Doxycycline attenuates isoproterenol- and transverse aortic banding-induced cardiac hypertrophy in mice.
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 beta-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.
Errami
Mounir
M
Division of Translational Research, University of Texas Southwestern Medical Center, 2201 Inwood Rd., Dallas, TX 75390-9185, USA. mounir.errami@utsouthwestern.edu
Galindo
Cristi L
CL
Tassa
Amina T
AT
Dimaio
John M
JM
Hill
Joseph A
JA
Garner
Harold R
HR
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000473:pathology*; D006332:Cardiomegaly / Q000139:chemically induced* / Q000517:prevention & control*; D004195:Disease Models, Animal; D004318:Doxycycline / Q000494:pharmacology / Q000627:therapeutic use*; D007545:Isoproterenol / Q000633:toxicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
D007545:Isoproterenol; D004318:Doxycycline