Chronic doxycycline exposure accelerates left ventricular hypertrophy and progression to heart failure in mice after thoracic aorta constriction

1 Institut National de la Santé et de la Recherche Médicale (INSERM) U698, F-75018, 2 Centre d'Explorations Fonctionnelles Intégré-Institut Fédératif de Recherche 02, F-75018, 3 INSERM U689, F-75010, 4 Université Paris Diderot, and 5 Assistance Publique, Hôpitaux de Paris, Paris, France Submitt...

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Published in:American journal of physiology. Heart and circulatory physiology 2008-07, Vol.295 (1), p.H352-H360
Main Authors: Vinet, Laurent, Rouet-Benzineb, Patricia, Marniquet, Xavier, Pellegrin, Noemie, Mangin, Laurence, Louedec, Liliane, Samuel, Jane-Lise, Mercadier, Jean-Jacques
Format: Article
Language:English
Subjects:
Animals
Aorta, Thoracic - surgery
Calcium-Binding Proteins - metabolism
Constriction
Disease Models, Animal
Disease Progression
Doxycycline - toxicity
Fibrosis
Heart
Heart failure
Heart Failure - diagnostic imaging
Heart Failure - enzymology
Heart Failure - etiology
Heart Failure - physiopathology
Hemodynamics - drug effects
Hypertrophy, Left Ventricular - chemically induced
Hypertrophy, Left Ventricular - diagnostic imaging
Hypertrophy, Left Ventricular - enzymology
Hypertrophy, Left Ventricular - physiopathology
Matrix Metalloproteinase 2 - metabolism
Matrix Metalloproteinase 9 - metabolism
Matrix Metalloproteinase Inhibitors
Mice
Myocardium - enzymology
Myocardium - pathology
Myosin Heavy Chains - genetics
Myosin Heavy Chains - metabolism
Natriuretic Peptide, Brain - genetics
Natriuretic Peptide, Brain - metabolism
Peptides
Polymerase Chain Reaction
Protease Inhibitors - toxicity
Ribonucleic acid
RNA
Rodents
Ryanodine Receptor Calcium Release Channel - metabolism
Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism
Time Factors
Tissues
Ultrasonography
Ventricular Remodeling - drug effects
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Summary:1 Institut National de la Santé et de la Recherche Médicale (INSERM) U698, F-75018, 2 Centre d'Explorations Fonctionnelles Intégré-Institut Fédératif de Recherche 02, F-75018, 3 INSERM U689, F-75010, 4 Université Paris Diderot, and 5 Assistance Publique, Hôpitaux de Paris, Paris, France Submitted 21 September 2007 ; accepted in final form 6 May 2008 Tetracycline is a powerful tool for controlling the expression of specific transgenes (TGs) in various tissues, including heart. In these mouse systems, TG expression is repressed/enhanced by adding doxycycline (Dox) to the diet. However, Dox has been shown to attenuate matrix metalloproteinase (MMP) expression and activity in various tissues, and MMP inactivation mitigates left ventricular (LV) remodeling in animal models of heart failure. Therefore, we examined the influence of Dox on LV remodeling and MMP expression in mice after transverse aortic constriction (TAC). One month after TAC, cardiac hypertrophy (99% vs. 67%) and the proportion of mice exhibiting congestive heart failure (CHF, 74% vs. 32%) were higher in the TAC + Dox group than in the TAC group ( P < 0.05). These differences were no longer seen 2 mo after TAC, although LV was more severely dilated in TAC + Dox mice than in TAC mice ( P < 0.05). One month after TAC, the increase in brain natriuretic peptide and β-myosin heavy chain mRNA levels was 1.6 and 1.7 times higher, respectively, in TAC + Dox mice than in TAC mice ( P < 0.01). MMP-2 gelatin zymographic activity increased 1.9- and 2.4-fold in TAC and TAC + Dox mice, respectively ( P < 0.01 and P < 0.05 relative to respective sham-operated animals), but the difference between TAC + Dox and TAC mice did not reach statistical significance. Dox did not significantly alter TAC-associated perivascular and interstitial myocardial fibrosis. These findings demonstrate that Dox accelerates the onset of cardiac hypertrophy and the progression to CHF following TAC in mice. Accordingly, care should be taken when designing and interpreting studies based on TG mouse models of LV hypertrophy using the tetracycline-regulated (tet)-on/tet-off system. pressure overload; matrix metalloproteinase; heart catheterization; echocardiography Address for reprint requests and other correspondence: L. Vinet, INSERM U698, G. H. Bichat-Claude Bernard, 46 rue Henri Huchard, 75877 Paris Cedex 18, France (e-mail: laurent.vinet{at}inserm.fr )
ISSN:0363-6135
1522-1539
DOI:10.1152/ajpheart.01101.2007