Stimulation of endothelial progenitor cells: a new putative effect of several cardiovascular drugs

The role of vascular endothelium in cardiovascular disorders is well recognized. Mature endothelial cells contribute to the repair of endothelial injury, but they only have a limited capacity to do so. This has led to growing interest and further investigation into circulating endothelial progenitor cells (EPCs) and their role in vascular healing, repair, and postnatal neovascularization. The current perception of vascular health is that of a balance between ongoing injury and resultant vascular repair, mediated at least in part by circulating EPCs. Circulating EPCs play an important role in accelerating endothelialization at areas of vascular damage, and EPC enumeration is a viable strategy for assessing reparative capacity. Recent studies have shown that EPCs are affected both in number and function by several cardiovascular risk factors as well as various cardiovascular disease states, such as hypertension, hypercholesterolemia, and coronary artery disease. The present review summarizes the most relevant studies on the effects of cardiovascular drugs on vascular function and EPCs, focusing on their mechanisms of action.     

Water extract of Korean red ginseng stimulates angiogenesis by activating the PI3K/Akt-dependent ERK1/2 and eNOS pathways in human umbilical vein endothelial cells

Angiogenesis is important for promoting cardiovascular disease, wound healing, and tissue regeneration. We investigated the effects of Korean red ginseng water extract (KRGE) on angiogenesis and its underlying signal mechanism. KRGE increased in vitro proliferation, migration, and tube formation of human umbilical vein endothelial cells, as well as stimulated in vivo angiogenesis without increasing VEGF expression. KRGE-induced angiogenesis was accompanied by phosphorylation of ERK1/2, phosphatidylinositol 3-kinase (Akt), and endothelial nitric oxide synthase (eNOS) as well as an increase in NO production. Inhibition of PI3K activity by wortmannin completely inhibited KRGE-induced angiogenesis and phosphorylation of Akt, ERK1/2, and eNOS, indicating that PI3K/Akt activation is an upstream event of the KRGE-mediated angiogenic pathway. The MEK inhibitor PD98059 blocked KRGE-induced ERK1/2 phosphorylation without affecting Akt and eNOS activation. However, the eNOS inhibitor N(G)-monomethyl-L-arginine effectively inhibited tube formation, but partially blocked proliferation and migration as well as ERK phosphorylation, without altering Akt and eNOS activation, revealing that the eNOS/NO pathway is partially involved in ERK1/2 activation. This study demonstrated that KRGE stimulates in vitro and in vivo angiogenesis through the activation of the PI3K/Akt-dependent ERK1/2 and eNOS signal pathways and their cross talk.     

Transfection of HGF gene enhances endothelial progenitor cell (EPC) function and improves EPC transplant efficiency for balloon-induced arterial injury in hypercholesterolemic rats

Risk factors for coronary heart disease can reduce the number of endothelial progenitor cells (EPCs) and impair EPC function, thus hindering their utility in the treatment of cardiovascular diseases. In the present study, we began exploring the feasibility of genetic modification of EPCs with hepatocyte growth factor (HGF) to counter the effects of these risk factors and enhance the biological functions of EPCs. The effects of HGF transfection on proliferation, migration and angiogenesis of EPCs were investigated. Additionally, the role of ERK1/2 in this process was evaluated through the observation of ERK1/2 and ERK1/2 phosphorylation as well as by pharmacological analysis. Finally, we evaluated the effect of HGF-transfected EPCs (HGF-EPCs) on neointima formation after balloon-induced arterial injury in hypercholesterolemic rats. Our data showed that EPCs transfected with the HGF gene released high levels of soluble HGF protein, which were maintained for at least nine days. Transfection with HGF also enhanced the proliferative, migratory and angiogenic capabilities of EPCs, and promoted the activation of ERK1/2 without affecting its expression. ERK1/2 blockade by the chemical inhibitor PD98059 partially inhibited these effects. In hypercholesterolemic rats, HGF-EPCs homed to the site of vascular injury at a significantly higher rate than did EPCs without the exogenous HGF gene. Furthermore, systemically applied HGF-EPCs were more effective in decreasing neointima formation and increasing re-endothelialization. These data suggest that gene delivery combined with EPC transplant may be a practical and promising therapy for the prevention of neointimal formation after vascular injury.     

