The Roles of Aerobic Exercise and Folate Supplementation in Hyperhomocysteinemia-Accelerated Atherosclerosis.

Background: Hyperhomocysteinemia (HHcy) is an independent risk factor for atherosclerosis. Effective interventions to reduce HHcy-accelerated atherosclerosis are required. Objectives: This study aimed to investigate the effects of aerobic exercise (AE) and folate (FA) supplementation on plasma homocysteine (Hcy) level and atherosclerosis development in a mouse model. Methods: Six-week-old female apoE-/- mice were grouped into five groups (N = 6-8): HHcy (1.8 g/L DL-homocysteine (DL-Hcy) in drinking water), HHcy + AE (1.8 g/L DL-Hcy and aerobic exercise training on a treadmill), HHcy + FA (1.8 g/L DL-Hcy and 0.006% folate in diet), HHcy + AE + FA (1.8 g/L DL-Hcy, 0.006% folate, and aerobic exercise training on a treadmill), and a control group (regular water and diet). All treatment was sustained for 8 weeks. Triglyceride, cholesterol, lipoprotein, and Hcy levels were determined enzymatically. Plaque and monocyte chemoattractant protein-1 (MCP-1) expression levels in mouse aortic roots were evaluated by immunohistochemistry. Results: Compared to the HHcy group (18.88 ± 6.13 µmol/L), plasma Hcy concentration was significantly reduced in the HHcy + AE (14.79 ± 3.05 µmol/L, p = 0.04), HHcy + FA (9.4 ± 3.85 µmol/L, p < 0.001), and HHcy + AE + FA (9.33 ± 2.21 µmol/L, p < 0.001) groups. Significantly decreased aortic root plaque area and plaque burden were found in the HHcy + AE and HHcy + AE + FA groups compared to those in the HHcy group (both p < 0.05). Plasma MCP-1 level and MCP-1 expression in atherosclerotic lesions were significantly decreased in the HHcy + AE and HHcy + AE + FA groups compared to the HHcy group (all p < 0.05). Conclusions: AE reduced atherosclerosis development in HHcy apoE-/- mice independently of reducing Hcy levels. FA supplementation decreased plasma Hcy levels without attenuating HHcy-accelerated atherosclerosis. AE and FA supplementation have distinct mechanisms in benefiting atherosclerosis.

[Multiple effect of simvastatin on vascular endothelium of hypercholesterolemia patients].

OBJECTIVE: To observe the multiple influence of cholesterol-lowering drug (simvastatin) on ankle brachial index (ABI), flow-mediated dilation (FMD) and nitroglycerin-mediated dilation (NMD) of brachial artery blood vessel endothelium, and plasma level of monocyte chemotactic protein 1 (MCP-1) of hypercholesterolemia patients without coronary heart disease (CHD). METHODS: In the study, 51 patients with hypercholesterolemia application were treated with simvastatin (20 mg/d) therapy for 12 weeks. The metabolic index, ankle brachial index (ABI), FMD of brachial artery blood vessel endothelium detected by color doppler ultrasound instrument, the NMD of artery endothelial and the level of MCP 1 were measured before and after therapy respectively. All the results were analyzed and compared with another 30 cases of hypercholesterolemia patients selected without simvastatin treatment. RESULTS: After simvastatin therapy, the TC (total cholesterol) and LDL-C (low density lipoprotein cholesterin) levels were reduced apparently,the values decreased from the original (6.06 ± 1.03) mmol/L and (3.60 ± 0.82) mmol/L to (4.98 ± 1.34) mmol/L and (3.41 ± 0.10) mmol/L respectively (P<0.01, P< 0.05). Compared with no simvastatin treatment, the bilateral ABI levels were significantly elevated. The right side of ABI (ABIR) elevated from 1.11 ± 0.06 to 1.19 ± 0.07, and the left side of ABI (ABIL) also elevated from 1.12 ± 0.06 to 1.19 ± 0.10 (both sides were P<0.01). The FMD significantly increased from 7.75% ± 11.30% to 14.20% ± 15.39% (P < 0.05). The plasma levels of MCP-1 were apparently reduced from (112.0 ± 7.8) ng/L to (108.9 ± 6.2) ng/L (P < 0.05). All these items showed no obvious change within the control group. CONCLUSION: The API, FMD and plasma levels of MCP-1 of hypercholesterolemia patients without clear coronary heart disease can be improved by simvastatin treatment.

Association between serum uric acid level and the severity of coronary artery disease in patients with obstructive coronary artery disease.

