Abstract 570: Progression To Heart Failure After Constriction Of The Thoracic Aorta In The Mouse Is Accelerated By Doxycycline
Conditional expression of transgenes using tetracycline-regulated systems is now widely used to study the function of various genes in the mouse heart. In these systems, transgene expression is repressed or enhanced by adding doxycycline (Dox) to mouse chow. Doxycycline has been shown to attenuate MMP expression and activity in various tissues. Results from animal models have shown that some MMP gene deletion mitigates left ventricular (LV) remodeling in models of chronic hemodynamic overload. Accordingly, we assessed the hypothesis that Dox influences LV remodeling and progression to congestive heart failure (CHF) after constriction of the thoracic aorta (TAC) in the mouse. TAC or sham surgery was performed in B6D2/F1 male mice (BW: 19–22g). Mice were randomly assigned to standard mouse chow (St) or St plus Dox starting 1 week before surgery until sacrifice. One or 2 months after surgery, mice underwent LV catheterization. BNP and β-MHC mRNA levels were quantified in LV samples by QRT-PCR. MMP2 and MMP9 were assessed in LV homogenates by gel zymography. The mortality rate at 2 months was 21 and 32% in TAC and TAC+Dox, respectively (ns). One month after TAC, cardiac hypertrophy was higher in TAC+Dox (n=18) than in TAC (n=22) (51 vs 39%, p<0.05). Similarly, the proportion of mice with CHF (lung weight > lung weight in shams + 2SD) was higher in TAC+Dox (n=18) than in TAC (n=22) (79 vs 36%, p<0.05). In contrast 2 months after TAC, cardiac hypertrophy and the proportion of mice with CHF were similar in both TAC+Dox and TAC. These results were confirmed by those of the hemodynamic study. One month after TAC, LV BNP mRNA level was 1.6 fold higher, and LV β-MHC mRNA level was 1.7 fold higher in TAC+Dox (n=9) than in TAC (n=9) (p=0.01). Active MMP2 increased 2.4 times in TAC+Dox (n=5) and 1.9 times in TAC (n=5) vs shams (n=6) (p<0.05), but the difference between TAC+Dox and TAC did not reach statistical significance. Active MMP9 was not detected in LV homogenates. We conclude that Dox accelerates the development of cardiac hypertrophy and progression to CHF following TAC in mice. Accordingly, great care should be taken in the experimental design and in data interpretation in models of LVH performed in conditional TG mice using the Tet-on/Tet-off system.