Abstract
Cardiovascular diseases (CVDs) are a major burden on the healthcare system: indeed, over two million new cases are diagnosed every year worldwide. Unfortunately, important drawbacks for the treatment of these patients derive from our current inability to stop the structural alterations that lead to heart failure, the common endpoint of many CVDs. In this scenario, a better understanding of the role of epigenetics – hereditable changes of chromatin that do not alter the DNA sequence itself – is warranted. To date, hyperacetylation of histones has been reported in hypertension and myocardial infarction, but the use of inhibitors for treating CVDs remains limited. Here, we studied the effect of the histone deacetylase inhibitor Givinostat on a mouse model of acute myocardial infarction. We found that it contributes to decrease endothelial-to-mesenchymal transition and inflammation, reducing cardiac fibrosis and improving heart performance and protecting the blood vessels from apoptosis through the modulatory effect of cardiac fibroblasts on endothelial cells. Therefore, Givinostat may have potential for the treatment of CVDs.
Highlights
Cardiac remodeling and fibrosis are compensatory mechanisms consequent to ischemic events[1] and they strictly determine the clinical outcome
There were no differences in the wall thickness (WT) parameter, which was calculated as Frontal Wall thickness+Posterior Wall thickness/2, between the two groups at day 30
We investigated the effect of Givinostat on human umbilical vein endothelial cells (HUVECs), which were serum-starved for 6 h and exposed to hypoxia for 18 h
Summary
Cardiac remodeling and fibrosis are compensatory mechanisms consequent to ischemic events[1] and they strictly determine the clinical outcome. Among the biological and molecular mechanisms involved in the adaptive response to a cardiac insult, histone deacetylase (HDAC)-mediated epigenetics processes are receiving a special attention. HDACs are common enzymes regulating deacetylation of core histones and are strictly correlated to the regulation of homeostatic gene expression of vascular and cardiac cell populations, including stem cell commitment[5]. HDACs activity is enhanced, resulting in increased proliferation, migration, and apoptosis of adventitial fibroblasts (FBs), endothelial cells (ECs), and muscle cells, as well as stimulation of macrophage (MP)
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