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Endothelial progenitor cells dysfunction and senescence: contribution to oxidative stress.

Imanishi T, Tsujioka H, Akasaka T - Curr Cardiol Rev (2008)

Bottom Line: Increased oxidant stress has been proposed as a molecular mechanism for endothelial dysfunction, in part by reducing nitric oxide (NO) bioavailability.We observed that Ang II accelerates both BM- and peripheral blood (PB)-derived EPCs senescence by a gp91phox-mediated increase of oxidative stress, resulting in EPCs dysfunction.In this review, we describe current understanding of the contributions of oxidative stress in cardiovascular disease, focusing on the potential mechanisms of EPCs senescence.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiovascular Medicine, Wakayama Medical University, 811-1, Kimiidera, Wakayama City, Wakayama 641-8510, Japan.

ABSTRACT
The identification of endothelial progenitor cells (EPCs) has led to a significant paradigm in the field of vascular biology and opened a door to the development of new therapeutic approaches. Based on the current evidence, it appears that EPCs may make both direct contribution to neovascularization and indirectly promote the angiogenic function of local endothelial cells via secretion of angiogenic factors. This concept of arterial wall repair mediated by bone marrow (BM)-derived EPCs provided an alternative to the local "response to injury hypothesis" for development of atherosclerotic inflammation. Increased oxidant stress has been proposed as a molecular mechanism for endothelial dysfunction, in part by reducing nitric oxide (NO) bioavailability. EPCs function may also be highly dependent on a well-controlled oxidant stress because EPCs NO bioavailability (which is highly sensitive to oxidant stress) is critical for their in vivo function. The critical question is whether oxidant damage directly leads to an impairment in EPCs function. It was revealed that activation of angiotensin II (Ang II) type 1 receptor stimulates nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase in the vascular endothelium and leads to production of reactive oxygen species. We observed that Ang II accelerates both BM- and peripheral blood (PB)-derived EPCs senescence by a gp91phox-mediated increase of oxidative stress, resulting in EPCs dysfunction. Consistently, both Ang II receptor 1 blockers (ARBs) and angiotensin converting enzyme (ACE) inhibitors have been reported to increase the number of EPCs in patients with cardiovascular disease. In this review, we describe current understanding of the contributions of oxidative stress in cardiovascular disease, focusing on the potential mechanisms of EPCs senescence.

No MeSH data available.


Related in: MedlinePlus

EPCs repair cardiovascular damage. Oxidative stress caused by dyslipidemia, diabetes mellitus, or hypertension interferes with the ability of EPCs proliferation, differentiation, and mobilization in bone marrow. Oxidative stress also induces EPCs senescence. These negative effects of oxidative stress on EPCs number and function bring the equilibrium between cellular repair and injury out of balance, resulting in the progression of cardiovascular damages.
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Figure 2: EPCs repair cardiovascular damage. Oxidative stress caused by dyslipidemia, diabetes mellitus, or hypertension interferes with the ability of EPCs proliferation, differentiation, and mobilization in bone marrow. Oxidative stress also induces EPCs senescence. These negative effects of oxidative stress on EPCs number and function bring the equilibrium between cellular repair and injury out of balance, resulting in the progression of cardiovascular damages.

