In their letter, Bogaard et al appreciate that HDAC inhibitors "may mitigate pulmonary vascular remodeling through effects on lung endothelial cells or vascular smooth muscle cells" 1,2 but are concerned about the possibility that "HDAC inhibitors threaten the heart's adaptive response to pressure overload." These concerns, which were addressed in our articles, 1,2 arise from their own study using trichostatin A, a broad-spectrum HDAC inhibitor, and valproic acid, which is not a broad-spectrum HDAC inhibitor, in a rat pulmonary artery banding model. 3 In their study, trichostatin A (but not valproic acid) worsened right ventricular function and was associated with exaggerated right ventricular fibrosis and capillary rarefaction. Although these observations do indeed raise questions, we emphasize that this single report does not seem to be representative of the many reports demonstrating the beneficial effects of HDAC inhibitors in the stressed or failing heart. 4 Furthermore, it would suggest that rather than rejecting a promising class of drugs a priori, we should be asking what class of HDAC inhibitors should be employed in the context of pulmonary hypertension and what are the relevant biological pathways that should be selectively targeted.The fortuitous discovery of an antihypertrophic action of HDAC inhibitors in cardiomyocytes nearly 10 years ago suggested a novel application for these compounds. Subsequent in vivo studies, focusing primarily on the left ventricle, have demonstrated that broadspectrum HDAC inhibitors can effectively halt and even reverse pathological cardiac hypertrophy from a variety of stimuli: genetic, pharmacological, and mechanical. 4 The remarkable efficacy of HDAC inhibitors shown in heart failure models is likely attributable to the ability of HDACs to target multiple cell types (eg, myocytes, fibroblasts, and immune cells) and diverse pathological mechanisms (eg, myocyte hypertrophy, fibrosis, and inflammation). The impact of HDAC inhibitors on inflammation in heart failure models has recently received particular attention and could be one of the principal mechanisms for their efficacious effects. Nontranscriptional effects of HDAC inhibitors in the heart have also been described. 5 Our data demonstrate that increases in class I-specific HDACs may be important in right ventricular pathological remodeling because they are specifically increased in this chamber in the setting of pulmonary hypertension, and inhibition with selective class I HDACspecific inhibitors leads to a reduction in pulmonary hypertension and protection of the right heart. We agree it will be very important to perform mechanistic, preclinical safety and efficacy studies with class-specific HDAC inhibitors to determine whether isoform-selective HDAC inhibition provides a more favorable therapeutic index than broad-spectrum HDAC inhibitors for the treatment of chronic, nononcological indications, such as heart failure in the setting of pulmonary hypertension. However, we continue to believe that the many and vari...

The typical response of the adult mammalian pulmonary circulation to a low oxygen environment is vasoconstriction and structural remodelling of pulmonary arterioles, leading to chronic elevation of pulmonary artery pressure (pulmonary hypertension) and right ventricular hypertrophy. Some mammals, however, exhibit genetic resistance to hypoxia-induced pulmonary hypertension1-3. We used a congenic breeding program and comparative genomics to exploit this variation in the rat and identified the gene, Slc39a12, as a major regulator of hypoxia-induced pulmonary vascular remodelling. Slc39a12 encodes the zinc transporter, ZIP12. We report that ZIP12 expression is increased in many cell types, including endothelial, smooth muscle and interstitial cells, in the remodelled pulmonary arterioles of rats, cows and humans susceptible to hypoxia-induced pulmonary hypertension. We show that ZIP12 expression in pulmonary vascular smooth muscle cells is hypoxia-dependent and that targeted inhibition of ZIP12 inhibits the rise in intracellular labile zinc in hypoxia-exposed pulmonary vascular smooth muscle cells and their proliferation in culture. We demonstrate that genetic disruption of ZIP12 expression attenuates the development of pulmonary hypertension in rats housed in a hypoxic atmosphere. This entirely novel and unexpected insight into the fundamental role of a zinc transporter in mammalian pulmonary vascular homeostasis suggests a new drug target for the pharmacological management of pulmonary hypertension.

Background Epigenetic programming, dynamically regulated by histone acetylation, is a key mechanism regulating cell proliferation and survival. Little is known about the contribution of histone deacetylase (HDAC) activity to the development of pulmonary arterial hypertension (PAH), a condition characterised by profound structural remodelling of pulmonary arteries and arterioles. Methods and results HDAC1 and HDAC5 protein levels were elevated in lungs from human idiopathic PAH and in lungs and right ventricles from rats exposed to hypoxia. Immunohistochemistry localised increased expression to remodelled vessels in the lung. Both valproic acid (VPA), a class I HDAC inhibitor, and suberoylanilide hydroxamic acid (SAHA), an inhibitor of class I, II and IV HDACs, mitigated the development and reduced established hypoxia-induced pulmonary hypertension in the rat. Both VPA and SAHA inhibited the “imprinted” highly proliferative phenotype of fibroblasts and R-cells from pulmonary hypertensive bovine vessels and PDGF-stimulated growth of human vascular smooth muscle cells in culture. Exposure to VPA and SAHA was associated with increased levels of p21and FOXO3 and reduced expression of survivin. The significantly higher level of expression of cKIT, MCP-1, IL-6, SDF-1, PDGFb and S100A4 in the R-cells were down regulated by VPA and SAHA treatment. Conclusions Increased HDAC activity contributes to the vascular pathology of pulmonary hypertension. The effectiveness of HDAC inhibitors VPA and SAHA, in models of PAH, support a therapeutic strategy based on HDAC inhibition in PAH.