Key result
HDAC inhibition fails to prevent RV hypertrophy and induces RV dysfunction, fibrosis, and capillary rarefaction.
Why the study?
Histone deacetylase inhibitors reduce pressure-overload-induced left ventricular hypertrophy and dysfunction, but their effects on right ventricular adaptation to pressure overload were unknown.
HDAC inhibition worsens right ventricular dysfunction and remodeling in a rat model of pressure overload, suggesting detrimental effects on RV adaptation.
Answers are grounded in this paper and cite their sources.
HDAC inhibition may worsen RV adaptation in pressure overload; leaves open relevance to human right heart failure.
Rationale Inhibitors of histone deacetylases (HDACs) reduce pressure-overload–induced left ventricular hypertrophy and dysfunction, but their effects on right ventricular (RV) adaptation to pressure overload are unknown. Objectives Determine the effect of the broad-spectrum HDAC inhibitors trichostatin A (TSA) and valproic acid (VPA) on RV function and remodeling after pulmonary artery banding (PAB) in rats. Methods Chronic progressive RV pressure-overload was induced in rats by PAB. After establishment of adaptive RV hypertrophy 4 weeks after surgery, rats were treated for 2 weeks with vehicle, TSA, or VPA. RV function and remodeling were determined using echocardiography, invasive hemodynamic measurements, immunohistochemistry, and molecular analyses after 2 weeks of HDAC inhibition. The effects of TSA were determined on the expression of proangiogenic and prohypertrophic genes in human myocardial fibroblasts and microvascular endothelial cells. Measurements and Main Results TSA treatment did not prevent the development of RV hypertrophy and was associated with RV dysfunction, capillary rarefaction, fibrosis, and increased rates of myocardial cell death. Similar results were obtained with the structurally unrelated HDAC inhibitor VPA. With TSA treatment, a reduction was found in expression of vascular endothelial growth factor and angiopoietin-1, which proteins are involved in vascular adaptation to pressure-overload. TSA dose-dependently suppressed vascular endothelial growth factor, endothelial nitric oxide synthase, and angiopoietin-1 expression in cultured myocardial endothelial cells, which effects were mimicked by selective gene silencing of several class I and II HDACs. Conclusions HDAC inhibition is associated with dysfunction and worsened remodeling of the pressure-overloaded RV. The detrimental effects of HDAC inhibition on the pressure-overloaded RV may come about via antiangiogenic or proapoptotic effects.
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Bogaard et al. (2011) studied Right ventricular pressure-overload and hypertrophy induced by pulmonary artery banding. Histone deacetylase (HDAC) inhibitors (trichostatin A [TSA] or valproic acid [VPA]) vs. Vehicle was evaluated on Right ventricular function and remodeling (hypertrophy, capillary rarefaction, fibrosis, and myocardial cell death). Two weeks of HDAC inhibition with trichostatin A or valproic acid after pulmonary artery banding failed to prevent RV hypertrophy and caused RV dysfunction, capillary rarefaction, and fibrosis.
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