Effects of resveratrol on endothelial progenitor cells and their contributions to reendothelialization in intima-injured rats

The aim of this study was to investigate the effects of resveratrol on endothelial progenitor cell (EPC) activities in vitro and on the mobilization of circulating EPCs, and reendothelialization in balloon-injured aorta of rats. After being isolated, cultured, and characterized, human EPCs were stimulated with resveratrol. We found that a low concentration of resveratrol (1 microM) led to significant enhanced activities of proliferation, migration, and adhesion, as well as promoting endothelial nitric acid synthetase (eNOS) expression in EPCs, whereas a high concentration (60 microM) inhibited the aforementioned functions and eNOS expression. In a rat model of injured aorta, a low dosage of resveratrol (10 mg/kg) increased the amount of EPCs in rat circulation as compared with placebo, whereas the result of a high dosage (50 mg/kg) did not reach statistical difference. In addition, 10 mg/kg of resveratrol both accelerated reendothelialization and inhibited neointimal formation; however, 50 mg/kg only reduced neointimal formation, which was not as effective as the previous one. eNOS expression in injured arteries was potently enhanced in the 10 mg/kg group, but not in the 50 mg/kg group.These findings suggest that a low dosage of resveratrol could markedly raise the proliferative, migrative, and adhesive activities of EPCs and upgrade eNOS expression in vitro as well as increase EPC mobilization, enhance eNOS expression, and accelerate the repair of injured artery; however, a high dosage cannot.     

肝X受体在百草枯致急性肺损伤小鼠肺组织中的表达及作用

目的研究肝X受体(Liver X receptors,LXRs)在百草枯(Paraquat,PQ)致急性肺损伤小鼠肺组织中的表达情况及保护作用。方法 48只雄性c57小鼠随机分为6组,对照组:0.1 m L生理盐水腹腔注射;A组(TO901317低剂量对照组):5 mg/kg TO901317腹腔注射;B组(TO901317高剂量对照组):20 mg/kg TO901317腹腔注射;C组(百草枯染毒组):百草枯28 mg/kg腹腔注射;D组(TO901317低剂量预处理组):百草枯染毒前0.5 h给予TO901317 5 mg/kg腹腔注射;E组(TO901317高剂量预处理组):百草枯染毒前0.5 h给予TO90131720 mg/kg腹腔注射。在百草枯染毒后72 h处死小鼠,收集肺组织及肺泡灌洗液标本。肺组织取出后测定肺湿重/干重比,肺组织切片后HE染色进行肺损伤评分,采用ELISA方法检测肺泡灌洗液中IL-1β和TNF-α含量,Western blot方法检测肺组织中LXRs(LXRα和LXRβ)及Toll样受体4(TLR-4)的表达。结果对照组小鼠肺组织中可检测到较高水平的LXRα和LXRβ表达,与对照组相比,百草枯中毒组小鼠LXRα和LXRβ表达明显减少,肺湿重/干重比及肺损伤评分显著增加,肺泡灌洗液中IL-1β和TNF-α含量明显增高,TLR-4表达明显增加。上述改变在TO901317预处理组明显减轻,减轻程度与TO901317剂量有关。结论肝X受体可以在正常小鼠肺组织的中表达,百草枯中毒可显著抑制肝X受体在小鼠肺组织中表达,应用LXRs激动剂TO901317能明显减轻百草枯导致的小鼠急性肺损伤程度,这一作用可能与LXRs抑制TLR-4在肺组织中的表达有关。     

The pleiotropic effects of ARB in vascular endothelial progenitor cells

Angiotensin II regulates blood pressure and contributes to endothelial dysfunction and the progression of atherosclerosis. Bone marrow-derived endothelial progenitor cells (EPCs) in peripheral blood contribute to postnatal vessel repair and neovascularization. Impaired EPC function in patients with hypertension and diabetes inhibits the endogenous repair of vascular lesions and leads to the progression of atherosclerosis. The number of EPCs in peripheral blood is inversely correlated with mortality and the occurrence of cardiovascular events. Angiotensin II-mediated signaling is implicated in oxidative stress, inflammation and insulin resistance, factors that cause EPC dysfunction. Blockade of the angiotensin II type 1 receptor may therefore present a new therapeutic target for enhancing EPC function.     

Rosiglitazone via upregulation of Akt/eNOS pathways attenuates dysfunction of endothelial progenitor cells,induced by advanced glycation end products

Background and purpose:

Advanced glycation end products (AGEs) and endothelial progenitor cells (EPCs) play key roles in pathogenesis of diabetes-related vascular complications. AGEs can induce dysfunction in EPCs. The peroxisome proliferator-activated receptor-gamma (PPARγ) agonists are widely used in the treatment of type 2 diabetes, and it remains unknown if they could attenuate EPC dysfunction induced by AGEs.

