Abstract 1823: Inhibition of Histone Deacetylases Accelerates Unloading-Induced Cardiac Atrophy
Background: Mechanical unloading of the diseased ventricle has emerged as an important treatment strategy in advanced heart failure. In rare instances, dramatic improvements in ventricular performance are seen, yet little is known regarding underlying mechanisms. Histone deacetylases (HDACs) are implicated in the control of cell growth and remodeling. Recent studies have demonstrated that HDAC inhibition (HDACi) suppresses pathological cardiac hypertrophy and attenuates re-induction of the fetal gene program. We hypothesized that HDACi would accelerate unloading-induced cardiac atrophy.
Methods: Mechanical unloading of murine hearts was accomplished by heterotopic transplantation into the abdomen of same-strain recipients (7 days). Two days prior to surgery, mice were randomized to daily sq injections of either trichostatin A (TSA, 1 mg/kg) or vehicle. Left ventricular (LV) cardiomyocyte area was measured from H&E sections (100 myocytes/heart), and LV transcript abundance was measured by quantitative real-time RT-PCR. Native hearts from recipient mice served as controls.
Results: Consistent with a role for HDACs in cardiac atrophy, the protein abundance of HDAC-1 (54%; p<0.05), -2 (52%; p<0.01) and -3 (40%; p<0.05) were significantly increased in untreated donor hearts. Unloading-induced cardiomyocyte atrophy was accelerated in hearts transplanted into TSA-treated mice (25±4% atrophy, TSA vs 13±1% atrophy, vehicle; p<0.05). Remarkably, TSA treatment did not blunt (p=NS) the dramatic (72-fold, p<0.05) up-regulation of fetal βMHC seen in vehicle-treated hearts, despite significant increases in the rate of atrophy development. The cyclin dependent kinase inhibitors (CDKIs) p21(Cip1/Waf1) and p27(Kip1), which are known to negatively regulate cardiac hypertrophy, were each increased (p21, 45%, p<0.1; p27, 31%, p<0.1) in TSA-treated hearts relative to control.
Conclusions: HDAC inhibition elicits a bona fide cardiomyocyte atrophy response during ventricular unloading in association with up-regulation of CDKI transcript expression. HDAC inhibition, however, does not blunt re-activation of the fetal gene program. These findings may have important implications for heart failure patients undergoing LV assist device support.
This research has received full or partial funding support from the American Heart Association, AHA South Central Affiliate (Arkansas, New Mexico, Oklahoma & Texas).