Sp1 elements in SULT2B1b promoter and 5′-untranslated region of mRNA: Sp1/Sp2 induction and augmentation by histone deacetylase inhibition

AbstractThe steroid/sterol sulfotransferase gene (SULT2B1) encodes for two isozymes of which one (SULT2B1b) sulfonates cholesterol and is selectively expressed in skin. The human SULT2B1 gene contains neither a TATAAA nor a CCAAT motif upstream of the coding region for SULT2B1b; however, this area is GC-rich. Of five Sp1 elements identified two had regulatory activity utilizing immortalized human keratinocytes: one element is located above the ostensible transcription initiation site, whereas the other is located within the 5′-untranslated region of the SULT2B1b mRNA. Sp1 and Sp2 transcription factors identified by supershift analyses induced reporter gene activity, an effect markedly augmented by histone deacetylase inhibition

Low body mass index is a risk factor forimpaired endothelium-dependent vasodilation in humans: role of nitric oxide and oxidative stress

AbstractObjectivesThe purpose of this study was to evaluate the relationship between body mass index (BMI), including low BMIs, and endothelial function.BackgroundEpidemiologic study has demonstrated that not only obesity but also a low BMI may be a risk factor for cardiovascular disease.MethodsThe forearm blood flow (FBF) response to acetylcholine (ACh) and isosorbide dinitrate (ISDN) was measured in 87 healthy young men (15 low BMI, 51 normal, 14 obese, and 7 extremely obese).ResultsPlasma concentrations of 8-hydroxy-2′-deoxyguanosine and serum concentrations of malondialdehyde-modified low-density lipoprotein were higher in low BMI, obese, and extremely obese subjects than in normal subjects and were similar among the low BMI, obese, and extremely obese groups. The FBF response to ACh was greater in the normal group than in the other groups (p < 0.001), and was lower in the extremely obese group as compared with the other groups (p < 0.001). The ACh-stimulated vasodilation was similar between the low BMI group and the obese group. The ISDN-stimulated vasodilation was similar in all four groups. There were no significant differences in ACh-stimulated vasodilation between the four groups after the nitric oxide (NO) synthase inhibitor NG-monomethyl-L-arginine infusion. Co-infusion of vitamin C augmented the FBF response to ACh in low BMI, obese, and extremely obese groups—but not in normal BMI group.ConclusionsThese findings suggest that not only obesity but also a low BMI may be a risk factor for impaired endothelium-dependent vasodilation through the increased oxidative stress, leading to the reduced bioavailability of NO

Effect of Saxagliptin on Endothelial Function in Patients with Type 2 Diabetes : A Prospective Multicenter Study

The dipeptidyl peptidase-4 inhibitor saxagliptin is a widely used antihyperglycemic agent in patients with type 2 diabetes. The purpose of this study was to evaluate the effects of saxagliptin on endothelial function in patients with type 2 diabetes. This was a prospective, multicenter, interventional study. A total of 34 patients with type 2 diabetes were enrolled at four university hospitals in Japan. Treatment of patients was initially started with saxagliptin at a dose of 5 mg daily. Assessment of endothelial function assessed by flow-mediated vasodilation (FMD) and measurement of stromal cell-derived factor-1α (SDF-1α) were conducted at baseline and at 3 months after treatment with saxagliptin. A total of 31 patients with type 2 diabetes were included in the analysis. Saxagliptin significantly increased FMD from 3.1 ± 3.1% to 4.2 ± 2.4% (P = 0.032) and significantly decreased total cholesterol from 190 ± 24 mg/dL to 181 ± 25 mg/dL (P = 0.002), glucose from 160 ± 53 mg/dL to 133 ± 25 mg/dL (P < 0.001), HbA1c from 7.5 ± 0.6% to 7.0 ± 0.6% (P < 0.001), urine albumin-to-creatinine ratio from 63.8 ± 134.2 mg/g to 40.9 ± 83.0 mg/g (P = 0.043), and total SDF-1α from 2108 ± 243 pg/mL to 1284 ± 345 pg/mL (P < 0.001). These findings suggest that saxagliptin is effective for improving endothelial function

