Suppression of histone deacetylases worsens right XXXX after pulmonary artery banding in @entity35 .

@entity1 @entity82 @entity10319 @entity1092 @entity409 @entity34313 @entity8158 @entity3996 @entity2052 @entity35 @entity67 @entity1002
RATIONALE: Inhibitors of histone deacetylases (HDACs) reduce pressure-overload-induced @entity1002 , but their effects on right ventricular (RV) adaptation to pressure overload are unknown. OBJECTIVES: Determine the effect of the broad-spectrum HDAC inhibitors @entity3996 ( @entity10319 ) and @entity1092 ( @entity2052 ) on RV function and remodeling after pulmonary artery banding (PAB) in @entity35 . METHODS: Chronic progressive RV pressure-overload was induced in @entity35 by PAB. After establishment of adaptive @entity8158 4 weeks after surgery, @entity35 were treated for 2 weeks with vehicle, @entity10319 , or @entity2052 . RV function and remodeling were determined using echocardiography, invasive hemodynamic measurements, immunohistochemistry, and molecular analyses after 2 weeks of HDAC inhibition. The effects of @entity10319 were determined on the expression of proangiogenic and prohypertrophic genes in @entity1 myocardial fibroblasts and microvascular endothelial cells. MEASUREMENTS AND MAIN RESULTS: @entity10319 treatment did not prevent the development of @entity8158 and was associated with @entity67 , capillary rarefaction, @entity82 , and increased rates of myocardial cell death. Similar results were obtained with the structurally unrelated HDAC inhibitor @entity2052 . With @entity10319 treatment, a reduction was found in expression of vascular endothelial growth factor and @entity34313 , which proteins are involved in vascular adaptation to pressure-overload. @entity10319 dose-dependently suppressed vascular endothelial growth factor, endothelial nitric oxide synthase, and @entity34313 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 @entity409 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.
