PT  - JOURNAL ARTICLE
AU  - Mounir Errami
AU  - Cristi L. Galindo
AU  - Amina T. Tassa
AU  - John M. DiMaio
AU  - Joseph A. Hill
AU  - Harold R. Garner
TI  - Doxycycline Attenuates Isoproterenol- and Transverse Aortic Banding-Induced Cardiac Hypertrophy in Mice
AID  - 10.1124/jpet.107.133975
DP  - 2008 Mar 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 1196--1203
VI  - 324
IP  - 3
4099  - http://jpet.aspetjournals.org/content/324/3/1196.short
4100  - http://jpet.aspetjournals.org/content/324/3/1196.full
SO  - J Pharmacol Exp Ther2008 Mar 01; 324
AB  - The United States Food and Drug Administration-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 β-adrenergic agonist isoproterenol (ISO) and induced by transverse aortic banding. DOX significantly attenuated CH in these models, causing a profound reduction of the hypertrophic phenotype and a lower heart/body weight ratio (p < 0.05, n ≥ 6). As expected, ISO increased matrix metalloprotease (MMP) 2 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 were confirmed by real-time reverse transcriptase-polymerase chain reaction. Genes (206) 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 endothelial differentiation sphingolipid G-protein-coupled receptor 1 receptor and activation of extracellular signal-regulated kinase, p38, and the transcription factor activating transcription factor-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. The American Society for Pharmacology and Experimental Therapeutics