Aging, Environment, & DiseaseArticle SummariesHistone Modifications

HDAC Inhibitors as a Treatment for Acute Myocardial Infarction

Milan 2018 imageHistone deacytylase (HDAC) inhibitors are gaining interest in the treatment of cardiovascular diseases for their ability to decrease the damage to heart tissue after an ischemic event [1]. Cardiovascular diseases increase HDAC activity, altering histone acetylation [6, 7]. HDAC inhibitors can be used to decrease these epigenetic changes caused by HDACs.  Ischemic events can lead to long term inflammation and fibrosis of the effected tissue if not treated properly [2]. HDAC inhibitors mediate the inflammation and cardiac hypertrophy in cardiovascular disease following tissue damage [3]. Milan et al studied the effects of the pan-HDAC inhibitor Givinostat on cardiovascular disease[4].

In this study, the researchers induced an acute myocardial infarction (AMI) by surgically ligating the left descending coronary artery in 10-week-old C57 mice. Following the AMI, mice were treated with Givinostat or saline daily for up to 30 days. Mice treated with saline showed significantly decreased fractional shortening seven days after AMI, compared to Givinostat treated mice. Givinostat treatment also decreased gene expression of collagen 1a1, collagen 1a2 and collagen 3a1 on day seven post AMI, indicating decreased fibrosis compared to saline treated mice.

To ensure that Givinostat controlled the inflammatory response after AMI, tnf-α, il-1α and il-1β expression levels were measured. All three markers of inflammation were decreased in heart tissue one day after AMI with Givinostat treatment, compared to saline treatment. To look at the specific role of macrophages in Givinostat treatment, separate and co-cultures of macrophages and cardiomyocytes or cardiac fibroblasts were treated with Givinostat or saline. Isolated macrophages in the M1 phase show decreased expression of the migration enhancer, mmp9, when treated with Givinostat. In macrophage and cardiomyocyte co-cultures, macrophages in the M2 phase had increased expression of bcl2, while Caspase 3 expression was decreased. This indicates a decrease in macrophage migration and enhanced protection from apoptosis during Givinostat treatment. Fibroblast cell cultures had decreased expression of p53 and increased expression of bone morphogenic protein 7 in the presence of Givinostat, a possible mechanism for decreased fibrosis and hypertrophy in the heart.

The authors found a potential mechanism for Givinostat to improve long-term heart function after an AMI by modulating the behavior of the different cell populations in cardiac tissue. Givinostat treatment immediately after injury resulted in decreased fibrosis and inflammation of the effected tissue.

Original Article

  1. M. M et al., “Givinostat reduces adverse cardiac remodeling through regulating fibroblasts activation.,” Cell Death and Disease, Jan. 2018.


  1.  M. TA, “Targeting inflammation in heart failure with histone deacetylase inhibitors.,” Molecular Medicine, Jun. 2011.
  2. S. Epelman, P. P. Liu, and D. L. Mann, “Role of Innate and Adaptive Immunity in Cardiac Injury and Repair,” Nat Rev Immunol, vol. 15, no. 2, pp. 117–129, Feb. 2015.
  3. M. TA., “Therapeutic potential for HDAC inhibitors in the heart.,” Annual Review of Pharmacology and Toxicology, 2011.
  4. M. M et al., “Givinostat reduces adverse cardiac remodeling through regulating fibroblasts activation.,” Cell Death and Disease, Jan. 2018.
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Aaron Barnett

Aaron Barnett