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CARDIOVASCULAR

Doxycycline Attenuates Isoproterenol- and Transverse Aortic Banding-Induced Cardiac Hypertrophy in Mice

Departments of Human Growth and Development (M.E., C.L.G., H.R.G.), Infectious Diseases (A.T.T.), Cardio-Thoracic Surgery (J.M.D.), and Internal Medicine (J.A.H.), University of Texas Southwestern Medical Center, Dallas, Texas

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.

Address correspondence to: Dr. Mounir Errami, Division of Translational Research, University of Texas Southwestern Medical Center, 2201 Inwood Rd., Dallas, TX 75390-9185. E-mail: mounir.errami{at}utsouthwestern.edu