HDACs In Smooth Muscle

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In contrast to striated muscles, little is known about the roles of HDACs in the control of gene expression in nonstriated smooth muscle. Dynamic changes in histone acetylation have been observed at smooth muscle-specific gene regulatory elements during differentiation (74), and these modifications are sensitive to histone deacetylase activity (75). As mentioned at the end of previous section, class II HDACs have been shown to associate with and repress the activity of the SRF and myocardin transcription factors (70,73). In addition to their roles in cardiac development, SRF and myocardin function as master regulators of smooth muscle cell differentiation (reviewed in ref. 76). Thus, although definitive experimental proof is lacking, it seems likely that class II HDACs will prove to regulate gene expression in smooth muscle via interactions with these and as-yet-unidentified factors. The class I HDAC HDAC8 has also been reported to be highly specific for developing smooth muscle cells, suggesting its involvement in smooth muscle gene expression (77).

Expression of class II HDAC7 is highly enriched in endothelial cells that line blood vessels (S. Chang and E.N. Olson, unpublished data), and targeted disruption of HDAC7 in mice leads to embryonic lethality owing to severely impaired vasculogenesis. Thus, class II HDACs may serve dual roles in the control of blood vessel formation, by regulating SRF and myocardin in the outer smooth muscle layer of the vessel and by coordinating gene expression in the inner endothelial cell layer. The target(s) of HDAC7 in endothelial cells remains unknown, although MEF2 is an obvious candidate. MEF2 is required for vascular development (78) and mediates endothelial cell survival (79). In addition, genetic studies in humans implicate MEF2 in protection from coronary artery disease and myocardial infarction (80). Studies to determine the interplay between HDAC7 and MEF2 in the control of these developmental and pathophysi-ological processes are forthcoming.

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