Impaired angiogenesis in aging myocardial microvascular endothelial cells is associated with reduced importin alpha and decreased nuclear transport of HIF1 alpha: mechanistic implications.
J Physiol Pharmacol
; 61(2): 133-9, 2010 Apr.
Article
in En
| MEDLINE
| ID: mdl-20436213
ABSTRACT
Aging is associated with increased incidence of myocardial infarctions and impaired angiogenesis - new capillary blood vessel formation from preexisting vessels. The molecular mechanism(s) of aging-related impairment of angiogenesis are unknown. In the present study we focused on the mechanism of activation of the gene for vascular endothelial growth factor (VEGF - the most potent stimulator of angiogenesis) in young and aging myocardial microvascular endothelial cells (MMEC). Activation of VEGF gene in the cell nucleus is mediated in part by the transcription factor hypoxia-inducible factor 1 alpha (HIF1 alpha). In order to activate VEGF gene, HIF1 alpha must first be transported to the nucleus, but the mechanisms of this transport are unknown. We hypothesized that reduced VEGF gene activation and impaired angiogenesis in myocardium during aging can result from downregulation of the nuclear transport receptor - importin alpha that leads to decreased transport of HIF1 alpha to the nucleus. We examined in MMEC isolated from young (3 months of age) and aging (24 months old) Fisher F-344 rats 1) in vitro angiogenesis; and 2) the expression of VEGF, importin alpha and HIF1 alpha. Aging MMEC exhibited a 3.7-fold reduction in angiogenesis and a corresponding reduction in VEGF (by 3-fold) and importin alpha (by 1.9-fold) levels compared to young MMEC. Aging MMEC also exhibited cytoplasmic accumulation (by 1.8-fold) of HIF1 alpha protein, reduced HIF1 alpha transport to the nucleus and decreased binding of HIF1 alpha protein to the VEGF gene promoter. This study is the first demonstration of the downregulation of importin alpha in aging MMEC and reduced nuclear transport of HIF1 alpha, which likely lead to decreased VEGF gene activation and impaired angiogenesis.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Neovascularization, Physiologic
/
Alpha Karyopherins
/
Vascular Endothelial Growth Factor A
/
Hypoxia-Inducible Factor 1, alpha Subunit
Type of study:
Risk_factors_studies
Limits:
Animals
Language:
En
Journal:
J Physiol Pharmacol
Journal subject:
FARMACOLOGIA
/
FISIOLOGIA
Year:
2010
Document type:
Article
Affiliation country:
United States