Paradoxical Blockade Of Cardiac Hypertrophy By Hdac Inhibitors

Given the potent antihypertrophic activity of class II HDACs, it was hypothesized that these inhibitors, which are general antagonists of both class I and class II HDACs, would stimulate pathologic cardiac growth. Paradoxically, treatment of cardiomyocytes with three independent HDAC inhibitors (TSA, sodium butyrate, and Helminthosporium car-bonum [HC]-toxin) repressed the increases in cell size, protein synthesis, and fetal gene expression normally evoked by hypertrophic agonists in vitro (63-66).

In retrospect, the observed inability of HDAC inhibitors to override class II HDAC-mediated repression of hypertrophy is not surprising, because class II HDAC catalytic activity is not required to repress the hypertrophic program (59). However, the antihypertrophic action of HDAC inhibitors remains paradoxical. The simplest interpretation of the data is that one or more HDACs play a positive role in the control of cardiac hypertrophy. Since the inhibitors used our studies antagonize the action of multiple HDACs, the identity of the putative prohypertrophic HDAC(s) remains unclear. However, a class I HDAC is a likely candidate, since class II HDACs suppress hypertrophy, and class III HDACs are resistant to inhibition by TSA.

The mechanism for HDAC inhibitor-mediated repression of cardiac hypertrophy remains unknown. We envision at least three possibilities (Fig. 6). First, HDAC inhibitors may stimulate expression of genes that encode repressors of cardiac growth. Second, HDAC inhibitors may repress expression of procardiac growth genes. Third, HDAC inhibitors may suppress cardiac hypertrophic signaling cascades, a hypothesis for which we have supporting evidence (B.C. Harrison and T.A. McKinsey, unpublished data).

HDAC inhibitors are in clinical development for treatment of cancer (67). Thus, the discovery that HDAC inhibitors repress cardiac hypertrophy in the face of stress may ultimately impact on the treatment of heart failure in humans. Recently, inhibitors of the class III HDAC Sir2 were shown to stimulate cardiomyocyte apoptosis (68). Given this finding, and the fact that class II HDACs repress pathological hypertrophy, future efforts to develop HDAC inhibitors as therapeutics for the heart will need to focus on specific inhibition of class I HDACs.

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