Obstructive sleep apnea combined dyslipidemia render additive effect on increasing atherosclerotic cardiovascular diseases prevalence.

BACKGROUND: Current study was designed to investigate the effects of obstructive sleep apnea (OSA) combined dyslipidemia on the prevalence of atherosclerotic cardiovascular diseases (ASCVD). METHODS: This was a cross-sectional study and subjects with documented dyslipidemia and without previous diagnosis of OSA were enrolled. Polysomnography was applied to evaluate apnea-hypopnea index (AHI). Based on AHI value, subjects were classified into four groups: without OSA, mild, moderate and severe OSA groups. Clinical characteristics and laboratory examination data were recorded. Relationship between AHI event and lipid profiles was analyzed, and logistic regression analysis was used to evaluate the effects of OSA combined dyslipidemia on ASCVD prevalence. RESULTS: Totally 248 subjects with dyslipidemia were enrolled. Compared to the other 3 groups, subjects with severe OSA were older, male predominant and had higher smoking rate. In addition, subjects with severe OSA had higher body mass index, waist-hip ratio, blood pressure, and higher rates of overweight and obesity. Serum levels of fasting plasma glucose, glycated hemoglobin, LDL-C and CRP were all significantly higher. ASCVD prevalence was considerably higher in subjects with severe OSA. AHI event in the severe OSA group was up to 35.4 ± 5.1 events per hour which was significantly higher than the other groups (P < 0.05 for trend). Pearson correlation analysis showed that only LDL-C was positively correlated with AHI events (r = 0.685, P < 0.05). Logistic regression analysis revealed that in unadjusted model, compared to dyslipidemia plus no-OSA group (reference group), OSA enhanced ASCVD risk in subjects with dyslipidemia, regardless of OSA severity. After extensively adjusted for confounding variables, the odds of dyslipidemia plus mild-OSA was reduced to insignificance. While the effects of moderate- and severe-OSA on promoting ASCVD risk in subjects with dyslipidemia remained significant, with severe-OSA most prominent (odds ratio: 1.52, 95% confidence interval: 1.13-2.02). CONCLUSION: OSA combined dyslipidemia conferred additive adverse effects on cardiovascular system, with severe-OSA most prominent.

Generating dual structurally and functionally skin-mimicking hydrogels by crosslinking cell-membrane compartments.

The skin is intrinsically a cell-membrane-compartmentalized hydrogel with high mechanical strength, potent antimicrobial ability, and robust immunological competence, which provide multiple protective effects to the body. Methods capable of preparing hydrogels that can simultaneously mimic the structure and function of the skin are highly desirable but have been proven to be a challenge. Here, dual structurally and functionally skin-mimicking hydrogels are generated by crosslinking cell-membrane compartments. The crosslinked network is formed via free radical polymerization using olefinic double bond-functionalized extracellular vesicles as a crosslinker. Due to the dissipation of stretching energy mediated by vesicular deformation, the obtained compartment-crosslinked network shows enhanced mechanical strength compared to hydrogels crosslinked by regular divinyl monomers. Biomimetic hydrogels also exhibit specific antibacterial activity and adequate ability to promote the maturation and activation of dendritic cells given the existence of numerous extracellular vesicle-associated bioactive substances. In addition, the versatility of this approach to tune both the structure and function of the resulting hydrogels is demonstrated through introducing a second network by catalyst-free click reaction-mediated crosslinking between alkyne-double-ended polymers and azido-decorated extracellular vesicles. This study provides a platform to develop dual structure- and function-controllable skin-inspired biomaterials.

Does continuous positive airway pressure therapy benefit patients with coronary artery disease and obstructive sleep apnea? A systematic review and meta-analysis.