Experimental approach:

EPCs isolated from healthy adults were cultured with various concentrations of AGEs (0, 50, 100 and 200 mg·L⁻¹) with or without rosiglitazone (10 nM), antibody for the receptors for AGE-human serum albumin (anti-receptor for advanced glycation end products (RAGE); 50 µg·mL⁻¹), phosphatidylinositol-3-kinase (PI3K) inhibitor ({"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002, 5 µM), nitric oxide (NO) synthase inhibitor (L-N^G-nitro-arginine methyl ester (L-NAME), 100 µM) or sodium nitroprusside (SNP, 25 µM). Proliferation, apoptosis, cell adhesion, migration and NO production in EPCs were assessed, and expressions of endothelial NO synthase (eNOS) and Akt were determined.

Key results:

Number, proliferation/migration capacities, eNOS and Akt phosphorylation as well as NO synthesized by EPCs were increased by rosiglitazone and reduced by AGEs. AGEs promoted while rosiglitazone reduced EPC apoptosis. The AGE-induced effects were significantly ameliorated by pre-incubation with rosiglitazone, RAGE antibody and SNP. The beneficial effects of rosiglitazone could be blocked by pretreatment with L-NAME and {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002.

Conclusions and implications:

The PPARγ agonist rosiglitazone increased EPC function and attenuated EPC dysfunction induced by AGEs via upregulating the Akt-eNOS signal pathways of EPCs.     

The effects of growth hormone and insulin-like growth factor-1 on the aging cardiovascular system and its progenitor cells

Aging is a major risk factor for the development of cardiovascular disease. Aging is also associated with a decline in the growth hormone (GH) and insulin-like growth factor-1 (IGF-1) axis. This axis impacts endothelial and vascular smooth muscle cell biology, as well as cardiac function. The number of endothelial progenitor cells (EPCs) also decreases with age and is emerging as a surrogate measurement of vascular senescence. Studies suggest that EPCs impact vascular health by modulating vascular repair and function. Current evidence demonstrates that EPC number and function is restored with a GH-mediated increase in serum IGF-1. Modulation of the GH and IGF-1 system may therefore provide a useful therapy in the prevention of age-associated changes in the cardiovascular system and in future regenerative cell-based therapies.     

Circulating endothelial progenitor cells as biomarkers for prediction of cardiovascular outcomes

Experimental studies suggest that bone marrow-derived endothelial progenitor cells (EPCs) play an important role in the maintenance of endothelial integrity and hemostasis. The number of circulating EPC has been shown to be inversely correlated with cardiovascular risk factors and vascular function and to predict cardiovascular events independent of both traditional and non-traditional risk factors. Thus, EPCs provide a clinical advantage over the use of other biomarkers as their measurement is directly associated with endothelial function, and available evidence suggests that they are consistently and significantly associated with a spectrum of cardiovascular complications, such as acute coronary syndromes and coronary artery disease. However, many issues in the field of EPC isolation and identification, particularly in regards to the effective and unequivocal molecular characterization of these cells still remain unresolved. In addition, simple EPC counts do not adequately describe cardiovascular disease risk. This limitation is attributable to variation in the definition of EPCs, the number of existing cardiovascular risk factors in different patients as well as a difference in the interaction between EPCs and other hematopoietic progenitor, inflammatory cells or platelets.     

Hypoxia inducible factor-1 alpha, endothelial progenitor cells, monocytes, cardiovascular risk, wound healing, cobalt and hydralazine: a unifying hypothesis

Bone marrow-derived mononuclear cells differentiate into endothelial cells in adult animals, including humans. These cells, endothelial progenitor cells (EPCs), play central roles in neovascularization in a variety of physiological and pathological processes. EPCs numbers are clinically relevant; in patients with vascular disease, EPC numbers are predictive of hard clinical endpoints and correlate with vascular health in patients without manifest atherosclerosis. EPCs express CXCR4 which allows homing to sites of neovascularization. The homing signal released by the target tissues is SDF-1 which is the ligand for CXCR4. With release of SDF-1 and reversal of the marrow/periphery gradient, EPCs are mobilized to the periphery where they are recruited to SDF-1 expressing tissues. The SDF-1/CXCR4 axis is the final common pathway for EPC mobilization by hypoxia, angiogenic peptides and G-CSF. Expression of SDF-1 in target tissues and CXCR4 in EPCs as well as angiogenic cytokines such as VEGF are regulated by hypoxia inducible factor-1 alpha (HIF-1 alpha). This paper discusses evidence suggesting that depressed HIF-1 alpha-mediated gene programming is the most fundamental of all cardiovascular risk factors and discusses the manipulation of this system with existing drugs such as cobalt or hydralazine. By stabilizing HIF-1 alpha protein, these compounds will enhance EPC mobilization and function, thereby improving cardiovascular health overall. This paper discusses why previous studies with EPC transplantation or mobilization with G-CSF have had negative results and proposes the use of Cobalt and Hydralazine to enhance EPC function to overcome the dysfunctional EPC phenotype that is seen in patients with vascular disease or cardiovascular risk factors.     

