RGD Reference Report - Sonic Hedgehog gene delivery to the rodent heart promotes angiogenesis via iNOS/netrin-1/PKC pathway. - Rat Genome Database

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Sonic Hedgehog gene delivery to the rodent heart promotes angiogenesis via iNOS/netrin-1/PKC pathway.

Authors: Ahmed, Rafeeq P H  Haider, Khawaja Husnain  Shujia, Jiang  Afzal, Muhammad Rizwan  Ashraf, Muhammad 
Citation: Ahmed RP, etal., PLoS One. 2010 Jan 5;5(1):e8576. doi: 10.1371/journal.pone.0008576.
RGD ID: 12879408
Pubmed: PMID:20052412   (View Abstract at PubMed)
PMCID: PMC2797399   (View Article at PubMed Central)
DOI: DOI:10.1371/journal.pone.0008576   (Journal Full-text)


BACKGROUND: We hypothesized that genetic modification of mesenchymal stem cells (MSCs) with Sonic Hedgehog (Shh) transgene, a morphogen during embryonic development and embryonic and adult stem cell growth, improved their survival and angiogenic potential in the ischemic heart via iNOS/netrin/PKC pathway.
METHODS/PRINCIPAL FINDINGS: MSCs from young Fisher-344 rat bone marrow were purified and transfected with pCMV Shh plasmid ((Shh)MSCs). Immunofluorescence, RT-PCR and Western blotting showed higher expression of Shh in (Shh)MSCs which also led to increased expression of angiogenic and pro-survival growth factors in (Shh)MSCs. Significantly improved migration and tube formation was seen in (Shh)MSCs as compared to empty vector transfected MSCs ((Emp)MSCs). Significant upregulation of netrin-1 and iNOS was observed in (Shh)MSCs in PI3K independent but PKC dependent manner. For in vivo studies, acute myocardial infarction model was developed in Fisher-344 rats. The animals were grouped to receive 70 microl basal DMEM without cells (group-1) or containing 1x10(6) (Emp)MSCs (group-2) and (Shh)MSCs (group-3). Group-4 received recombinant netrin-1 protein injection into the infarcted heart. FISH and sry-quantification revealed improved survival of (Shh)MSCs post engraftment. Histological studies combined with fluorescent microspheres showed increased density of functionally competent blood vessels in group-3 and group-4. Echocardiography showed significantly preserved heart function indices post engraftment with (Shh)MSCs in group-3 animals.
CONCLUSIONS/SIGNIFICANCE: Reprogramming of stem cells with Shh maximizes their survival and angiogenic potential in the heart via iNOS/netrin-1/PKC signaling.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
myocardial infarction treatmentISOShh (Rattus norvegicus)12879408; 12879408 RGD 
myocardial infarction treatmentIMP 12879408 RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
positive regulation of endothelial cell chemotaxis  IDA 12879408 RGD 
positive regulation of sprouting angiogenesis  IDA 12879408 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Shh  (sonic hedgehog signaling molecule)

Genes (Mus musculus)
Shh  (sonic hedgehog)

Genes (Homo sapiens)
SHH  (sonic hedgehog signaling molecule)


Additional Information