The prevalent co-morbidity of coronary artery disease (CAD) and obstructive sleep apnea (OSA) has attracted great interest. However, effects of continuous positive airway pressure (CPAP) in patients with OSA and CAD for cardiovascular outcomes and deaths are still controversial. Usage of CPAP among patients with CAD and OSA could decrease the risk of cardiovascular events and death in adults. PubMed, EMBASE, Web of science, and Cochrane Library were systematically searched. Studies that described association of CPAP treatment with cardiovascular events in CAD and OSA patients were included. The main outcome was the major adverse cardiovascular events (MACE), including all-cause death, cardiovascular death, myocardial infarction (MI), stroke, and repeat revascularization. Summary relative risks (risk ratios [RRs]) and 95% confidence intervals (CIs) of outcomes were pooled and heterogeneity was assessed with the I2 statistic. Nine studies enrolling 2590 participants with OSA and CAD were included and extracted data. There was significant association of CPAP with reduced risk of MACE (RR, 0.73, 95% CI [0.55, 0.96]), particularly among those with AHI less than 30 events/h (RR, 0.43, 95% CI [0.22, 0.84]). Similarly, the same result was found in all-cause death (RR, 0.66, 95% CI, [0.46, 0.94]) and cardiovascular death (RR, 0.495, 95% CI [0.292, 0.838]). Our data suggested that CPAP usage, compared to usual care, was associated with reduced risks of cardiovascular outcomes or death in patients with OSA and CAD, particularly in the subgroup with AHI less than 30 events/h, which still needs further studies to confirm.

Advanced glycation end products depress function of endothelial progenitor cells via p38 and ERK 1/2 mitogen-activated protein kinase pathways.

OBJECTIVE: Advanced glycation end products (AGEs) and endothelial progenitor cells (EPCs) play divergent roles in the process of atherosclerosis. We investigated the effects of AGE-human serum albumin (AGE-HSA) on receptor expression for AGEs (RAGE) and EPCs apoptosis. METHODS: The human mononuclear cells were obtained by Ficoll density gradient centrifugation and cultured in M199 medium containing rh-VEGF (30 ng/ml), rh-b-FGF(6 ng/ml) and 20% NBCS for 8 days. The adhesive EPCs were sequentially harvested after 24 h synchronization and challenged with AGE-HSA (concentration range from 0 to 300 microg/ml) for 24 h and 200 microg/ml AGE-HSA (time range from 0 to 36 h). EPCs apoptosis and migration were determined, expressions of RAGE, phosphorylated ERK1/2, JNK and p38 mitogen-activated protein kinase (MAPK) of EPCs were quantified by fluorescent quantitation RT-PCR and Western-blot, effect of AGE-HSA on NF-kappaB activtiy was determined by EMSA (electrophoretic mobility shift assay) in the presence and absence of special MAPK pathways pathway inhibitors. RESULTS: AGE-HSA upregulated the expression of RAGE, this effect could be significantly inhibited by p38 MAPK and ERK MAPK inhibitor, but not by JNK MAPK inhibitor. AGE-HSA also promoted EPCs apoptosis and inhibited EPCs migration and increased NF-kappaB activity, these effects could be significantly attenuated by the anti-RAGE neutralizing antibody as well as by p38 and ERK MAPK inhibitors. CONCLUSION: AGE-HSA could promote atherosclerosis by upregulating EPCs RAGE expressions and promoting EPCs apoptosis via p38, ERK MAPK pathways, activation of NF-kappaB might also play a role in this process.

[Effects of shexiang baoxin pill on function and nitric oxide secretion of endothelial progenitor cells].

OBJECTIVE: To investigate the effects of Shexiang Baoxin Pill (SBP) on function of endothelial progenitor cells (EPCs) and its nitric oxide (NO) secretion. METHODS: Total mononuclear cells were isolated from human peripheral blood by ficoll density gradient centrifugation and inoculated on the human fibro-ligandin encrusting plate. After 7 days of in vitro culture, adherent cells were collected and incubated with SBP for 24 h. The proliferation, migration, adhesive activity, vasculogenesis capacity and NO secretion of EPCs were assayed using MTT, Transwell chamber, adhesion determination, in vitro vasculogenesis kit and nitrate reductase method, respectively. RESULTS: EPCs incubated with SBP showed the capacities higher than those of control in proliferation, migration, adhesion, in vitro vasculogenesis, and with a higher NO concentration in the culture supernatant. CONCLUSION: SBP can improve the function of EPCs, which might be a novel mechanism of its effects in improving vascular endothelial function and promoting angiogenesis.

Protective effect of silymarin against rapamycin-induced apoptosis and proliferation inhibition in endothelial progenitor cells.

