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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

Ang II stimulates gp91phox expression, a subunit of NADPH oxidase, via the angiotensin type 1 (AT1) receptor, which leads to the increase in superoxide (O2-). Furthermore, peroxynitrite is formed form the inteaction of O2- with nitric oxide (NO). Both superoxide and peroxynitrite inactivate telomerase activity, which induces the impairment of telomere structure integrity, resulting in senescence.
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Figure 3: Ang II stimulates gp91phox expression, a subunit of NADPH oxidase, via the angiotensin type 1 (AT1) receptor, which leads to the increase in superoxide (O2-). Furthermore, peroxynitrite is formed form the inteaction of O2- with nitric oxide (NO). Both superoxide and peroxynitrite inactivate telomerase activity, which induces the impairment of telomere structure integrity, resulting in senescence.

Mentions: We have shown that in animal models of hypertension, as well as in subjects with essential hypertension, EPCs become precociously senescent and dysfunctional [134]. Higher blood pressure is associated with lower EPCs levels in the general population [135], and in diabetic subjects [136]. Hyperreactivity of the renin-angiotensin system (RAS) has been recognized as one link between hypertension and altered EPCs biology. Bahlmann et al. [136] documents that angiotensin receptor antagonists increase the number of EPCs in patients with type II diabetes mellitus. This effect seems to be a class effect, because they have demonstrated it with standard doses of 2 long acting ARBs (olmesartan or irbesartan). In contrast, in patients treated with standard antihypertensives, they did not observe any effects of EPCs. Ramipril is an angiotensin-converting enzyme (ACE) inhibitor used to reduce RAAS activation in patients with stable CAD. Min et al. [137] showed that increased numbers of EPCs could be cultured from ramipril-treated patients with stable CAD and that ACE inhibition resulted in improved functional properties like adhesion, proliferation, migration, and in vitro vasculogenesis assay, independent of any impact on blood pressure. These results show that EPCs are sensitive to Ang II signalling and that this should indeed impact on number and function. Our group has shown that Ang II increases the rate of senescence of EPCs and that this appears to be a consequence of its ability to stimulate expression of gp91phox and thus O2- formation [138]. In addition, we have demonstrated that the ability of Ang II to induce senescence also involves the suppression of telomerase [138]. Our group also noticed an expected increase in formation of a marker of oxidative stress-peroxynitrite, which is formed of O2- with NO in the Ang II-treated EPCs [138]. Increased O2- production is a feature of Ang II-dependent hypertension [139]. Thus, under conditions of Ang II excess, Ang II most likely contributes to the decline in formation of the vascular endothelium at least in part by the mechanisms via Ang II-induced EPCs senescence (Fig. (3)). On the other hand, it has been demonstrated that Ang II and angiotensin peptides promote hematopoietic progenitor cell proliferation and hematopoietic recovery after radiation therapy and chemotherapy [140]. Murohara et al reported that the Ang II-AT1 receptor pathway plays an important role in angiogenesis associated with ischemia and tumor growth [141, 142]. These results appear to be contradictory to protective effects of RAS suppression on EPCs function. Recent studies suggested that the intracellular redox state is a critical modulator of the balance between self-renewal and differentiation in dividing precursor cells and that anti-oxidant may preserve their stemness [143]. It is plausible that a reduction in oxidative stress resulted in restoration of the impaired faction of EPCs in spontaneous hypertensive rats as well as patients with metabolic disorders, although it remains to be determined whether RAS inhibition stimulates EPCs function under physiological conditions in healthy subjects.


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

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

Ang II stimulates gp91phox expression, a subunit of NADPH oxidase, via the angiotensin type 1 (AT1) receptor, which leads to the increase in superoxide (O2-). Furthermore, peroxynitrite is formed form the inteaction of O2- with nitric oxide (NO). Both superoxide and peroxynitrite inactivate telomerase activity, which induces the impairment of telomere structure integrity, resulting in senescence.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Ang II stimulates gp91phox expression, a subunit of NADPH oxidase, via the angiotensin type 1 (AT1) receptor, which leads to the increase in superoxide (O2-). Furthermore, peroxynitrite is formed form the inteaction of O2- with nitric oxide (NO). Both superoxide and peroxynitrite inactivate telomerase activity, which induces the impairment of telomere structure integrity, resulting in senescence.
Mentions: We have shown that in animal models of hypertension, as well as in subjects with essential hypertension, EPCs become precociously senescent and dysfunctional [134]. Higher blood pressure is associated with lower EPCs levels in the general population [135], and in diabetic subjects [136]. Hyperreactivity of the renin-angiotensin system (RAS) has been recognized as one link between hypertension and altered EPCs biology. Bahlmann et al. [136] documents that angiotensin receptor antagonists increase the number of EPCs in patients with type II diabetes mellitus. This effect seems to be a class effect, because they have demonstrated it with standard doses of 2 long acting ARBs (olmesartan or irbesartan). In contrast, in patients treated with standard antihypertensives, they did not observe any effects of EPCs. Ramipril is an angiotensin-converting enzyme (ACE) inhibitor used to reduce RAAS activation in patients with stable CAD. Min et al. [137] showed that increased numbers of EPCs could be cultured from ramipril-treated patients with stable CAD and that ACE inhibition resulted in improved functional properties like adhesion, proliferation, migration, and in vitro vasculogenesis assay, independent of any impact on blood pressure. These results show that EPCs are sensitive to Ang II signalling and that this should indeed impact on number and function. Our group has shown that Ang II increases the rate of senescence of EPCs and that this appears to be a consequence of its ability to stimulate expression of gp91phox and thus O2- formation [138]. In addition, we have demonstrated that the ability of Ang II to induce senescence also involves the suppression of telomerase [138]. Our group also noticed an expected increase in formation of a marker of oxidative stress-peroxynitrite, which is formed of O2- with NO in the Ang II-treated EPCs [138]. Increased O2- production is a feature of Ang II-dependent hypertension [139]. Thus, under conditions of Ang II excess, Ang II most likely contributes to the decline in formation of the vascular endothelium at least in part by the mechanisms via Ang II-induced EPCs senescence (Fig. (3)). On the other hand, it has been demonstrated that Ang II and angiotensin peptides promote hematopoietic progenitor cell proliferation and hematopoietic recovery after radiation therapy and chemotherapy [140]. Murohara et al reported that the Ang II-AT1 receptor pathway plays an important role in angiogenesis associated with ischemia and tumor growth [141, 142]. These results appear to be contradictory to protective effects of RAS suppression on EPCs function. Recent studies suggested that the intracellular redox state is a critical modulator of the balance between self-renewal and differentiation in dividing precursor cells and that anti-oxidant may preserve their stemness [143]. It is plausible that a reduction in oxidative stress resulted in restoration of the impaired faction of EPCs in spontaneous hypertensive rats as well as patients with metabolic disorders, although it remains to be determined whether RAS inhibition stimulates EPCs function under physiological conditions in healthy subjects.

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