Mentions: Clinical studies clearly demonstrate that high EPCs levels are associated with reduced cardiovascular event rates underlying the vasculoprotective action of EPCs [107, 108]. The rejuvenation of the endothelium by circulating EPCs may represent a novel approach in the prevention of atherosclerotic disease. However, limitations in therapy may come from the negative influence of cardiovascular risk factors, which are apparently overwhelming the organism’s repair mechanisms, bringing the equilibrium between vascular repair and injury out of balance (Fig. (2)). Cardiovascular risk factors negatively influence EPCs number and function, whereas vasculoprotection is at least in part mediated by functional active EPCs. Therefore, EPCs may present a cellular risk marker, integrating the positive and negative mediators affecting the endothelial monolayer. Multiple factors seem to be involved in the aging-associated deterioration of EPCs quantity and function. The chronic exposure to cardiovascular risk factors continuously damages endothelial cells and requires their intensive replacement. Conversely, cardiovascular risk factors possibly affect EPCs mobilization, integration in injured vascular sites, and angiogenic capacity (Fig. (2)). Recent studies have underlined the detrimental effects of type 1 and 2 diabetes on EPCs function [5, 109]. Loomans et al. [109] have demonstrated that the media from EPCs culture of type 1 diabetic patients not only possess evidence of reduced angiogenic capacity, but also contain an inhibitor for in vitro tube formation. Tepper et al. [5] reported that the proliferation and tube formation of EPCs were impaired in patients with type 2 diabetes compared with normal subjects. In both studies, decreased number and dysfunction of EPCs was inversely related to the levels of hemoglobin A1c, implying that the degree of glycemic dysregulation was associated with EPCs pathophysiology. Although these studies have clarified an adverse effect of DM on the functional activity of EPCs, the underlying mechanisms remain unsolved. The EPCs dysfunction may also be result of their accelerated senescence. We showed that hyperglycemia (HG) increases the rate of EPCs senescence, which effect is inhibited by an inhibitor p38 MAPK, SB203580 [110]. We also have demonstrated that high glucose (HG) levels can accelerate the p38 MAPK pathway in EPCs [110]. Seeger et al [111] have demonstrated that the redunction of EPCs induced by high glucose (HG) in vitro is associated with a profound upregulation of p38 mitogen activated protein kinase (MAPK) phosphorylation and is completely blocked by p38 inhibitors. Furthermore, EPCs cultivated from patients with CAD show an increased p38 phosphorylation compared with EPCs from healthy control subjects. Interestingly, they have shown that HG further augment the phosphorylation of the p38 downstream kinase stress-activated kinase (MSK)1 and the transcription factor camp-responsive element-binding protein (CREB). Several studies demonstrate that p38 MAPK blockade inhibition is associated with increased angiogenesis [112-114]. Because NAD(P)H oxidase activation promotes p38 MAPK phosphorylation [111], it is tempting to speculate that increased p38 MAPK phosphorylation may represent an additional potential pathway whereby NAD(P)H oxidase may alter EPCs function in DM. Therefore, p38 MAPK inhibitors and/or NAD(P)H inhbition might be a promising tool to augment the yield of ex-vivo-expanded EPCs for cell therapy, specially for the patients with DM. In this context, Sorrentino et al. [115] have demonstrated that short-term in vivo rosiglitazone treatment in diabetic subjects reduced EPCs NAD(P)H oxidase activity and restored NO availability, suggesting that PPAR-γ agonist exerts a direct on NAD(P)H oxidase in diabetic EPCs. Of note, in vitro treatment with the PPAR-γ agonist pioglitazone prevented oxidative stress-induced apoptosis in human EPCs, further suggesting a role of PPAR-γ for EPCs function [116]. We have also shown that pioglitazone reduces Ang II-induced acceleration of senescence in EPCs [117]. Collectively, therapeutic interventions that improve vascular activity in EPCs by PPAR-γ agonists may have tremendous potential for the treatment of cardiovascular diseases.


Endothelial progenitor cells dysfunction and senescence: contribution to oxidative stress.

Imanishi T, Tsujioka H, Akasaka T - Curr Cardiol Rev (2008)

EPCs repair cardiovascular damage. Oxidative stress caused by dyslipidemia, diabetes mellitus, or hypertension interferes with the ability of EPCs proliferation, differentiation, and mobilization in bone marrow. Oxidative stress also induces EPCs senescence. These negative effects of oxidative stress on EPCs number and function bring the equilibrium between cellular repair and injury out of balance, resulting in the progression of cardiovascular damages.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2801859&req=5

