Fibrosis, which is defined as excessive accumulation of fibrous connective tissue, contributes to the pathogenesis of numerous diseases involving diverse organ systems. Cardiac
fibrosis predisposes individuals to
myocardial ischemia, arrhythmias and
sudden death, and is commonly associated with diastolic dysfunction.
Histone deacetylase (
HDAC) inhibitors block cardiac
fibrosis in pre-clinical models of
heart failure. However, which HDAC
isoforms govern cardiac
fibrosis, and the mechanisms by which they do so, remains unclear. Here, we show that selective inhibition of class I HDACs potently suppresses
angiotensin II (Ang II)-mediated cardiac
fibrosis by targeting two key effector cell populations, cardiac fibroblasts and bone marrow-derived fibrocytes. Class I HDAC inhibition blocks cardiac fibroblast cell cycle progression through derepression of the genes encoding the
cyclin-dependent kinase (CDK) inhibitors, p15 and p57. In contrast, class I
HDAC inhibitors block agonist-dependent differentiation of fibrocytes through a mechanism involving repression of ERK1/2 signaling. These findings define novel roles for class I HDACs in the control of pathological cardiac
fibrosis. Furthermore, since fibrocytes have been implicated in the pathogenesis of a variety of human diseases, including heart, lung and
kidney failure, our results suggest broad utility for
isoform-selective
HDAC inhibitors as
anti-fibrotic agents that function, in part, by targeting these circulating mesenchymal cells.