Carbamazepine alone and in combination with doxycycline attenuates isoproterenol-induced cardiac hypertrophy
Abstract
Overview
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.
Keywords
Cardiac hypertrophy, gene expression, drug repurposing, FDA approved.
Article Information
Correspondence
Mounir Errami, Division of Translational Research, University of Texas Southwestern Medical Center, 2201 Inwood Road, Dallas, Texas 75390-9185, USA. E-mail: merrami@collin.edu
Acknowledgements
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).
Received
2010-05-15T00:00:00
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