sdLDL-C and Cardiovascular Events

Aim: There is little information on the relationships of serum small dense low-density lipoprotein cholesterol (sdLDL-C) levels and serum triglyceride (TG) levels with cardiovascular events in patients with coronary artery disease (CAD) and type 2 diabetes mellitus (DM) who are receiving statins. The aim of this study was to evaluate the relationships of serum TG levels and sdLDL-C levels as residual risks for cardiovascular events in patients with CAD and type 2 DM who were being treated with statins. Methods: The subjects were divided into four groups based on TG levels and sdLDL-C levels: sdLDL-C of ＜40.0 mg/dL and TG of ＜150 mg/dL, sdLDL-C of ≥ 40.0 mg/dL and TG of ＜150 mg/dL, sdLDL-C of ＜40.0 mg/dL and TG of ≥ 150 mg/dL, and sdLDL-C of ≥ 40.0 mg/dL and TG of ≥ 150 mg/dL. During a median follow-up period of 1419 days, cardiovascular events occurred in 34 patients. Results: The incidences of cardiovascular events were significantly higher in patients with sdLDL-C of ≥ 40.0 mg/dL and TG of ＜150 mg/dL and in patients with sdLDL-C of ≥ 40.0 mg/dL and TG of ≥ 150 mg/dL, but not in patients with sdLDL-C of ＜40.0 mg/dL and TG of ≥ 150 mg/dL, than in patients with sdLDL-C of ＜40.0 mg/dL and TG of ＜150 mg/dL. Conclusions: Under the condition of treatment with statins, patients with CAD and type 2 DM who had sdLDL-C levels of ≥ 40.0 mg/dL had a high risk for cardiovascular events even though serum TG levels were controlled at ＜150 mg/dL

Diagnostic Criteria of FMD and NID

Background - Diagnostic criteria of flow-mediated vasodilation (FMD), an index of endothelial function, and nitroglycerin-induced vasodilation (NID), an index of vascular smooth muscle function, of the brachial artery have not been established. The purpose of this study was to propose diagnostic criteria of FMD and NID for normal endothelial function and normal vascular smooth muscle function. Methods and Results - We investigated the cutoff values of FMD and NID in subjects with (risk group) and those without cardiovascular risk factors or cardiovascular diseases (no-risk group) in 7277 Japanese subjects (mean age 51.4±10.8 years) from the Flow-Mediated Dilation Japan study and the Flow-Mediated Dilatation Japan Registry study for analysis of the cutoff value of FMD and in 1764 Japanese subjects (62.2±16.1 years) from the registry of Hiroshima University Hospital for analysis of the cutoff value of NID. Receiver-operator characteristic curve analysis of FMD to discriminate subjects in the no-risk group from patients in the risk group showed that the optimal cutoff value of FMD to diagnose subjects in the no-risk group was 7.1%. Receiver-operator characteristic curve analysis of NID to discriminate subjects in the no-risk group from patients in the risk group showed that the optimal cutoff value of NID to diagnose subjects in the no-risk group was 15.6%. Conclusions - We propose that the cutoff value for normal endothelial function assessed by FMD of the brachial artery is 7.1% and that the cutoff value for normal vascular smooth muscle function assessed by NID of the brachial artery is 15.6% in Japanese subjects

Endothelial Dysfunction, Increased Arterial Stiffness, and Cardiovascular Risk Prediction in Patients With Coronary Artery Disease: FMD‐J (Flow‐Mediated Dilation Japan) Study A

