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Abstract
Pharmacological modulation of class I histone deacetylases (HDAC) has been evaluated as a therapeutic strategy for pulmonary hypertension (PH) in experimental models of PH. However, information of their expression, regulation and transcriptional targets in human PH and the therapeutic potential of isoform-selective enzyme modulation are lacking. Comprehensive analysis of expression and regulation of class I HDACs (HDAC1, HDAC2, HDAC3 and HDAC8) was performed in cardiopulmonary tissues and adventitial fibroblasts isolated from pulmonary arteries (PAAF) of idiopathic pulmonary arterial hypertension (IPAH) patients and healthy donors. Cellular functions and transcriptional targets of HDAC enzymes were investigated. Therapeutic effects of pan-HDAC (Vorinostat), class-selective (VPA) and isoform-selective (CAY10398, Romidepsin, PCI34051) HDAC inhibitors were evaluated ex vivo (IPAH-PAAF, IPAH-PASMC) and in vivo (rat chronic hypoxia-induced PH and zebrafish angiogenesis). Our screening identifies dysregulation of class I HDAC isoforms in IPAH. Particularly, HDAC1 and HDAC8 were consistently increased in IPAH-PAs and IPAH-PAAFs, whereas HDAC2 and HDAC8 showed predominant localization with ACTA2-expressing cells in extensively remodeled IPAH-PAs. Hypoxia not only significantly modulated protein levels of deacetylase (HDAC8), but also significantly caused dynamic changes in the global histone lysine acetylation levels (H3K4ac, H3K9/K14ac and H3K27ac). Importantly, isoform-specific RNA-interference revealed that HDAC isoforms regulate distinct subset of transcriptome in IPAH-PAAFs. Reduced transcript levels of KLF2 in IPAH-PAAFs was augmented by HDAC8 siRNA and HDAC inhibitors, which also attenuated IPAH-associated hyperproliferation and apoptosis-resistance ex vivo, and mitigated chronic hypoxia-induced established PH in vivo, at variable degree. Class I HDAC isoforms are significantly dysregulated in human PAH. Isoform-selective HDAC inhibition is a viable approach to circumvent off-target effects.
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1 Max-Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (GRID:grid.418032.c) (ISNI:0000 0004 0491 220X); German Center for Lung Research (DZL), Giessen, Germany (GRID:grid.452624.3)
2 Hammersmith Hospital, Imperial College London, Center for Pharmacology and Therapeutics, Experimental Medicine, London, UK (GRID:grid.7445.2) (ISNI:0000 0001 2113 8111)
3 Philipps University Marburg, Institute of Molecular Biology and Tumor Research, Marburg, Germany (GRID:grid.10253.35) (ISNI:0000 0004 1936 9756)
4 Heidelberg University, Department of Anatomy and Developmental Biology, CBTM, Medical Faculty Mannheim, Mannheim, Germany (GRID:grid.7700.0) (ISNI:0000 0001 2190 4373)
5 Justus-Liebig-University Giessen, Department of Internal Medicine, Giessen, Germany (GRID:grid.8664.c) (ISNI:0000 0001 2165 8627)
6 Max-Planck Institute for Heart and Lung Research, Bad Nauheim, Germany (GRID:grid.418032.c) (ISNI:0000 0004 0491 220X); German Center for Lung Research (DZL), Giessen, Germany (GRID:grid.452624.3); Justus-Liebig-University Giessen, Department of Internal Medicine, Giessen, Germany (GRID:grid.8664.c) (ISNI:0000 0001 2165 8627)