Backs et al. report that protein kinase A (PKA) may protect the heart from stress by inducing the proteolytic cleavage of a histone deacetylase.

Prolonged stress can induce harmful remodeling of cardiac muscle, eventually leading to heart failure. These pathological changes are partly driven by calcium/calmodulin-dependent protein kinase II (CaMKII), which phosphorylates the histone deacetylase HDAC4, triggering its export from the nucleus so that it no longer inhibits the stress-responsive transcription factor MEF2, thereby inducing the expression of cardiac-remodeling genes. Backs et al. investigated whether other signaling pathways affect HDAC4 activity and found that PKA bound to the deacetylase and stimulated its cleavage by a serine protease.

The resulting N-terminal fragment of HDAC4 could still bind and repress MEF2, but it no longer contained the serine residues targeted by CaMKII and therefore remained in the nucleus to inhibit MEF2 even when this kinase was active. The HDAC4 fragment generated by PKA may therefore protect cardiac tissue from stress-induced remodeling.

PKA and CaMKII are both activated downstream of the β-adrenergic receptor. Authors Eric Olson and Johannes Backs think that sustained adrenergic stimulation may favor CaMKII activation and pathogenic cardiac remodeling, whereas shorter bursts of adrenaline (during physical exercise, for example) may activate PKA and promote cardioprotection. The Backs lab now wants to investigate whether HDAC4 cleavage can be manipulated to treat cardiovascular disease, either by targeting the yet-to-be identified protease or by overexpressing the HDAC4 fragment in heart tissue using adenovirus.

et al
J. Cell Biol.