Extranuclear Roles for Class IIa HDACs in the Heart

Nontranscriptional roles for class IIa HDACs in the heart are also emerging. HDAC4 was shown to associate with cardiac sarcomeres and decrease myofilament calcium sensitivity by promoting deacetylation of muscle LIM protein (MLP) (Gupta et al. 2008). Consistent with this, HDAC inhibitor treatment increased calcium sensitivity of myofilaments from skinned fibers. It is not known whether deacetylation of MLP is governed by HDAC4 or another HDAC. Indeed, for many years it was believed that class IIa HDACs lacked intrinsic catalytic activity, because recombinant forms of the enzymes failed to deacetylate canonical HDAC substrates; catalytic activity of class IIa HDACs was attributed to associated class I HDACs (Fischle et al. 2002). However, subsequent work led to the identification of a synthetic substrate that is efficiently deacetylated by class IIa HDACs (Heltweg et al. 2004). Additional studies revealed that class IIa HDACs are relatively insensitive to commonly used HDAC inhibitors (Bradner et al. 2010), including those used in the contractility studies. As such, further investigation is needed to address the role of HDAC4 and other HDACs in the control of cardiac contractility, as well as the general role of class IIa HDAC catalytic activity in the heart.

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