BackgroundThe usefulness of vascular function tests for management of patients with a history of coronary artery disease is not fully known.Methods and ResultsWe measured flow‐mediated vasodilation (FMD) and brachial–ankle pulse wave velocity (baPWV) in 462 patients with coronary artery disease for assessment of the predictive value of FMD and baPWV for future cardiovascular events in a prospective multicenter observational study. The first primary outcome was coronary events, and the second primary outcome was a composite of coronary events, stroke, heart failure, and sudden death. During a median follow‐up period of 49.2 months, the first primary outcome occurred in 56 patients and the second primary outcome occurred in 66 patients. FMD above the cutoff value of 7.1%, derived from receiver‐operator curve analyses for the first and second primary outcomes, was significantly associated with lower risk of the first (hazard ratio, 0.27; 95% confidence interval, 0.06–0.74; P=0.008) and second (hazard ratio, 0.32; 95% confidence interval, 0.09–0.79; P=0.01) primary outcomes. baPWV above the cutoff value of 1731 cm/s was significantly associated with higher risk of the first (hazard ratio, 1.86; 95% confidence interval, 1.01–3.44; P=0.04) and second (hazard ratio, 2.19; 95% confidence interval, 1.23–3.90; P=0.008) primary outcomes. Among 4 groups stratified according to the combination of cutoff values of FMD and baPWV, stepwise increases in the calculated risk ratio for the first and second primary outcomes were observed.ConclusionsIn patients with coronary artery disease, both FMD and baPWV were significant predictors of cardiovascular events. The combination of FMD and baPWV provided further cardiovascular risk stratification

FMD, PWV, and Cardiovascular Events

Background The usefulness of vascular function tests for management of patients with a history of coronary artery disease is not fully known. Methods and Results We measured flow‐mediated vasodilation (FMD) and brachial–ankle pulse wave velocity (baPWV) in 462 patients with coronary artery disease for assessment of the predictive value of FMD and baPWV for future cardiovascular events in a prospective multicenter observational study. The first primary outcome was coronary events, and the second primary outcome was a composite of coronary events, stroke, heart failure, and sudden death. During a median follow‐up period of 49.2 months, the first primary outcome occurred in 56 patients and the second primary outcome occurred in 66 patients. FMD above the cutoff value of 7.1%, derived from receiver‐operator curve analyses for the first and second primary outcomes, was significantly associated with lower risk of the first (hazard ratio, 0.27; 95% confidence interval, 0.06–0.74; P=0.008) and second (hazard ratio, 0.32; 95% confidence interval, 0.09–0.79; P=0.01) primary outcomes. baPWV above the cutoff value of 1731 cm/s was significantly associated with higher risk of the first (hazard ratio, 1.86; 95% confidence interval, 1.01–3.44; P=0.04) and second (hazard ratio, 2.19; 95% confidence interval, 1.23–3.90; P=0.008) primary outcomes. Among 4 groups stratified according to the combination of cutoff values of FMD and baPWV, stepwise increases in the calculated risk ratio for the first and second primary outcomes were observed. Conclusions In patients with coronary artery disease, both FMD and baPWV were significant predictors of cardiovascular events. The combination of FMD and baPWV provided further cardiovascular risk stratification

Sarpogrelate Hydrochloride, a Selective 5-hydroxytryptamine(2A) Antagonist, Augments Autologous Bone Marrow Mononuclear Cell Implantation-induced Improvement in Endothelium-dependent Vasodilation in Patients With Critical Limb Ischemia

Background: The purpose of this study was to determine the effect of a combination of bone marrow mononuclear cell (BM-MNC) implantation and sarpogrelate, a selective 5-HT2A antagonist, on endothelial function in patients with critical limb ischemia (CLI). Methods: We evaluated the leg blood flow (LBF) responses to acetylcholine (ACh) and sodium nitroprusside before and after BM-MNC implantation in 16 patients with CLI. We divided patients with CLI into 2 groups: those cotreated with sarpogrelate orally for 12 weeks (sarpogrelate group, n = 8) and those who remained on conventional therapy (control group, n = 8). LBF was measured by strain gauge plethysmography. Results: BM-MNC implantation improved ankle brachial pressure index, transcutaneous oxygen pressure, and pain-free walking time, There was no significant difference in these parameters between the 2 groups. Before BM-MNC implantation, LBF responses to ACh were similar in the sarpogrelate group and control group. Twelve weeks of BM-MNC implantation enhanced LBF responses to ACh in the sarpogrelate and control groups. After 12 weeks of BM-MNC implantation, LBF response to ACh was significantly greater in the sarpogrelate group than in the control group. BM-MNC implantation did not alter the LBF responses to sodium nitroprusside in either group. Conclusions: These findings suggest that BM-MNC implantation improved not only limb ischemic symptoms but also endothelium-dependent vasodilation in patients with CLI. A combination of BM-MNC implantation and sarpogrelate had a more beneficial effect on vascular function in these patients