Circulation (New York, N.Y.), 2012-07, Vol.126 (4), p.455-467
2012
Details
- Autor(en) / Beteiligte
- Titel
- Histone Deacetylation Inhibition in Pulmonary Hypertension Therapeutic Potential of Valproic Acid and Suberoylanilide Hydroxamic Acid
- Ist Teil von
- Circulation (New York, N.Y.), 2012-07, Vol.126 (4), p.455-467
- Ort / Verlag
- Hagerstown, MD: Lippincott Williams & Wilkins
- Erscheinungsjahr
- 2012
- Link zum Volltext
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- 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. 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. 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.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0009-7322eISSN: 1524-4539DOI: 10.1161/CIRCULATIONAHA.112.103176Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_3799888
- Format
- –
- Schlagworte
- Animals, Biological and medical sciences, Blood and lymphatic vessels, Cardiology. Vascular system, Cell Proliferation - drug effects, Cells, Cultured, Disease Models, Animal, Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous, Histone Deacetylase 1 - antagonists & inhibitors, Histone Deacetylase 1 - metabolism, Histone Deacetylase Inhibitors - pharmacology, Histone Deacetylase Inhibitors - therapeutic use, Histone Deacetylases - drug effects, Histone Deacetylases - metabolism, Humans, Hydroxamic Acids - pharmacology, Hydroxamic Acids - therapeutic use, Hypertension, Pulmonary - drug therapy, Hypertension, Pulmonary - etiology, Hypertension, Pulmonary - metabolism, Hypoxia - complications, Lung - drug effects, Lung - metabolism, Lung - pathology, Male, Medical sciences, Muscle, Smooth, Vascular - drug effects, Muscle, Smooth, Vascular - metabolism, Muscle, Smooth, Vascular - pathology, Platelet-Derived Growth Factor - pharmacology, Pneumology, Pulmonary Artery - drug effects, Pulmonary Artery - metabolism, Pulmonary Artery - pathology, Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases, Rats, Rats, Sprague-Dawley, Valproic Acid - pharmacology, Valproic Acid - therapeutic use, Vorinostat