Impaired angiogenesis in aging myocardial microvascular endothelial cells is associated with reduced importin alpha and decreased nuclear transport of HIF1alpha: mechanistic implications

• Autorzy: Ahluwalia A. , Narula J. , Jones M.K. , Deng X. , Tarnawski A.S.
• Języki publikacji: EN

Abstrakty

EN

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 (HIF1). In order to activate VEGF gene, HIF1 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 that leads to decreased transport of HIF1 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 and HIF1. Aging MMEC exhibited a 3.7-fold reduction in angiogenesis and a corresponding reduction in VEGF (by 3-fold) and importin (by 1.9-fold) levels compared to young MMEC. Aging MMEC also exhibited cytoplasmic accumulation (by 1.8-fold) of HIF1 protein, reduced HIF1 transport to the nucleus and decreased binding of HIF1 protein to the VEGF gene promoter. This study is the first demonstration of the downregulation of importin in aging MMEC and reduced nuclear transport of HIF1, which likely lead to decreased VEGF gene activation and impaired angiogenesis.

Słowa kluczowe

EN

aging; angiogenesis; capillary blood vessel; cardiovascular disease; hypoxia inducible factor-1alpha; mechanistic implication; molecular mechanism; myocardial infarction; myocardial microvascular endothelial cell; nuclear transport; vascular endothelial growth factor

• Wydawca: -
• Czasopismo: Journal of Physiology and Pharmacology
• Rocznik: 2010
• Tom: 61
• Numer: 2
• Opis fizyczny: p.133-139,fig.,ref.

Twórcy

autor

Ahluwalia A.

• University of California, Irvine, CA, USA

autor

Narula J.

autor

Jones M.K.

autor

Deng X.

autor

Tarnawski A.S.

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