Resveratrol reduces endothelial progenitor cells senescence through augmentation of telomerase activity by Akt-dependent mechanisms

Background and purpose:

Recent studies have shown that resveratrol increased endothelial progenitor cells (EPCs) numbers and functional activity. However, the mechanisms remain to be determined. Previous studies have demonstrated that increased EPC numbers and activity were associated with the inhibition of EPC senescence, which involves activation of telomerase. Therefore, we investigated whether resveratrol inhibits the onset of EPC senescence through telomerase activation, leading to potentiation of cellular activity.

Experimental approach:

After prolonged in vitro cultivation, EPCs were incubated with or without resveratrol. The senescence of EPCs were determined by acidic β-galactosidase staining. The bromo-deoxyuridine incorporation assay or a modified Boyden chamber assay were employed to assess proliferative or migratory capacity, respectively. To further examine the underlying mechanisms of these effects, we measured telomerase activity and the phosphorylation of Akt by western blotting.

Key results:

Resveratrol dose dependently prevented the onset of EPCs senescence and increased the proliferation and migration of EPCs. The effect of resveratrol on senescence could not be abolished by eNOS inhibitor or by an oestrogenic receptor antagonist. Resveratrol significantly increased telomerase activity and Akt phosphorylation. Pre-treatment with the PI3K inhibitor, {"type":"entrez-nucleotide","attrs":{"text":"LY294002","term_id":"1257998346","term_text":"LY294002"}}LY294002, significantly attenuated resveratrol-induced telomerase activity.

Conclusions and implications:

Resveratrol delayed the onset of EPC senescence and this effect was accompanied by activation of telomerase through the PI3K-Akt signalling pathway. The inhibition of EPCs senescence by resveratrol might protect EPCs against dysfunction induced by pathological factors in vivo and improve EPC functional activities in a way that may be important for cell therapy.     

Dronedarone hydrochloride enhances the bioactivity of endothelial progenitor cells via regulation of the AKT signaling pathway

Cardiovascular disease (CVD) and its complications are the leading cause of morbidity and mortality in the world. Because of the side effects and incomplete recovery from current therapy, stem cell therapy emerges as a potential therapy for CVD treatment, and endothelial progenitor cell (EPC) is one of the key stem cells used for therapeutic applications. The effect of this therapy required the expansion of EPC function. To enhance the EPC activation, proliferation, and angiogenesis using dronedarone hydrochloride (DH) is the purpose of this study. DH received approval for atrial fibrillation treatment and its cardiovascular protective effects were already reported. In this study, DH significantly increased EPC proliferation, tube formation, migration, and maintained EPCs surface marker expression. In addition, DH treatment up-regulated the phosphorylation of AKT and reduced the reactive oxygen species production. In summary, the cell priming by DH considerably improved the functional activity of EPCs, and the use of which might be a novel strategy for CVD treatment.     

Dysfunction of endothelial progenitor cells under diabetic conditions and its underlying mechanisms

Cardiovascular complications have been major concerns in the treatment of diabetes, and up to 80% of all deaths in diabetic patients are linked to cardiovascular problems. Impaired angiogenesis is one of the most serious symptoms associated with diabetes, resulting in delayed wound healing and lower limb amputation. Endothelial progenitor cells (EPCs), a subpopulation of adult stem cells, are recruited from bone marrow to the injured vessel to promote endothelial regeneration and neovascularization, playing an important role in angiogenesis. Interestingly, several clinical studies have showed that the number of recruited EPCs is reduced and their function is decreased under diabetic conditions, implying that diabetic EPC dysfunction may contribute to defective angiogenesis and resultant cardiovascular complications in diabetes. To recover the functional abilities of diabetic EPCs and to address possible application of EPC cell therapy to diabetic patients, some studies provided explanations for diabetic EPC dysfunction including increased oxidative stress, involvement of the inflammatory response, alteration in the nitric oxide pathway and reduced signals for EPC recruitment. This review discusses clinical evidence of impairment of EPC functions under diabetic conditions and the suggested mechanisms for diabetic EPC dysfunction.     

