Heart disease is the leading cause of death for both men and women with over 600,000 deaths/year (25% of mortality). Coronary heart disease is the most common type of heart disease with about 715,000 patients suffering a heart attack each year. Death rates in our patient population in the southeast are even higher with African Americans having higher rates yet. Our VA patients reflect our local population with elevated risk of heart disease often presenting with hypertension, diabetes, obesity or overweight, smoking and excessive alcohol use. VA patients who have incurred LV injury due to myocardial infarction (MI) undergo ventricular remodeling, which can lead to chamber dilation and progress to congestive heart fail-ure. Monocyte-derived macrophages are believed to play a major role in the regulation of infarct healing. Post-MI repair is made up of a biphasic process with phase I mediated by inflammatory M1 macrophages that are phagocytic, and secrete high levels of MMPs, and proinflammatory mediators. By contrast the M2 macrophages produce anti-inflammatory cytokines and communicate with myofibroblasts, endothelial cells, parenchymal and local progenitor cells to help coordinate remodeling and repair of the damaged tissue. The controlled recruitment of the inflammatory monocytes and resulting macrophages is essential for proper healing but excessive or prolonged recruitment of these inflammatory monocytes and M1 macrophage results in deleterious remodeling and heart failure. Recent studies have demonstrated that increasing the M1 to M2 polarization appears to be an attractive strategy for decreasing inflammation and improvement of infarct healing and repair. Our preliminary data provide evidence for the first time that class I HDACs regulate M1 to M2 polarization of macrophages of the post-MI heart. Therefore, we hypothesize that class I HDACs serve as a master regulator of macrophage polarization and HDAC inhibitors reprogram the infiltrating monocytes and resulting macrophages toward the M2 phenotype in the post-MI heart. We have proposed Three Aims to test our hypothesis.
Aim 1) Demonstrate that inhibition of class I HDACs attenuates M1 macrophage recruitment and promotes M1 to M2 polarization, which fosters infarct healing.
Aim 2) Determine if targeted delivery of a class I HDAC inhibitor to inflammatory monocytes attenuates MI injury.
Aim 3) Determine if treatment with a class I selective HDAC inhibitor in a murine model of chronic inflammation commonly seen in patients with atherosclerosis, results in reduced deleterious remodeling and preservation of ventricular function. Our approach will allow us to directly test whether targeted delivery of class I HDAC inhibitors to monocytes and macrophages can override the overwhelming inflammatory extracellular signaling milieu in the acute MI ventricle to reprogram macrophage phenotype to influence M1 to M2 transition. Importantly, our study will give us important new molecular insights into the role of class I HDACs in regulating macrophage polarization and possibly open a new translational approach for treatment of post-MI VA patients. It is hoped that the findings of this application will be translated into new and successful clinical treatment strategies to ameliorate post-MI injury for our Veterans.
Congestive heart failure is the leading cause of death in the United States. Many cardiac genes, which contribute to fibrosis are dysregulated in a heart attack and the change in their expression levels have been shown to contribute to increased fibrosis and more damage to the heart muscle in the post myocardial infarcted heart. We have discovered that inhibition of an enzyme called histone deacetylase, which is known to play an important role regulating gene expression prevents the dysregulation of the genes contributing to fibrosis. Our findings will be critical to he potential development of HDAC inhibitors for the treatment of heart disease.
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