Figure 2: EPCs repair cardiovascular damage. Oxidative stress caused by dyslipidemia, diabetes mellitus, or hypertension interferes with the ability of EPCs proliferation, differentiation, and mobilization in bone marrow. Oxidative stress also induces EPCs senescence. These negative effects of oxidative stress on EPCs number and function bring the equilibrium between cellular repair and injury out of balance, resulting in the progression of cardiovascular damages.
Mentions: Clinical studies clearly demonstrate that high EPCs levels are associated with reduced cardiovascular event rates underlying the vasculoprotective action of EPCs [107, 108]. The rejuvenation of the endothelium by circulating EPCs may represent a novel approach in the prevention of atherosclerotic disease. However, limitations in therapy may come from the negative influence of cardiovascular risk factors, which are apparently overwhelming the organism’s repair mechanisms, bringing the equilibrium between vascular repair and injury out of balance (Fig. (2)). Cardiovascular risk factors negatively influence EPCs number and function, whereas vasculoprotection is at least in part mediated by functional active EPCs. Therefore, EPCs may present a cellular risk marker, integrating the positive and negative mediators affecting the endothelial monolayer. Multiple factors seem to be involved in the aging-associated deterioration of EPCs quantity and function. The chronic exposure to cardiovascular risk factors continuously damages endothelial cells and requires their intensive replacement. Conversely, cardiovascular risk factors possibly affect EPCs mobilization, integration in injured vascular sites, and angiogenic capacity (Fig. (2)). Recent studies have underlined the detrimental effects of type 1 and 2 diabetes on EPCs function [5, 109]. Loomans et al. [109] have demonstrated that the media from EPCs culture of type 1 diabetic patients not only possess evidence of reduced angiogenic capacity, but also contain an inhibitor for in vitro tube formation. Tepper et al. [5] reported that the proliferation and tube formation of EPCs were impaired in patients with type 2 diabetes compared with normal subjects. In both studies, decreased number and dysfunction of EPCs was inversely related to the levels of hemoglobin A1c, implying that the degree of glycemic dysregulation was associated with EPCs pathophysiology. Although these studies have clarified an adverse effect of DM on the functional activity of EPCs, the underlying mechanisms remain unsolved. The EPCs dysfunction may also be result of their accelerated senescence. We showed that hyperglycemia (HG) increases the rate of EPCs senescence, which effect is inhibited by an inhibitor p38 MAPK, SB203580 [110]. We also have demonstrated that high glucose (HG) levels can accelerate the p38 MAPK pathway in EPCs [110]. Seeger et al [111] have demonstrated that the redunction of EPCs induced by high glucose (HG) in vitro is associated with a profound upregulation of p38 mitogen activated protein kinase (MAPK) phosphorylation and is completely blocked by p38 inhibitors. Furthermore, EPCs cultivated from patients with CAD show an increased p38 phosphorylation compared with EPCs from healthy control subjects. Interestingly, they have shown that HG further augment the phosphorylation of the p38 downstream kinase stress-activated kinase (MSK)1 and the transcription factor camp-responsive element-binding protein (CREB). Several studies demonstrate that p38 MAPK blockade inhibition is associated with increased angiogenesis [112-114]. Because NAD(P)H oxidase activation promotes p38 MAPK phosphorylation [111], it is tempting to speculate that increased p38 MAPK phosphorylation may represent an additional potential pathway whereby NAD(P)H oxidase may alter EPCs function in DM. Therefore, p38 MAPK inhibitors and/or NAD(P)H inhbition might be a promising tool to augment the yield of ex-vivo-expanded EPCs for cell therapy, specially for the patients with DM. In this context, Sorrentino et al. [115] have demonstrated that short-term in vivo rosiglitazone treatment in diabetic subjects reduced EPCs NAD(P)H oxidase activity and restored NO availability, suggesting that PPAR-γ agonist exerts a direct on NAD(P)H oxidase in diabetic EPCs. Of note, in vitro treatment with the PPAR-γ agonist pioglitazone prevented oxidative stress-induced apoptosis in human EPCs, further suggesting a role of PPAR-γ for EPCs function [116]. We have also shown that pioglitazone reduces Ang II-induced acceleration of senescence in EPCs [117]. Collectively, therapeutic interventions that improve vascular activity in EPCs by PPAR-γ agonists may have tremendous potential for the treatment of cardiovascular diseases.

Bottom Line: Increased oxidant stress has been proposed as a molecular mechanism for endothelial dysfunction, in part by reducing nitric oxide (NO) bioavailability.We observed that Ang II accelerates both BM- and peripheral blood (PB)-derived EPCs senescence by a gp91phox-mediated increase of oxidative stress, resulting in EPCs dysfunction.In this review, we describe current understanding of the contributions of oxidative stress in cardiovascular disease, focusing on the potential mechanisms of EPCs senescence.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiovascular Medicine, Wakayama Medical University, 811-1, Kimiidera, Wakayama City, Wakayama 641-8510, Japan.

ABSTRACT
The identification of endothelial progenitor cells (EPCs) has led to a significant paradigm in the field of vascular biology and opened a door to the development of new therapeutic approaches. Based on the current evidence, it appears that EPCs may make both direct contribution to neovascularization and indirectly promote the angiogenic function of local endothelial cells via secretion of angiogenic factors. This concept of arterial wall repair mediated by bone marrow (BM)-derived EPCs provided an alternative to the local "response to injury hypothesis" for development of atherosclerotic inflammation. Increased oxidant stress has been proposed as a molecular mechanism for endothelial dysfunction, in part by reducing nitric oxide (NO) bioavailability. EPCs function may also be highly dependent on a well-controlled oxidant stress because EPCs NO bioavailability (which is highly sensitive to oxidant stress) is critical for their in vivo function. The critical question is whether oxidant damage directly leads to an impairment in EPCs function. It was revealed that activation of angiotensin II (Ang II) type 1 receptor stimulates nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase in the vascular endothelium and leads to production of reactive oxygen species. We observed that Ang II accelerates both BM- and peripheral blood (PB)-derived EPCs senescence by a gp91phox-mediated increase of oxidative stress, resulting in EPCs dysfunction. Consistently, both Ang II receptor 1 blockers (ARBs) and angiotensin converting enzyme (ACE) inhibitors have been reported to increase the number of EPCs in patients with cardiovascular disease. In this review, we describe current understanding of the contributions of oxidative stress in cardiovascular disease, focusing on the potential mechanisms of EPCs senescence.

No MeSH data available.


Related in: MedlinePlus