Histone Deacetylase Inhibitor An7 Increases Survival and May Attenuate Lv Dilatation in Mice with Chronic Volume Overload

Background: Valve dysfunction leads to chronic volume overload (VO) on the heart which eventually progresses to heart failure. Hearts subjected to volume overload are challenged with the initiation of progressive left ventricular (LV) remodelling, chamber dilatation, cardiomyocyte elongation and extracellular matrix (ECM) degradation. Alterations of the ECM architecture are partly attributed to changes in the expression of matrix metalloproteases (MMPs) 2 and 9. On the other hand, emerging evidence suggests that epigenetic changes, such as post-translational modification of histones by histone deacetylases (HDAC) play an important role in MMP2 and MMP9 gene regulation during cardiac remodeling.

Working hypothesis: We hypothesize that HDAC inhibition could mediate downregulation of MMP2/9 expression and activity, as previously reported, and thus attenuate VO-induced progression to heart failure.

Methods: 1.We has successfully established a mouse model for VO by introducing aorto-caval shunt (fistula) between exposed abdominal aorta and vena cava. MMP levels were determined by real-time PCR and their enzymatic (gelatinase) activity was estimated by Zymography assays. 2. VO-induced Mice were treated with either vehicle- control or with the HDAC inhibitor AN7 (30 mg/kg 3x / week) for 4 weeks followed by an echocardiography scan.

Results: A significant increase in MMP2 and MMP9 expression was detected in 4 weeks- VO mice, concomitantly with elevated MMP2/9 gelatinase activity. Treatment with AN7 resulted in longer time to treatment failure (increased survival), as well as with a trend towards attenuation of LV dilatation compared to control animals.

Conclusion: Our findings suggest that HDAC inhibitors may attenuate VO progression and thus may hold therapeutic promise for VO-induced heart failure. This phenomenon may be mediated, at least in part, by reduced enzymatic activity of MMP2/9.