The effects of HMG-CoA reductase inhibitor on vascular progenitor cells

Circulating bone marrow-derived vascular progenitor cells contribute to angiogenesis, atherosclerosis, and the response to vascular injury. These vascular progenitor cells consist of two cell groups, endothelial progenitor cells (EPCs) and smooth muscle progenitor cells (SMPCs). Although HMG-CoA reductase inhibitors (statins) have been reported to inhibit atherosclerosis partially by increased EPCs, the effects of statins on SMPCs are unclear. Therefore, we investigated the relationship between EPCs and SMPCs and whether pravastatin has atheroprotective effects on SMPCs. Peripheral mononuclear cells (MNCs) were isolated and cultured on fibronectin-coated dishes in SMPC medium. MNCs were stained with acetylated low density lipoprotein and lectin, or alpha-smooth muscle actin, and cell numbers were counted. mRNA expression and vascular endothelial growth factor (VEGF) protein synthesis of MNCs were evaluated. Pravastatin significantly increased the number of EPC and decreased the number of SMPC. mRNA expression of VEGF, endothelial nitric oxide synthase, VEGF receptor-2 (KDR), and Akt were up-regulated, and VEGF secretion was increased by pravastatin. The present study demonstrated that pravastatin has promotive effects on the differentiation from MNCs to EPC cells, while inhibitory effects to SMPC cells. Our findings suggest a previously unreported mechanism of the effect of statin therapy on vascular progenitor cells.     

Effects of metoprolol,methyldopa, and nifedipine on endothelial progenitor cells in patients with gestational hypertension and preeclampsia

Endothelial progenitor cells (EPCs) are critical for vascular regeneration and function, but are reduced in hypertensive disorders of pregnancy. We aimed to determine the possible effects of antihypertensive drugs, such as metoprolol, methyldopa, and nifedipine, on EPC number and functions in patients with gestational hypertension and preeclampsia. We collected blood samples from 30 normal pregnant women, 67 patients with gestational hypertension and 48 patients with preeclampsia. The patients received no drug or an antihypertensive drug, such as metoprolol, methyldopa, or nifedipine, between 20 and 24 weeks of gestation. The number of EPCs and circulating endothelial cells (CECs) in the blood was measured by flow cytometry. Moreover, colony formation and migration assays were performed on the isolated EPCs. Both the systolic and diastolic blood pressure (BP) increased, while the percentage of flow‐mediated vasodilatation (FMD) decreased in patients with gestational hypertension and preeclampsia, compared to the healthy controls at 20 weeks of gestation. CEC number increased in the patients, whereas EPC counts decreased. Furthermore, EPC colony formation and migration abilities were also impaired in the patients. However, administration of metoprolol, methyldopa, or nifedipine effectively restored the systolic and diastolic BP, FMD%, EPCs, and CEC numbers, as well as EPC migration capacity. Endothelial progenitor cells colony formation ability selectively improved with methyldopa and nifedipine. In patients receiving no drugs, most of these indexes worsened within 4 weeks (study duration). This study revealed a new pharmacological action of these antihypertensive drugs against gestational hypertension and preeclampsia, thus supporting their clinical use.     

Ginkgo biloba extract reduces endothelial progenitor-cell senescence through augmentation of telomerase activity

Our previous studies have shown that Ginkgo biloba extract increased endothelial progenitor-cell (EPC) numbers and functional activity. However, the mechanisms remain to be determined. Recent studies have demonstrated that increased EPC numbers and activity were associated with the inhibition of EPC senescence, which involved activation of telomerase. Therefore, we investigated whether Ginkgo biloba extract inhibited the onset of EPC senescence through telomerase activation, leading to potentiation of cellular activity. After ex vivo cultivation, EPCs became senescent as determined by acidic ss-galactosidase staining. Ginkgo biloba extract dose-dependently prevented the onset of EPC senescence in culture. Moreover, Ginkgo biloba extract increased proliferation of EPCs as assessed by MTT assay and colony-forming capacity. To get further insights into the underlying mechanisms of these effects, we measured telomerase activity and determined the phosphorylation of Akt by Western blotting. Ginkgo biloba extract significantly increased telomerase activity and phosphorylation of the serine/threonine protein kinase Akt, a downstream effector of phosphoinositide 3-kinase (PI3K). Moreover, pretreatment with PI3K inhibitor, LY294002, significantly attenuated the Ginkgo biloba extract-induced telomerase activity. Taken together, the results indicated that Ginkgo biloba extract delayed the onset of EPC senescence, which may be related to activation of telomerase through the PI3k/Akt signaling pathway. The inhibition of EPC senescence by Ginkgo biloba extract in vitro may improve the functional activity of EPCs in a way that is important for potential cell therapy.     

