Doxycycline attenuates isoproterenol- and transverse aortic banding-induced cardiac hypertrophy in mice

Mounir Errami, Cristi L. Galindo, Amina T. Tassa, John M. DiMaio, Joseph A Hill, Harold R. Garner

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1196-1203
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume324
Issue number3
DOIs
StatePublished - Mar 2008

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Doxycycline
Cardiomegaly
Isoproterenol
Metalloproteases
Activating Transcription Factor 2
Phenotype
Adrenergic Agonists
Sphingolipids
Extracellular Signal-Regulated MAP Kinases
United States Food and Drug Administration
G-Protein-Coupled Receptors
Cytoskeleton
Reverse Transcriptase Polymerase Chain Reaction
Transcriptome
Genes
Extracellular Matrix
Real-Time Polymerase Chain Reaction
Signal Transduction
Transcription Factors
Up-Regulation

ASJC Scopus subject areas

  • Pharmacology

Cite this

Doxycycline attenuates isoproterenol- and transverse aortic banding-induced cardiac hypertrophy in mice. / Errami, Mounir; Galindo, Cristi L.; Tassa, Amina T.; DiMaio, John M.; Hill, Joseph A; Garner, Harold R.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 324, No. 3, 03.2008, p. 1196-1203.

Research output: Contribution to journalArticle

Errami, Mounir ; Galindo, Cristi L. ; Tassa, Amina T. ; DiMaio, John M. ; Hill, Joseph A ; Garner, Harold R. / Doxycycline attenuates isoproterenol- and transverse aortic banding-induced cardiac hypertrophy in mice. In: Journal of Pharmacology and Experimental Therapeutics. 2008 ; Vol. 324, No. 3. pp. 1196-1203.
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