Analysis of the Specific Role of Histone Deacetylase 2 (HDAC2) for Atrial Remodeling in Atrial Fibrillation

• Applicant: Dr. Jan Sebastian Schulte
• Subject Area: Pharmacology
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 460291259

Atrial fibrillation is the most common persistent arrhythmia in the elderly and increases the risk of stroke, heart failure, hospitalization and death. Structural and functional remodeling processes, which are summarized under the term "atrial remodeling", play a central role in the development and, above all, the chronification of this rhythm disorder. To date, no effective therapy exists that could stop the development of atrial remodeling in atrial fibrillation. We recently showed that the anticonvulsant valproic acid, which has been used for decades, delays atrial remodeling and the development of atrial fibrillation in mice with myocardial expression of the repressor CREM (cAMP responsive element modulator) isoform IbΔC-X. CREM-IbΔC-X-transgenic mice are a well-described mouse model with extensive atrial remodeling associated with spontaneous onset of atrial fibrillation. In this model, valproic acid reduced the development of characteristic components of atrial remodeling that are also present in other animal models of atrial fibrillation and in patients with atrial fibrillation. Valproic acid acts as an inhibitor of histone deacetylases (HDACs) and inhibits the HDAC isoforms 1, 2, 3 and 8 in therapeutic doses. The overall aim of the project is to investigate the individual functional significance of these HDAC isoforms for atrial remodeling associated with atrial fibrillation. Since there are no specific inhibitors for these individual isoforms so far, we will investigate the effect of genetically switching off these isoforms in CREM-IbΔC-X-transgenic mice by crossing them with corresponding "knockout" mice. The focus of the work program is on the HDAC2 isoform, since we have already shown that the knockout of this one HDAC isoform leads to a reduced expression of ultrastructural changes in atria of CREM-IbΔC-X-transgenic mice. In the context of this proposal, we will comprehensively investigate which components of structural and functional remodelling are affected by the elimination of HDAC2 in CREM-IbΔC-X-transgenic mice and whether the elimination of HDAC2 is ultimately sufficient to delay the development of atrial fibrillation. In the form of key experiments, the analysis will be extended to the isoforms 1, 3 and 8. Thus, the aim is to identify an optimal profile of HDAC inhibition by precise mapping of the effects of these HDACs, which positively influences as many components of atrial remodeling as possible and slows down the development of atrial fibrillation.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Frank Ulrich Müller