Histone deacetylase signaling in cardioprotection

Abstract

Cardiovascular disease (CVD) represents a major challenge for health care systems, both in terms of the high mortality associated with it and the huge economic burden of its treatment. Although CVD represents a diverse range of disorders, they share common compensatory changes in the heart at the structural, cellular, and molecular level that, in the long term, can become maladaptive and lead to heart failure. Treatment of adverse cardiac remodeling is therefore an important step in preventing this fatal progression. Although previous efforts have been primarily focused on inhibition of deleterious signaling cascades, the stimulation of endogenous cardioprotective mechanisms offers a potent therapeutic tool. In this review, we discuss class I and class II histone deacetylases, a subset of chromatin-modifying enzymes known to have critical roles in the regulation of cardiac remodeling. In particular, we discuss their molecular modes of action and go on to consider how their inhibition or the stimulation of their intrinsic cardioprotective properties may provide a potential therapeutic route for the clinical treatment of CVD.

Fig. 1

Basic structural difference of class I and class II HDACs. In contrast to class I HDACs, class II HDACs have a large N-terminal region. This allows an exposure to multiple cellular processes, such as modification by proteolysis, phosphorylation or recruitment of interacting proteins. Moreover class II HDACs function as scaffold proteins. In this context, they are able to bind to other proteins and chromatin modifiers (e.g., methyl transferases and class I HDACs). Moreover, via the N-terminus they are recruited to distinct transcription factors. The deacetylase activity is low compared to class I HDACs. HDAC histone deacetylase

Fig. 2

HDAC inhibitors (HDACi) target the deacetylation domain. HDACi are drugs with different specificities on HDACs. Because the deacetylase activity of class II HDACs is low, they primarily inhibit class I HDACs. Many of their functions are related to unspecific increase in acetylation activity within the nucleus and the cytoplasm. HDAC histone deacetylase, HDACi HDAC inhibitor

Fig. 3

How protein kinase A (PKA) acts on class II HDACs. 1 PKA phosphorylates HDAC5 at S280 and inhibits 14-3-3 binding. 2 PKA inhibits protein kinase D (PKD) activation. 1+2 This results in nuclear accumulation of HDAC5 and consequent repression of transcriptional activity, thereby counteracting the phosphorylation of HDAC5 by PKD at S259 and S489, subsequent binding to the chaperon 14-3-3 and nuclear export (black arrow on HDAC5). 3 HDAC4 is cleaved by a PKA-dependent mechanism. The N-terminal cleavage product accumulates in the nucleus and inhibits myocyte enhancer factor 2 (MEF2). The cleavage takes place between binding sites for MEF2 and serum response factor (SRF), indicating that PKA leads to a shift in the affinity of HDAC4 towards MEF2 inhibition. 4 PKA is also able to directly inhibit MEF2 by phosphorylation at T20. All mechanisms lead to a reduced activation of hypertrophic transcription factors such as MEF2 and the related pathological gene program. PKA protein kinase A, PKD protein kinase D, HDAC histone deacetylase, SRF serum response factor

Fig. 4

Therapeutic potential of class II HDACs: 1 Preventing nuclear export. Inhibition of phosphorylation could be achieved by small molecules that inhibit kinase activity or interrupt kinase-HDAC binding. Reduced phosphorylation would lead to reduced 14-3-3 binding with the consequence of nuclear accumulation of class II HDACs. This would result in inhibition of transcription, depending on the targeted kinase and targeted class II HDAC. 2 Enhancing nuclear import. Dephosphorylation of class II HDACs by activation of specific phosphatases leads to reduced 14-3-3 binding, to nuclear import and to nuclear accumulation of class II HDACs with the consequence of transcriptional repression. Phosphatases could be further investigated as potential drug target. 3 Induction of HDAC4 cleavage. Proteolysis of HDAC4, resulting in nuclear accumulation of the N-terminus leads to inhibition of MEF2. The advantage of this approach would be a more specific targeting of gene programs that are driven by MEF2, known to be active in pathological cardiac remodeling. So far, proteases in this pathway that could serve as potential drug targets are unknown. HDAC histone deacetylase