β-adrenergic signaling is involved in the development of cardiac hypertrophy (CH), justifying the use of β-blockers as a therapy to minimize and postpone the consequences of this disease. Evidence suggests that adenylate cyclase, a downstream effector of the β-adrenergic pathway, might be a therapeutic target. We examined the effects of the anti-epileptic drug carbamazepine (CBZ), an inhibitor of adenylate cyclase. In a murine cardiac hypertrophy model, carbamazepine significantly attenuates isoproteronol (ISO)-induced cardiac hypertrophy. Carbamazepine also has an effect in transverse aortic banding induced cardiac hypertrophy (TAB) (P=0.07). When carbamazepine was given in combination with the antibiotic doxycycline (DOX), which inhibits matrix metalloproteinases (MMPs), therapeutic outcome measured by heart weight-to-body weight and heart weight-to-tibia length ratios was improved compared to either drug alone. Additionally, the combination therapy resulted in an increase in the survival rate over a 56-day period compared to that of untreated mice with cardiac hypertrophy or either drug used alone. Moreover, in support of a role for carbamaze - pine as a β-adrenergic antagonist via cAMP inhibition, a lower heart rate and a lower level of the activated phosphorylated form of the cAMP Response Element-Binding (CREB) were observed in heart extracts from mice treated with carbamazepine. Gene expression analysis identified 19 genes whose expression is significantly altered in treated animals and might be responsible for the added benefit provided by the combination therapy. These results suggest that carbamazepine acts as a β-adrenergic antagonist. Carbamazepine and doxycycline are approved by the US Food and Drug Administration (FDA) as drugs that might complement medications for cardiac hypertrophy or serve as an alternative therapy to traditional β- blockers. Furthermore, these agents reproducibly impact the expression of genes that may serve as additional therapeutic targets in the management of cardiac hypertrophy.
Cardiac hypertrophy, gene expression, drug repurposing, FDA approved.
Mounir Errami, Division of Translational Research, University of Texas Southwestern Medical Center, 2201 Inwood Road, Dallas, Texas 75390-9185, USA. E-mail: firstname.lastname@example.org
The authors wish to thank
Angela George, Robin Frink, Charles German and
Joe Steninger for excellent technical help, Dr
Wayne Fisher for discussions and comments and
Linda Gunn for administrative assistance. This
work was supported by the P.O’B. Montgomery
Distinguished Chair (HG), the Hudson
Foundation (HG) and National Institute of Health
cardiology fellowship (CLG).
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