Received for publication November 7, 2007.
Revised December 11, 2007.
Accepted for publication December 17, 2007.

DOXYCYCLINE ATTENUATES ISOPROTERENOL- AND TRANSVERSE AORTIC BANDING- INDUCED CARDIAC HYPERTROPHY IN MICE

Abstract

The FDA-approved antibiotic doxycycline (DOX) inhibits matrix metalloproteases, which contribute to the development of cardiac hypertrophy (CH). We hypothesized that DOX might serve as a treatment for CH. The efficacy of DOX was tested in two mouse models of CH: induced by the beta-adrenergic agonist isoproterenol (ISO) and induced by transverse aortic banding (TAB). DOX significantly attenuated CH in these models, causing a profound reduction of the hypertrophic phenotype and a lower heart-to-body weight ratio (p<0.05, n 6). As expected, ISO increased MMP2 and 9 activities, and administration of DOX reversed this effect. Transcriptional profiles of normal, ISO-, and ISO+DOX-treated mice were examined using microarrays and the results confirmed by real-time RT-PCR. 206 genes were differentially expressed between normal and ISO mice that were reversibly altered between ISO- and ISO+DOX-treated mice, indicating their potential role in CH development and DOX-induced improvement. These genes included those involved in the regulation of cell proliferation and fate, stress and immune responses, cytoskeleton and extracellular matrix organization, and cardiac-specific signal transduction. The overall gene expression profile suggested that MMP2/9 inactivation was not the only mechanism whereby DOX exerts its beneficial effects. Western blot analysis identified potential signaling events associated with CH, including up-regulation of EDG1 receptor and activation of ERK, p-38, and the transcription factor ATF-2, which were reduced after administration of DOX. These results suggest that DOX might be evaluated as a potential CH therapeutic and also provide potential signaling mechanisms to investigate in the context of CH phenotype development and regression.

Key words: Antibiotic, Cardiac Diseases, Drug discovery, Drug repurposing, Matrix Metalloproteases, Mouse models