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Reprogramming ageing and longevity genes restores paracrine angiogenic properties of early outgrowth cells


Paneni, Francesco; Costantino, Sarah; Kränkel, Nicolle; Cosentino, Francesco; Lüscher, Thomas F (2016). Reprogramming ageing and longevity genes restores paracrine angiogenic properties of early outgrowth cells. European Heart Journal, 37(22):1733-1737.

Abstract

AIMS: Impaired tissue vascularization is a major determinant of cardiovascular disease (CVD) in the elderly. Accumulation of reactive oxygen species (ROS) may interfere with vascular repair, but the underlying mechanisms remain unknown. Early outgrowth cells (EOCs) play an important role in endothelial repair. We investigated whether key lifespan genes involved in ROS, i.e. the mitochondrial adaptor p66(Shc) and the AP-1 transcription factor JunD, contribute to age-related EOCs dysfunction in humans.
METHODS AND RESULTS: Early outgrowth cells were isolated and cultured from peripheral blood mononuclear cells of young and old healthy volunteers. Early outgrowth cells isolated from aged individuals displayed p66(Shc) gene up-regulation and reduced JunD expression. Deregulation of p66(Shc) and JunD in aged EOCs led to up-regulation of NADPH oxidase, reduced expression of manganese superoxide dismutase (MnSOD) and increased O2 (-) generation. This was associated with an impairment of EOCs-induced migration of mature endothelial cells. Secretome profiling revealed that angiogenic chemokines such as stromal-derived factor-1 and monocyte chemoattractant protein-1 were deregulated in conditioned medium collected from aged EOCs. Interestingly, p66(Shc) silencing or JunD overexpression blunted age-related O2 (-) production via the NADPH/MnSOD axis, and restored paracrine angiogenic potential of aged EOCs.
CONCLUSION: Reprogramming ageing and longevity genes preserves EOCs functionality by affecting their paracrine properties. These findings set the basis for novel therapeutic strategies to improve for vascular repair after injury and in CVD in the elderly.

Abstract

AIMS: Impaired tissue vascularization is a major determinant of cardiovascular disease (CVD) in the elderly. Accumulation of reactive oxygen species (ROS) may interfere with vascular repair, but the underlying mechanisms remain unknown. Early outgrowth cells (EOCs) play an important role in endothelial repair. We investigated whether key lifespan genes involved in ROS, i.e. the mitochondrial adaptor p66(Shc) and the AP-1 transcription factor JunD, contribute to age-related EOCs dysfunction in humans.
METHODS AND RESULTS: Early outgrowth cells were isolated and cultured from peripheral blood mononuclear cells of young and old healthy volunteers. Early outgrowth cells isolated from aged individuals displayed p66(Shc) gene up-regulation and reduced JunD expression. Deregulation of p66(Shc) and JunD in aged EOCs led to up-regulation of NADPH oxidase, reduced expression of manganese superoxide dismutase (MnSOD) and increased O2 (-) generation. This was associated with an impairment of EOCs-induced migration of mature endothelial cells. Secretome profiling revealed that angiogenic chemokines such as stromal-derived factor-1 and monocyte chemoattractant protein-1 were deregulated in conditioned medium collected from aged EOCs. Interestingly, p66(Shc) silencing or JunD overexpression blunted age-related O2 (-) production via the NADPH/MnSOD axis, and restored paracrine angiogenic potential of aged EOCs.
CONCLUSION: Reprogramming ageing and longevity genes preserves EOCs functionality by affecting their paracrine properties. These findings set the basis for novel therapeutic strategies to improve for vascular repair after injury and in CVD in the elderly.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Cardiology
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:7 June 2016
Deposited On:06 Feb 2017 15:31
Last Modified:12 Feb 2017 08:15
Publisher:Oxford University Press
ISSN:0195-668X
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1093/eurheartj/ehw073
PubMed ID:26941203

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