For this study, peripheral blood samples were collected from human volunteers. Mononuclear cells (MNC) were separated by density centrifugation and were induced to differentiate into endothelial progenitor cells (EPCs) in vitro. Different concentrations of rapamycin and silymarin were introduced to the EPCs over 24 hours and then EPCs were analyzed for proliferation, migration, apoptosis and angiogenesis. Compared with the control group, rapamycin (1, 10, 100 ng/mL) inhibited the proliferation and migration of EPCs in a concentration dependent manner (P<0.05). Silymarin (50, 100 µg/mL) enhanced the proliferation and migration of EPCs and inhibited apoptosis in a concentration dependent manner (P<0.05). By adding rapamycin (1 ng/mL) and silymarin (25, 50, 100 µg/mL) over 24 hours, silymarin inhibited the pro-apoptotic effect of rapamycin on EPCs, and reversed the inhibition of proliferation, migration and angiogenesis of EPCs by rapamycin (P<0.05).

Oxidized high-density lipoprotein impairs endothelial progenitor cells' function by activation of CD36-MAPK-TSP-1 pathways.

AIMS: High-density lipoprotein (HDL) levels inversely correlate with cardiovascular events due to the protective effects on vascular wall and stem cells, which are susceptible to oxidative modifications and then lead to potential pro-atherosclerotic effects. We proposed that oxidized HDL (ox-HDL) might lead to endothelial progenitor cells (EPCs) dysfunction and investigated underlying mechanisms. RESULTS: ox-HDL was shown to increase apoptosis and intracellular reactive oxygen species levels, but to reduce migration, angiogenesis, and cholesterol efflux of EPCs in a dose-dependent manner. p38 mitogen-activated protein kinase (MAPK) and NF-κB were activated after ox-HDL stimulation, which also upregulated thrombospondin-1 (TSP-1) expression without affecting vascular endothelial growth factor. Effects caused by ox-HDL could be significantly attenuated by pretreatment with short hairpin RNA-mediated CD36 knockdown or probucol. Data of in vivo experiments and the inverse correlation of ox-HDL and circulating EPC numbers among patients with coronary artery diseases (CAD) or CAD and type 2 diabetes also supported it. Meanwhile, HDL separated from such patients could significantly increase cultured EPC's caspase 3 activity, further supporting our proposal. INNOVATION: This is the most complete study to date of how ox-HDL would impair EPCs function, which was involved with activation of CD36-p38 MAPK-TSP-1 pathways and proved by not only the inverse relationship between ox-HDL and circulating EPCs in clinic but also pro-apoptotic effects of HDL separated from patients' serum. CONCLUSION: Activation of CD36-p38 MAPK-TSP-1 pathways contributes to the pathological effects of ox-HDL on EPCs' dysfunction, which might be one of the potential etiological factors responsible for the disturbed neovascularization in chronic ischemic disease.

[Changes of antioxidative capacity and endothelial function before and after treatment among patients with high altitude pulmonary edema].

OBJECTIVE: To investigate the changes of antioxidative capacity and endothelial function among patients with high altitude pulmonary edema (HAPE). METHODS: The serum levels of SOD, MDA, GSH, NO, NOS and ET-1 were measured before and after treatment among 34 cases of patients with HAPE, and 20 local healthy volunteers served as control. RESULTS: The serum levels of SOD, GSH, NO and NOS were lower in patient-group before treatment than after treatment and those in control-group significantly (P < 0.01), while the concentration of MDA and ET-1 were higher in patient-group before treatment than after treatment and those in the control-group significantly (P < 0.01). The serum levels of SOD, MDA, GSH, NO, NOS and ET-1 were not different between patient-group after treatment and the control-group (P > 0.05). CONCLUSION: The results indicated that changes of SOD, MDA, GSH, NO, NOS and ET-1 may participate in the course of HAPE.

Rehabilitation training improves exercise tolerance after percutaneous coronary intervention.

The aim of this present study was to investigate the effects of training on exercise tolerance of patients with coronary heart disease after percutaneous coronary intervention. Fifty-seven cases of coronary heart disease after percutaneous coronary intervention were divided randomly into the rehabilitation training group (26 cases) and control group (31 cases). Patients in the rehabilitation training group received rehabilitation training at different stages and exercise intensities 3 d after percutaneous coronary intervention for 3 months. The heart rate, blood pressure, ECG changes in treadmill exercise test, and the frequency of anginal episodes were observed. The results showed that NST and ΣST of ECG and the frequency of anginal episodes were significantly reduced in the rehabilitation training group. In addition, exercise tolerance was improved and the total exercise time was lengthened in these patients. Moreover, ST segment depression time and emergence time of angina with exercise were also lengthened compared with controls (P < 0.05, or 0.01). However, the heart rate and blood pressure before and after exercise of the two groups were similar. The study indicated that rehabilitation training could significantly relieve angina, amend ischemic features of ECG, and improve exercise tolerance of coronary heart disease patients after percutaneous coronary intervention.

High-altitude pulmonary edema is associated with coagulation and fibrinolytic abnormalities.

OBJECTIVES: High-altitude pulmonary edema (HAPE) can develop in unacclimatized persons after acute ascent to high altitude and is associated with fibrinolytic and coagulation abnormalities. The authors investigated whether fibrinolytic and coagulation abnormalities were associated with the severity of HAPE. METHODS: Sixty-one patients who developed HAPE after acute ascent to altitudes above 3600 m were recruited. Twenty unacclimatized controls who acutely ascended to the same altitude and 20 acclimatized inhabitants served as controls. Tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) levels were measured using chromogenic substrate assays. Plasma fibrinogen concentration was determined by the sodium sulphite fractionation method. The concentrations of fibrin/fibrinogen degradation products (FDP) and D-dimer were measured by enzyme linked immunosorbent assay. RESULTS: The plasma concentrations of D-dimer, fibrinogen, FDP and t-PA and PAI-1 were significantly higher in patients with HAPE than controls. In addition, these abnormalities were correlated with the severity of HAPE. The plasma concentrations of D-dimer and fibrinogen recovered to normal upon recovery from HAPE while t-PA, PAI-1 and FDP levels in HAPE patients still remained significantly increased over those of unacclimatized controls. CONCLUSION: The development of HAPE is associated with abnormalities in the fibrinolysis and coagulation system, and these abnormalities correlate with the severity of HAPE.

Incidence of high altitude illnesses among unacclimatized persons who acutely ascended to Tibet.

High altitude illnesses pose health threats to unwary travelers after their acute ascent to high altitude locations. The incidence of high altitude illnesses among unacclimatized persons who acutely ascend to Tibet has not been previously reported. In the present study, we surveyed the incidence of high altitude illness among 3628 unacclimatized persons who had no previous high altitude experience and who traveled to Tibet by air to an altitude of 3600 m. These subjects were asked to answer questions in a written questionnaire about symptoms associated with high altitude illnesses that occurred within 2 weeks of their first arrival, their severity, and possible contributing factors. Physical examination and appropriate laboratory tests were also performed for hospitalized subjects. We found that 2063 respondents had mild acute mountain sickness with an incidence of 57.2%, and 249 (12.07%) of them were hospitalized for treatment. The incidence of high altitude pulmonary edema was 1.9%, while no case of high altitude cerebral edema was found. Additionally, there was no report of death. Psychological stresses and excessive physical exertions possibly contributed to the onset of HAPE. Acute mountain sickness is common among unacclimatized persons after their acute ascent to Tibet. The incidence of HAPE and HACE, however, is very low among them.

AGEs increased migration and inflammatory responses of adventitial fibroblasts via RAGE, MAPK and NF-kappaB pathways.

OBJECTIVE: Advanced glycation end products (AGEs) and vascular adventitial fibroblasts (AFs) are involved in diabetes-related vascular complications. However, the effect of AGEs on AFs remains unclear. The aim of this study was to observe the impact of AGEs on cell migration capacity and associated inflammatory responses of AFs. METHODS AND RESULTS: Isolated vascular AFs of Sprague-Dawley rats were cultured, harvested after 24h synchronization and challenged with AGE-HSA. AGE-HSA upregulated the expression of receptor for advanced glycation end products (RAGE), significantly increased the migration capacity and inflammatory mediators MCP-1, IL-6, VCAM-1 expressions on AFs. These effects could be significantly attenuated by anti-RAGE neutralizing antibody, p38, ERK1/2 and JNK MAPK inhibitors as well as by candesartan. AGE-HAS also upregulated NF-kappaB transcriptional activity and I-kappaB-alpha phosphorylation, effect that was significantly inhibited by candesartan. CONCLUSIONS: AGE-HSA increased the migration capacity and inflammatory responses of rat AFs via RAGE-MAPK-NF-kappaB pathways. Candesartan effectively inhibited these effects which might be a novel vascular protection mechanism of candesartan.

Palmitic acid promotes endothelial progenitor cells apoptosis via p38 and JNK mitogen-activated protein kinase pathways.

OBJECTIVE: Recent studies have demonstrated that palmitic acid (PA) could regulate endothelial progenitor cells (EPCs) function (migration, proliferation, survival and angiogenesis) via various signal pathways, but the effect of PA on EPCs apoptosis and associated mechanisms are still elusive. METHODS: The human EPCs were obtained by Ficoll density gradient centrifugation and cultured in M199 medium containing rh-VEGF (30ng/mL), rh-b-FGF (6ng/mL) and 10% fetal bovine serum for 7 days. The adhesive EPCs were harvested, then challenged with different concentrations of PA (ranging from 0 to 800mumol/L) for 48h and 400 micromol/L PA for different time periods (ranging from 0 to 60h) after 12h synchronization with serum-free medium. The EPCs apoptosis was determined by flow cytometry, expression of caspase-3, phosphorylated ERK1/2, JNK and p38 mitogen-activated protein kinase (MAPK) were quantified by Western blot. The effect of PA on caspase-3 activity in the absence or presence of specific MAPK pathway inhibitors was determined by colorimetry. RESULTS: PA increased EPCs apoptosis in a dose- and time-dependent manner, upregulated phosphorylated-p38 and -JNK, caspase-3 expression of EPCs while ERK expression was not affected. PA-induced EPCs apoptosis could be partly ameliorated by p38 inhibitor SB203580 and JNK inhibitor SP600125, but not by ERK1/2 inhibitor PD98059. CONCLUSION: These findings suggested that PA promoted EPCs apoptosis via p38 and JNK MAPKs pathways.

PPAR gamma protects cardiomyocytes against oxidative stress and apoptosis via Bcl-2 upregulation.

Cardiovascular disease (CVD) is a leading cause of death and disabilities worldwide. Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists possess potent anti-inflammatory actions and have recently emerged as potential therapeutic agents for CVD. Here we show that H2O2 induced apoptosis in cardiomyocytes with a marked down-regulation of Bcl-2 protein. The PPARgamma agonist rosiglitazone protected cardiomyocytes from oxidative stress and apoptosis. Cardiomyocytes constitutively overexpressing PPARgamma were resistant to oxidative stress-induced apoptosis and protected against impairment of mitochondrial function. On the contrary, cells expressing a dominant negative mutant of PPARgamma were highly sensitive to oxidative stress. Cells overexpressing PPARgamma exhibited an almost 3 fold increase in Bcl-2 protein content; whereas, in PPARgamma dominant negative expressing cells, Bcl-2 was barely detected. Bcl-2 knockdown by siRNA in cells overexpressing PPARgamma results in increased sensitivity to oxidative stress, suggesting that Bcl-2 up-regulation mediated the protective effects of PPARgamma. These data suggest that, in oxidative stress-induced cardiomyocyte apoptosis, PPARgamma protects cells from oxidative stress through upregulating Bcl-2 expression. These findings provide further support for the use of PPARgamma agonists in ischemic cardiac disease.

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 (PPARgamma) 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 microg mL(-1)), phosphatidylinositol-3-kinase (PI3K) inhibitor (LY294002, 5 microM), nitric oxide (NO) synthase inhibitor (L-N(G)-nitro-arginine methyl ester (L-NAME), 100 microM) or sodium nitroprusside (SNP, 25 microM). 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 LY294002. CONCLUSIONS AND IMPLICATIONS: The PPARgamma agonist rosiglitazone increased EPC function and attenuated EPC dysfunction induced by AGEs via upregulating the Akt-eNOS signal pathways of EPCs.