Class lib HDACs in the Heart

The function of class IIb HDACs in the heart remains largely unknown. HDAC6 is a microtubule deacetylase (Hubbert et al. 2002), and microtubules comprise a major component of the cardiomyocyte cytoskeleton. The accumulation of stable, polymerized microtubules is thought to contribute to myocardial dysfunction in cardiac hypertrophy and heart failure (Hein et al. 2000; Tagawa et al. 1997), and HDAC inhibition in cultured cardiomyoytes decreases the total amount of tubulin associated with polymerized microtubules (Davis et al. 2003).

As highlighted elsewhere in this book, HDAC6 also plays an important role in the regulation of autophagy (Lee et al. 2010b), and autophagy is emerging as an important regulator, both positive and negative, of heart failure (Rothermel and Hill 2008). It will be interesting to determine whether selective inhibition of HDAC6 affects heart failure progression in animal models through effects on tubulin stability, autophagy or other mechanisms.

HDAC10 is the other class IIb HDAC. HDAC10 has not been studied in the heart. However, knockdown of HDAC10 expression in cancer cells induces expression of an endogenous thioredoxin inhibitor, thioredoxin-interacting protein (Lee et al. 2010a). Given the fact that thioredoxin suppresses class IIa HDAC nuclear export (Ago et al. 2008), it is possible that HDAC10 will affect genes involved in cardiac hypertrophy.

0 0

Post a comment