RGD Reference Report - Histone deacetylation inhibition in pulmonary hypertension: therapeutic potential of valproic acid and suberoylanilide hydroxamic acid. - Rat Genome Database

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Histone deacetylation inhibition in pulmonary hypertension: therapeutic potential of valproic acid and suberoylanilide hydroxamic acid.

Authors: Zhao, L  Chen, CN  Hajji, N  Oliver, E  Cotroneo, E  Wharton, J  Wang, D  Li, M  McKinsey, TA  Stenmark, KR  Wilkins, MR 
Citation: Zhao L, etal., Circulation. 2012 Jul 24;126(4):455-67. doi: 10.1161/CIRCULATIONAHA.112.103176. Epub 2012 Jun 18.
RGD ID: 9590133
Pubmed: PMID:22711276   (View Abstract at PubMed)
PMCID: PMC3799888   (View Article at PubMed Central)
DOI: DOI:10.1161/CIRCULATIONAHA.112.103176   (Journal Full-text)

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. METHODS AND 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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
pulmonary hypertension  ISOHdac1 (Rattus norvegicus)9590133; 9590133protein:increased expression:lung:RGD 
pulmonary hypertension  IEP 9590133; 9590133; 9590133; 9590133; 9590133protein:increased expression:lung:RGD 
pulmonary hypertension  IEP 9590133; 9590133protein:decreased expression:lung:RGD 
pulmonary hypertension  ISOHdac5 (Rattus norvegicus)9590133; 9590133protein:increased expression:lung:RGD 
pulmonary hypertension  ISOHDAC1 (Homo sapiens)9590133; 9590133protein:increased expression:lung:RGD 
pulmonary hypertension  ISOHDAC2 (Homo sapiens)9590133; 9590133protein:decreased expression:lung:RGD 
pulmonary hypertension  ISOHDAC3 (Homo sapiens)9590133; 9590133protein:decreased expression:lung:RGD 
pulmonary hypertension  ISOHDAC4 (Homo sapiens)9590133; 9590133protein:increased expression:lung:RGD 
pulmonary hypertension  ISOHDAC5 (Homo sapiens)9590133; 9590133protein:increased expression:lung:RGD 
Right Ventricular Hypertrophy  ISOHdac1 (Rattus norvegicus)9590133; 9590133protein:increased expression:Right Ventricular:RGD 
Right Ventricular Hypertrophy  ISOHdac5 (Rattus norvegicus)9590133; 9590133protein:increased expression:Right Ventricular:RGD 
Right Ventricular Hypertrophy  IEP 9590133; 9590133protein:increased expression:Right Ventricular:RGD 

Objects Annotated

Genes (Rattus norvegicus)
Hdac1  (histone deacetylase 1)
Hdac2  (histone deacetylase 2)
Hdac3  (histone deacetylase 3)
Hdac4  (histone deacetylase 4)
Hdac5  (histone deacetylase 5)

Genes (Mus musculus)
Hdac1  (histone deacetylase 1)
Hdac2  (histone deacetylase 2)
Hdac3  (histone deacetylase 3)
Hdac4  (histone deacetylase 4)
Hdac5  (histone deacetylase 5)

Genes (Homo sapiens)
HDAC1  (histone deacetylase 1)
HDAC2  (histone deacetylase 2)
HDAC3  (histone deacetylase 3)
HDAC4  (histone deacetylase 4)
HDAC5  (histone deacetylase 5)


Additional Information