to reverse cardiac hypertrophy, and this is accompanied by repression of MEF2 activity.
Cardiac hypertrophy was simulated using transverse aortic constriction (TAC) for four weeks in a transgenic MEF2-lacZ mouse model, followed by six weeks of vehicle (AT-) or atenolol treatment (AT+). Physiological responses in cardiac function, fibrosis, and cardiomyocyte size in TAC+AT+ mice were consistent with cardiac hypertrophy and demonstrated increased MEF2 activity compared to control (TAC-AT-). Atenolol treatment resulted in an overall improvement in cardiac function of TAC+ mice, showing a decrease in cardiomyocyte size, fibrosis and MEF2 activity. RNA was isolated from the left ventricle of the heart to determine changes in mRNA and lncRNA using RNA-seq. Atenolol reversed the expression of a specific subset of genes and lncRNA that become upregulated by TAC which corresponded to gene ontology terms related to metabolism and the immune system.
Together, these data demonstrate that atenolol treatment during cardiac hypertrophy inhibits MEF2 activity and concomitantly leads to improved cardiac function. Thus, inhibition of MEF2 may be necessary to improve or reverse the effects of long-term heart failure.
Author Disclosures: S. Wales: None. S. Hashemi: None. K. Dadson: None. S. Tuerdi: None. J. Zhao: None. G. Sweeney: None. J. Grigull: None. J.C. McDermott: None.
- © 2015 by American Heart Association, Inc.