Chronic doxycycline exposure in mice after transverse aortic constriction accelerated the onset of congestive heart failure (74% vs. 32%, P<0.05) and cardiac hypertrophy at 1 month.
Does doxycycline accelerate left ventricular hypertrophy and progression to heart failure in mice after transverse aortic constriction?
Doxycycline accelerates the onset of cardiac hypertrophy and progression to heart failure following transverse aortic constriction in mice, highlighting a significant confounding factor when using tetracycline-regulated transgenic mouse models.
Absolute Event Rate: 74% vs 32%
p-value: p=<0.05
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.
Vinet et al. (Sat,) conducted a other in Left ventricular hypertrophy and heart failure. Doxycycline vs. No doxycycline (TAC alone) was evaluated on Congestive heart failure at 1 month (p=<0.05). Chronic doxycycline exposure in mice after transverse aortic constriction accelerated the onset of congestive heart failure (74% vs. 32%, P<0.05) and cardiac hypertrophy at 1 month.
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