Histone deacetylation inhibition in pulmonary hypertension: therapeutic potential of valproic acid and suberoylanilide hydroxamic acid.
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, a condition characterized by profound structural remodeling of pulmonary arteries and arterioles.


RESULTS
HDAC1 and HDAC5 protein levels were elevated in lungs from human idiopathic pulmonary arterial hypertension and in lungs and right ventricles from rats exposed to hypoxia. Immunohistochemistry localized increased expression to remodeled vessels in the lung. Both valproic acid, a class I HDAC inhibitor, and suberoylanilide hydroxamic acid (vorinostat), an inhibitor of class I, II, and IV HDACs, mitigated the development of and reduced established hypoxia-induced pulmonary hypertension in the rat. Both valproic acid and suberoylanilide hydroxamic acid inhibited the imprinted highly proliferative phenotype of fibroblasts and R-cells from pulmonary hypertensive bovine vessels and platelet-derived growth factor-stimulated growth of human vascular smooth muscle cells in culture. Exposure to valproic acid and suberoylanilide hydroxamic acid was associated with increased levels of p21 and FOXO3 and reduced expression of survivin. The significantly higher levels of expression of cKIT, monocyte chemoattractant protein-1, interleukin-6, stromal-derived factor-1, platelet-derived growth factor-b, and S100A4 in R-cells were downregulated by valproic acid and suberoylanilide hydroxamic acid treatment.


CONCLUSIONS
Increased HDAC activity contributes to the vascular pathology of pulmonary hypertension. The effectiveness of HDAC inhibitors, valproic acid, and suberoylanilide hydroxamic acid, in models of pulmonary arterial hypertension supports a therapeutic strategy based on HDAC inhibition in pulmonary arterial hypertension.
Centre for Pharmacology and Therapeutics, Experimental Medicine, Imperial College London, Du Cane Rd, London W12 ONN, UK. l.zhao@imperial.ac.uk
Lan
L
Zhao
Chien-Nien
CN
Chen
Nabil
N
Hajji
Eduardo
E
Oliver
Emanuele
E
Cotroneo
John
J
Wharton
Daren
D
Wang
Min
M
Li
Timothy A
TA
McKinsey
Kurt R
KR
Stenmark
Martin R
MR
Wilkins
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D056284:Histone Deacetylase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006655:Histone Deacetylases / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology* / Q000627:therapeutic use*; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D000860:Hypoxia / Q000150:complications; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014635:Valproic Acid / Q000494:pharmacology* / Q000627:therapeutic use*; D000077337:Vorinostat
D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D010982:Platelet-Derived Growth Factor; D000077337:Vorinostat; D014635:Valproic Acid; C110550:HDAC1 protein, human; C404500:HDAC5 protein, human; C515890:Hdac1 protein, rat; C498619:Hdac5 protein, rat; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases