Jia-Shiong Chen

Ambulatory pulse pressure as a novel predictor for long-term prognosis in essential hypertensive patients.

The prognostic value of ambulatory blood pressure (BP) monitoring for long-term prognosis varies in recent studies. The study aimed to investigate the role of ambulatory BP parameters in mortality and cardiovascular (CV) events in hypertensive patients. A series of 412 participants (59.3±4.0 years) who received ambulatory BP monitoring for their fluctuated BP, either untreated or treated since 1995, were enroled. The mortality and CV events were obtained by follow-up and linked to the National Death Registry in Taiwan. There were 233 untreated and 179 treated patients. The latter were older with more comorbidity when compared with the former. After follow-up for 8.5±1.7 years, both ambulatory systolic BP and pulse pressure (PP) could predict all-cause mortality, non-CV mortality, CV disease and stroke after adjusting for baseline covariates. However, only ambulatory PP could predict CV mortality and coronary heart disease. Ambulatory PP is better than ambulatory systolic BP, particularly in prediction of all-cause mortality. There was no predictive value of office BP in any outcome. In conclusion, ambulatory PP is a good predictor for long-term outcomes in hypertensive patients. The parameters of ambulatory rather than office BP could be applied for risk stratification either before or under antihypertensive treatment.

Reduced number and impaired function of circulating endothelial progenitor cells in patients with abdominal aortic aneurysm

AIM Circulating endothelial progenitor cells (EPCs) are associated with coronary artery disease (CAD) and predict its outcome. Although the pathophysiology of abdominal aortic aneurysm (AAA) is different, it shares some risk factors with CAD. Therefore, the correlation between EPCs and AAA was investigated. METHODS AND RESULTS Seventy-eight subjects (age 77.2 ± 7.8 years) with suspected AAA were prospectively enrolled. Cut-off values (men, 3.5-5.5 cm; women, 3-5 cm) were used to define normal aorta, small AAA, and large AAA on thoraco-abdominal computer tomography. Endothelial function was measured by flow-mediated vasodilation (FMD). Flow cytometry and colony-forming units (CFUs) were used to evaluate circulating EPC numbers. Circulating EPCs were defined as mononuclear cells with low CD45 staining and double-positive staining for KDR, CD34, or CD133. Late out-growth EPCs were cultured from six patients with large AAAs and six age- and sex-matched controls to evaluate proliferation, adhesion, migration, tube formation, and senescence. FMD was significantly lower with large (5.26% ± 3.11%) and small AAAs (6.31% ± 3.66%) than in controls (8.88% ± 4.83%, P=0.008). Both CFUs (normal 38.39 ± 12.99, small AAA 21.22 ± 7.14, large AAA 6.98 ± 1.97; P=0.026) and circulating EPCs (CD34(+)/KDR(+) and CD133(+)/KDR(+)) were significantly fewer in AAA patients than in controls. On multivariate analysis, CFUs and circulating EPCs (CD34(+)/KDR(+)) were independently, inversely correlated to AAA diameter. Proliferation, adhesion, migration, tube formation, and senescence of late EPCs were significantly impaired in AAA patients. CONCLUSION The number and function of EPCs were impaired in AAA patients, suggesting their potential role in AAA.

Ginkgo biloba extract reduces high-glucose-induced endothelial adhesion by inhibiting the redox-dependent interleukin-6 pathways

BackgroundChronic elevation of glucose level activates vascular inflammation and increases endothelial adhesiveness to monocytes, an early sign of atherogenesis. This study aimed to elucidate the detailed mechanisms of high-glucose-induced endothelial inflammation, and to investigate the potential effects of Ginkgo biloba extract (GBE), an antioxidant herbal medicine, on such inflammation.Materials and methodsHuman aortic endothelial cells were cultured in high glucose or mannitol as osmotic control for 4 days. The expression of cytokines and adhesion molecules and the adhesiveness of endothelial cells to monocytes were examined. The effects of pretreatment of GBE or N-acetylcysteine, an antioxidant, were also investigated.ResultsEither high glucose or mannitol significantly increased reactive oxygen species (ROS) production, interleukin-6 secretion, intercellular adhesion molecule-1 (ICAM-1) expression, as well as endothelial adhesiveness to monocytes. The high-glucose-induced endothelial adhesiveness was significantly reduced either by an anti-ICAM-1 antibody or by an interleukin-6 neutralizing antibody. Interleukin-6 (5 ng/ml) significantly increased endothelial ICAM-1 expression. Piceatannol, a signal transducer and activator of transcription (STAT) 1/3 inhibitor, but not fludarabine, a STAT1 inhibitor, suppressed high-glucose-induced ICAM-1 expression. Pretreatment with GBE or N-acetylcysteine inhibited high-glucose-induced ROS, interleukin-6 production, STAT1/3 activation, ICAM-1 expression, and endothelial adhesiveness to monocytes.ConclusionsLong-term presence of high glucose induced STAT3 mediated ICAM-1 dependent endothelial adhesiveness to monocytes via the osmotic-related redox-dependent interleukin-6 pathways. GBE reduced high-glucose-induced endothelial inflammation mainly by inhibiting interleukin-6 activation. Future study is indicated to validate the antioxidant/anti-inflammatory strategy targeting on interleukin-6 for endothelial protection in in vivo and clinical hyperglycemia.

Simvastatin Attenuates Oxidative Stress, NF-κB Activation, and Artery Calcification in LDLR-/- Mice Fed with High Fat Diet via Down-regulation of Tumor Necrosis Factor-α and TNF Receptor 1

Simvastatin (SIM) is anti-inflammatory. We used low density lipoprotein receptor knockout (LDLR-/-) mice and human aortic smooth muscle cells (HASMCs) as model systems to study the effect of SIM on arterial calcification and to explore the potential mechanisms contributing to this protective effect. High-fat diet (HFD) caused the LRLR -/- to develop dyslipidemia, diabetics, atherosclerosis and aortic smooth muscle calcification. SIM, N-acetyl cysteine (NAC, a ROS scavenger) and apocynin (APO, a NADPH oxidase inhibitor) did not significantly retard the development of dyslipidemia or diabetic. However, those treatments were still effective in attenuating the HFD-induced atherosclerosis and aortic smooth muscle calcification. These findings suggest that the protective effect of SIM against aortic calcification is not contributed by the cholesterol lowering effect. SIM, NAC and APO were found to attenuate the HFD induced elevation of serum TNF-α, soluble TNFR1 (sTNFR1), 3-nitro-tyrosine. We hypothesized that the pro-inflammatory cytokine, oxidative stress and TNFR1 played a role in inducing aortic calcification. We used HASMC to investigate the role of TNF-α, oxidative stress and TNFR1 in inducing aortic calcification and to elucidate the mechanism contributes the protective effect of SIM against aortic calcification. We demonstrated that treating HASMC with TNF-α induced cell Ca deposit and result in an increase in ALP, NADPH oxidase activity, NF-kB subunit p65, BMP2, MSX2, and RUNX2 expression. SIM suppressed the TNF-α induced activation of NADPH oxidase subunit p47, the above-mentioned bone markers and TNFR1 expression. Furthermore, p65, p47 and TNFR1 siRNAs inhibited the TNF-α-mediated stimulation of BMP-2, MSX2, RUNX2 expression. SIM, APO, and NAC either partially inhibit or completely block the TNF-α induced H2O2 or superoxide production. These results suggest that SIM may, independent of its cholesterol-lowering effect, suppresses the progression of vascular diseases through the inhibition of the inflammation mediators TNF-α and TNFR1.

Direct Renin Inhibition with Aliskiren Improves Ischemia-Induced Neovasculogenesis in Diabetic Animals via the SDF-1 Related Mechanism

Objective Aliskiren is a direct renin inhibitor which is suggested to modify proangiogenic cells in addition to lower blood pressure. Given that angiogenesis is impaired in the presence of diabetes mellitus, we would like to investigate whether and how aliskiren enhances endothelial progenitor cells (EPCs) and improves ischemic-induced neovasculogenesis by an effect independent of blood pressure reduction in diabetic animals. Methods Streptozotocin-induced diabetic mice were administered with either aliskiren (5 or 25 mg/kg/day) using an osmotic pump or hydralazine (2 or 10 mg/kg/day) given in drinking water for two weeks prior to a hind-limb ischemia surgery. Laser Doppler imaging and flow cytometry were used to evaluate the degree of neovasculogenesis and the circulating levels of EPCs, respectively. Results In streptozotocin-induced diabetic mice, aliskiren enhanced the recovery of limb perfusion and capillary density, increased the number of circulating Sca-1+/Flk-1+ EPC-like cells, and elevated the levels of the plasma vascular endothelial growth factor (VEGF) and stromal cell-derived factor (SDF)-1α in a dose-dependent manner, whereas there were no such effects in hydralazine-treated mice. Intraperitoneal administration of anti-SDF-1 neutralizing monoclonal antibodies abolished the effects of aliskiren. Conclusions Independent of the reduction of blood pressure, aliskiren enhanced ischemia-induced neovasculogenesis in a dose-dependent manner via VEGF/SDF-1α related mechanisms in diabetic mice.

Clinical predictors of the response to short-term thiazide treatment in nondiabetic essential hypertensives

Blood pressure (BP) response to diuretics is varied in hypertensive patients. This study aimed to identify the patients who may respond better or worse to thiazide diuretics. Nondiabetic patients with treated or untreated hypertension were evaluated if they did not take diuretics and their office systolic BP (SBP) >140 mm Hg or diastolic BP (DBP) >90 mm Hg. Diet and life style modification were advised in addition to the concomitant medication, if there were, for 2 weeks. Additional hydrochlorothiazide 50 mg was given per day for another 2 weeks. Both office and 24-h ambulatory BP were checked. The changes of office SBP were used for the response to thiazide treatment. A total of 92 patients were enrolled. Compared with those in the quartile of worst response, patients in the quartile of best response were older with increased baseline SBP and pulse pressure (PP) and reduced heart rate. Reduced baseline awake, but not increased sleep DBP was associated with better response to thiazide. Besides, baseline age, SBP and PP were correlated to the response to thiazide treatment. Among these variables, increased baseline mean BP independently predicted the best and reduced SBP predicted the worst responders. Accordingly, patients with higher mean BP respond better to thiazide treatment no matter with or without concomitant medication. Patients with mainly diastolic hypertension with lower SBP responded poorly to thiazide treatment. The findings may help to individualized use of thiazide in nondiabetic hypertensives.

Rivaroxaban, a factor Xa inhibitor, improves neovascularization in the ischemic hindlimb of streptozotocin-induced diabetic mice

BackgroundFactor Xa inhibitor is used for preventing venous thromboembolism (VTE) in adult patients receiving orthopedic operation. However, the role of factor Xa inhibitor, rivaroxaban, in angiogenesis is still unknown.Methods and resultsStreptozotocin (STZ)–induced diabetic mice with model of hind-limb ischemia, were divided into non-diabetic control, diabetic control, and low- and high-dose rivaroxaban treatment groups, in order to evaluate the effect of rivaroxaban in angiogenesis. Doppler perfusion imaging showed that blood flow recovery was significantly increased, and more capillary density occurred in the rivaroxaban treatment group. In vitro studies, human endothelial progenitor cells (EPCs) treated with rivaroxaban had significant functional improvement in migration and senescence under hyperglycemic conditions. Rivaroxaban also increased endothelial nitric oxide synthase (eNOS) as well as vascular endothelial growth factor (VEGF) expressions in hyperglycemia-stimulated EPCs.ConclusionsRivaroxaban promoted vessel formation in diabetic mice and improved endothelial progenitor cell function under hyperglycemic conditions. These effects may be associated with enhancement of expression of eNOS and VEGF.

Aliskiren directly improves endothelial progenitor cell function from Type II diabetic patients.

Endothelial progenitor cell (EPC) functions are impaired in the presence of diabetes mellitus. Aliskiren is a direct renin inhibitor, which is expected to modify proangiogenic cells. This study aimed to investigate whether and how aliskiren could improve the function of EPCs from patients with type II diabetes (T2DM).