title: Chronic doxycycline exposure accelerates left ventricular hypertrophy and progression to heart failure in mice after thoracic aorta constriction.
abstract: 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 beta-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.
authors.affiliation: INSERM U698, G. H. Bichat-Claude Bernard, 75877 Paris Cedex 18, France. laurent.vinet@inserm.fr
authors.forename: Laurent
authors.initials: L
authors.lastname: Vinet
authors.forename: Patricia
authors.initials: P
authors.lastname: Rouet-Benzineb
authors.forename: Xavier
authors.initials: X
authors.lastname: Marniquet
authors.forename: Noémie
authors.initials: N
authors.lastname: Pellegrin
authors.forename: Laurence
authors.initials: L
authors.lastname: Mangin
authors.forename: Liliane
authors.initials: L
authors.lastname: Louedec
authors.forename: Jane-Lise
authors.initials: JL
authors.lastname: Samuel
authors.forename: Jean-Jacques
authors.initials: JJ
authors.lastname: Mercadier
mesh_terms: D000818:Animals; D001013:Aorta, Thoracic / Q000601:surgery; D002135:Calcium-Binding Proteins / Q000378:metabolism; D003250:Constriction; D004195:Disease Models, Animal; D018450:Disease Progression; D004318:Doxycycline / Q000633:toxicity*; D005355:Fibrosis; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000201:enzymology / Q000209:etiology* / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D017379:Hypertrophy, Left Ventricular / Q000139:chemically induced* / Q000000981:diagnostic imaging / Q000201:enzymology / Q000503:physiopathology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism; D020097:Natriuretic Peptide, Brain / Q000235:genetics / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011480:Protease Inhibitors / Q000633:toxicity*; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D013997:Time Factors; D014463:Ultrasonography; D020257:Ventricular Remodeling / Q000187:drug effects*; D000099211:Phospholamban
chemical_list: D002135:Calcium-Binding Proteins; D004318:Doxycycline; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D061965:Matrix Metalloproteinase Inhibitors; D018995:Myosin Heavy Chains; D020097:Natriuretic Peptide, Brain; D011480:Protease Inhibitors; D019837:Ryanodine Receptor Calcium Release Channel; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban; C522362:Mmp2 protein, mouse; C501830:Mmp9 protein, mouse; C506947:Atp2a2 protein, mouse