Abstract 3890: Inhibition Of Histone Deacetylase Activity Represses Matrix Metalloproteinase-9 Induction And Preserves Cardiac Function Post Myocardial Infarction
Background: Myocardial remodeling, which occurs following myocardial infarction (MI), can manifest in LV dilation. Post-MI, increased expression of matrix metalloproteinases (MMPs), such as MMP-9, is associated with deleterious effects on extracellular matrix remodeling (ECM). Histone deacetylases (HDACs) are a class of enzymes that can greatly affect the transcriptional regulation of genes during pathological conditions. This study tested the hypothesis that suppression of HDACs would repress the MMP-9 induction following MI and lead to more favorable ECM remodeling, thereby preventing LV dilation post-MI.
Methods and Results: MI was induced in transgenic mice with the MMP-9 promoter sequences fused to the β-galactosidase (β-gal) gene. Twelve hours prior to MI, mice were administered the HDAC inhibitor trichostatin A (TSA, 2 mg/kg/day) or vehicle. TSA (n=10) or vehicle treatment (n=14) continued until hearts were harvested 7 days post-MI. The post-MI change in LV end-diastolic volume (echo) was lower in the TSA treated mice (50±9 %) than in mice administered vehicle (73±12%). β-gal staining of the post-MI LV was lower in the TSA mice compared to vehicle (FIGURE⇓). Immunohistological staining and zymographic levels of MMP-9 were lower with TSA than in vehicle. This decrease in MMP-9 protein abundance with TSA was complemented by an increase in fibrillar collagen and periostin compared to vehicle.
Conclusion: Suppression of HDAC activity by TSA reduced MMP-9 expression and affects ECM and LV remodeling following MI. TSA treatment, through inhibition of the histone deacetylases, may provide a novel therapeutic means to attenuate adverse LV remodeling post-MI.