RGD Reference Report - Epigenetic attenuation of mitochondrial superoxide dismutase 2 in pulmonary arterial hypertension: a basis for excessive cell proliferation and a new therapeutic target. - Rat Genome Database

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Epigenetic attenuation of mitochondrial superoxide dismutase 2 in pulmonary arterial hypertension: a basis for excessive cell proliferation and a new therapeutic target.

Authors: Archer, Stephen L  Marsboom, Glenn  Kim, Gene H  Zhang, Hannah J  Toth, Peter T  Svensson, Eric C  Dyck, Jason R B  Gomberg-Maitland, Mardi  Thébaud, Bernard  Husain, Aliya N  Cipriani, Nicole  Rehman, Jalees 
Citation: Archer SL, etal., Circulation. 2010 Jun 22;121(24):2661-71. doi: 10.1161/CIRCULATIONAHA.109.916098. Epub 2010 Jun 7.
RGD ID: 27095884
Pubmed: PMID:20529999   (View Abstract at PubMed)
PMCID: PMC2914302   (View Article at PubMed Central)
DOI: DOI:10.1161/CIRCULATIONAHA.109.916098   (Journal Full-text)


BACKGROUND: Excessive proliferation and impaired apoptosis of pulmonary artery (PA) smooth muscle cells (PASMCs) contribute to vascular obstruction in patients and fawn-hooded rats (FHRs) with PA hypertension (PAH). Expression and activity of mitochondrial superoxide dismutase-2 (SOD2), the major generator of H(2)O(2), is known to be reduced in PAH; however, the mechanism and therapeutic relevance of this are unknown.
METHODS AND RESULTS: SOD2 expression in PASMCs is decreased in PAH patients and FHRs with PAH. FHR PASMCs have higher proliferation and lower apoptosis rates than Sprague-Dawley rat PASMCs. Moreover, FHR PASMCs have hyperpolarized mitochondria, low H(2)O(2) production, and reduced cytoplasmic and mitochondrial redox state. Administration of SOD2 small interfering RNA to normal PASMCs recapitulates the FHR PAH phenotype, hyperpolarizing mitochondria, decreasing H(2)O(2), and inhibiting caspase activity. Conversely, SOD2 overexpression in FHR PASMCs or therapy with the SOD-mimetic metalloporphyrin Mn(III)tetrakis (4-benzoic acid) porphyrin (MnTBAP) reverses the hyperproliferative PAH phenotype. Importantly, SOD-mimetic therapy regresses PAH in vivo. Investigation of the SOD2 gene revealed no mutation, suggesting a possible epigenetic dysregulation. Genomic bisulfite sequencing demonstrates selective hypermethylation of a CpG island in an enhancer region of intron 2 and another in the promoter. Differential methylation occurs selectively in PAs versus aortic SMCs and is reversed by the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine, restoring both SOD2 expression and the ratio of proliferation to apoptosis. Expression of the enzymes that mediate gene methylation, DNA methyltransferases 1 and 3B, is upregulated in FHR lungs.
CONCLUSIONS: Tissue-specific, epigenetic SOD2 deficiency initiates and sustains a heritable form of PAH by impairing redox signaling and creating a proliferative, apoptosis-resistant PASMC. SOD augmentation regresses experimental PAH. The discovery of an epigenetic component to PAH may offer new therapeutic targets.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
SOD2HumanPulmonary Arterial Hypertension  ISOSod2 (Rattus norvegicus)protein:decreased expression:pulmonary arteryRGD 
SOD2HumanPulmonary Arterial Hypertension  IEP protein:decreased expression:small pulmonary arteryRGD 
Sod2RatPulmonary Arterial Hypertension  ISOSOD2 (Homo sapiens)protein:decreased expression:small pulmonary arteryRGD 
Sod2RatPulmonary Arterial Hypertension  IEP protein:decreased expression:pulmonary arteryRGD 
Sod2MousePulmonary Arterial Hypertension  ISOSod2 (Rattus norvegicus)protein:decreased expression:pulmonary arteryRGD 
Sod2MousePulmonary Arterial Hypertension  ISOSOD2 (Homo sapiens)protein:decreased expression:small pulmonary arteryRGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Sod2Ratnegative regulation of membrane hyperpolarization  IMP  RGD 
Sod2Ratpositive regulation of hydrogen peroxide biosynthetic process  IMP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Sod2  (superoxide dismutase 2)

Genes (Mus musculus)
Sod2  (superoxide dismutase 2, mitochondrial)

Genes (Homo sapiens)
SOD2  (superoxide dismutase 2)


Additional Information