Physiological differences between human and rat primary hepatocytes in response to liver X receptor activation by 3-[3-[N-(2-chloro-3-trifluoromethylbenzyl)-(2,2-diphenylethyl)amino]propyloxy]phenylacetic acid hydrochloride (GW3965)

The liver is central to the maintenance of glucose and lipid homeostasis, and liver X receptors (LXRs) are key regulators of expression of the genes involved. So far, effects of activation of LXR in human hepatocytes have not been well characterized. Here we show that treatment of primary human hepatocytes with the synthetic LXR ligand 3-[3-[N-(2-chloro-3-trifluoromethylbenzyl)-(2,2-diphenylethyl)amino]propyloxy]phenylacetic acid hydrochloride (GW3965) results in reduced output of bile acids and very low density lipoprotein triglycerides and induced expression of adipose differentiation-related protein accompanied by increased lipid storage. Genome wide-expression profiling identified novel human LXR target genes in the glycolytic and lipogenic pathways and indicated that LXR activation reduced hepatic insulin sensitivity. Comparative experiments showed significant differences in the response to GW3965 between human and rat hepatocytes, raising the question as to how well rodent models reflect the human situation. In summary, the risk of hepatic steatosis upon pharmaceutical targeting of LXR may be a particularly serious consequence in humans.     

Atorvastatin inhibits homocysteine-induced dysfunction and apoptosis in endothelial progenitor cells

Aim:

To investigate the protective effects of atorvastatin on homocysteine (Hcy)-induced dysfunction and apoptosis in endothelial progenitor cells (EPCs) and the possible molecular mechanisms.

Methods:

EPCs were divided into six groups: Hcy treatment groups (0, 50, and 500 μmol/L) and atorvastatin pretreatment groups (0.1, 1, and 10 μmol/L). EPC proliferation, migration, in vitro vasculogenesis activity, and apoptosis rate were assayed by the MTT assay, modified Boyden chamber assay, in vitro vasculogenesis kit, and AnnexinV-FITC apoptosis detection kit, respectively. The level of reactive oxygen species (ROS) in cells was measured using H₂DCF-DA as a fluorescence probe. The activity of NADPH oxidase was evaluated with lucigenin-enhanced chemiluminescence. NO in the supernatant was detected by the nitrate reductase assay. The eNOS mRNA expression and p-eNOS, p-Akt, p-p38MAPK protein expression were measured by RT-PCR and Western blotting analysis, respectively. Caspase-3 activity was determined by colorimetric assay.

Results:

Hcy does-dependently impaired the proliferation, migration and in vitro vasculogenesis capacity of EPCs, induced cell apoptosis, increased ROS accumulation and NADPH oxidase activation, and decreased the secretion of NO compared with the control group (P<0.05 or P<0.01). The detrimental effects of Hcy were attenuated by atorvastatin pretreatment. Furthermore, Hcy caused a significant downregulation of eNOS mRNA, p-eNOS, and p-Akt protein expression as well as an upregulation of p-p38MAPK protein expression and caspase-3 activity. These effects of Hcy on EPCs were reversed by atorvastatin in a does-dependent manner.

Conclusion:

Atorvastatin inhibited homocysteine-induced dysfunction and apoptosis in endothelial progenitor cells, which may be related to its effects on suppressing oxidative stress, up-regulating Akt/eNOS and down-regulating the p38MAPK/caspase-3 signaling pathway.     

内皮祖细胞的迁移及对血管修复作用的研究进展

血管内皮损伤及其修复功能发生障碍在心血管疾病的发生发展过程中起着重要作用,内皮祖细胞是干细胞的一种亚型,为内皮细胞的前体细胞,在成年机体内主要定居在骨髓干细胞池中,具有高增殖潜能.多种因素可刺激EPCs从骨髓动员到外周血液,在细胞因子等作用下归巢到血管损伤部位并分化为成熟内皮细胞.本文就骨髓EPCs从动员到分化为内皮细胞过程中不同标志物的表达及可能存在的分子信号机制进行综述.