Table 2.
Inhibitors of HDACs involved in PAH development
| Inhibitors | Targets HDACs | Function | Targets genes/proteins and Signaling pathway | Models | References |
|---|---|---|---|---|---|
| Apicidin | Class I | Inhibit fibroblast and monocytes/macrophages activation; attenuate right ventricular hypertrophy and pulmonary vascular remodeling | Inhibit pro-inflammatory cytokines and pro-fibrogenic mediators (TIMP1) expression; Inhibit IGF-1/pAKT signaling; |
Human-PAH Rat-hypoxia Neonatal mouse-hypoxia Fibroblasts, PASMC and PAEC |
[124] [125] |
| MC1855 | Class I | Inhibit PASMC proliferation and migration | Inhibit Akt Phosphorylation and Cyclin D1 expression | Rat PASMC-PDGF | [122] |
| MC1568 | I Class IIa | Inhibit PAEC proliferation and migration | Increase MEF2-miRNA-424/503, connexins 37/40, and Klf 2 and 4 |
Rat-MCT, sugen5416/hypoxia PAEC |
[107] |
| MGCD0103 | Class I | Inhibit PASMC proliferation pulmonary vascular remodeling | Increase FOXO3a, P27;SOD3 |
Rat-hypoxia PASMC-hypoxia |
[121] [127] |
| SAHA | Class I, II and IV | Inhibit fibroblast and PASMC proliferation and inflammation | Increase p21 and FOXO3 levels, reduced the expression of survivin and cytokines |
Human-PAH Rat-hypoxia Bovine vascular fibroblasts, PASMC-PDGF |
[123] [124] |
| Scriptaid | Class I, II and IV | Reduce PAH | Reduce Nox transcription and ROS production |
Rat-MCT HLF and HLMVEC |
[126] |
| VPA | Class I | Inhibit fibroblast and PASMC proliferation and inflammation | Increase p21 and FOXO3 levels, reduced the expression of survivin and cytokines |
Human-PAH Rat-hypoxia, MCT Bovine vascular fibroblasts, PASMC-PDGF |
[123] [132] |
Drugs: MCT, monocrotaline; SAHA, suberoylanilide hydroxamic acid; TSA, trichostatin A; VPA, valproic acid
Cell types: PAEC, pulmonary artery endothelial cells; PASMCs, pulmonary artery smooth muscle cells; HLF, human lung fibroblasts; HLMVEC, Human lung microvascular endothelial cells
Target genes/proteins: FOXO, forkhead box O; GF-1, insulin growth factor 1; KLF4, Kruppel-like factor; MEF2, myocyte enhancer factor; Nox, NADPH oxidase; p21, cyclin-dependent kinase inhibitor 1; p27, cyclin-dependent kinase inhibitor 1B; PDGF, platelet-derived growth factor; ROS, reactive oxygen species; SOD, superoxide dismutase; TIMP1, TIMP metallopeptidase inhibitor 1