BACKGROUND: Many studies have shown that the serum uric acid (SUA) level is one of the cardiovascular risk factors. The aim of the study is to evaluate the relationship between SUA levels and the severity of coronary artery disease (CAD) assessed by angiography and the Syntax score in patients with obstructive CAD. METHODS: Participants who visited our hospital for a coronary angiography, from December 2007 to September 2012, were eligible for this analysis. SUA and other blood parameters after at least 12-hour fast were determined. First, the patients were divided into tertiles according to their Syntax scores (low Syntax score group: Syntax score ≤ 10.0; moderate Syntax score group: 10.0 18.0). Second, to clarify the association between SUA levels and major adverse cardiovascular events (MACEs), all patients were divided into two subgroups on the basis of SUA levels. The cutoff value of SUA was defined by diagnostic criteria of hyperuricemia. Patients were separated into normal SUA group (n = 251, with SUA <416 µmol/L for men and SUA <357 µmol/L for women) and high SUA group (n = 96, with SUA ≥ 416 µmol/L for men and SUA ≥ 357 µmol/L for women). All participants were followed for a mean of 22.0 months (1-75 months, interquartile range: 28 months) for major adverse cardiovascular events (MACEs), including all-cause death, recurrent nonfatal myocardial infarction (re-MI) and recurrent percutaneous coronary intervention (re-PCI). RESULTS: A total of 347 patients were registered for the study. The SUA levels in the high Syntax score group were significantly higher than that of the moderate Syntax score group and the low Syntax score group ((392.3 ± 81.6) µmol/L vs. (329.9 ± 71.0) µmol/L, P < 0.001; (392.3 ± 81.6) µmol/L vs. (311.4 ± 64.7) µmol/L, P < 0.001). The SUA level was positively correlated not only with the Syntax score (r = 0.421, P < 0.001; 95% CI: 0.333-0.512), but also with the number of diseased vessels (r = 0.298, P < 0.001; 95% CI: 0.194-0.396). After multiple linear regression analysis, SUA levels were identified to be independently correlated with a high Syntax score (B = 0.033, 95% CI 0.023-0.042, P < 0.001). Compared with the normal SUA subgroup, the high SUA subgroup tended to have a higher Syntax score (19.9 ± 8.7 vs. 13.6 ± 7.5, P < 0.001) and more multi-vessel disease (70.8% vs. 46.6%, P < 0.001). Follow-up data showed a higher incidence of MACE in the high SUA subgroup (20.8% vs. 6.0%, P < 0.001). Binary Logistic regression analysis indicated that the elevated SUA can predict the long-term prognosis of patients with obstructive CAD (OR = 2.968, 95% CI 1.256-7.011, P = 0.013). Kaplan-Meier analysis showed a significantly lower event-free survival rate in patients with high SUA levels than in the normal SUA subgroup (79.2% vs. 94.0%, Log rank = 17.645, P < 0.001). CONCLUSIONS: SUA levels were independently associated with the severity of CAD in patients with obstructive CAD. An elevated SUA is associated with cardiovascular events and may be useful as a biomarker of the severity of CAD.

Low density lipoprotein cholesterol level inversely correlated with coronary flow velocity reserve in patients with Type 2 diabetes.

OBJECTIVES: To evaluate the association of coronary artery endothelial function and plasma levels of low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C) in patients with Type 2 Diabetes Mellitus (DM). METHODS: We investigated 90 participants from our institution between October 2007 to March 2010: non-DM (n = 60) and DM (n = 30). As an indicator of coronary endothelial dysfunction, we used non-invasive Doppler echocardiography to quantify coronary flow velocity reserve (CFVR) in the distal part of the left descending artery after rest and after intravenous adenosine administration. RESULTS: Plasma level of LDL-C was significantly higher in patients with DM than in non-DM (3.21 ± 0.64 vs. 2.86 ± 0.72 mmo/L, P < 0.05), but HDL-C level did not differ between the groups (1.01 ± 0.17 vs. 1.05 ± 0.19 mmo/L). Furthermore, the CFVR value was lower in DM patients than non-diabetics (2.45 ± 0.62 vs. 2.98 ± 0.68, P < 0.001). Plasma levels of LDL-C were negatively correlated with CFVR in all subjects (r = -0.35, P < 0.001; 95% confidence interval (CI): -0.52 - -0.15) and in the non-DM (r = -0.29, P < 0.05; 95% CI: -0.51- -0.05), with an even stronger negative correlation in the DM group (r = -0.42, P < 0.05; 95% CI: -0.68 - -0.06). Age (ß = -0.019, s = 0.007, sß = -0.435, 95% CI: -0.033 - -0.005, P = 0.008), LDL-C (ß = -0.217, s = 0.105, sß = -0.282, 95% CI: -0.428 - -0.005, P = 0.045) remained independently correlated with CFVR in the DM group. However, we found no correlation between HDL-C level and CFVR in any group. CONCLUSIONS: Diabetes may contribute to coronary artery disease (CAD) by inducing dysfunction of the coronary artery endothelium. Increased LDL-C level may adversely impair coronary endothelial function in DM. HDL-C may lose its endothelial-protective effects, in part as a result of pathological conditions, especially under abnormal glucose metabolism.

Association between serum resistin level and cardiovascular events in postmenopausal women with acute coronary syndrome undergoing percutaneous coronary intervention.

BACKGROUND: As an adipocytokine, resistin has been proposed as a link between inflammation, metabolic disorder and atherosclerosis. The aim of the study is to evaluate whether serum resistin is associated with acute coronary syndrome (ACS) and major adverse cardiovascular events (MACEs) among postmenopausal women with ACS undergoing percutaneous coronary intervention (PCI). METHODS: A total of 106 consecutive postmenopausal women who underwent coronary angiography for evaluation of suspected myocardial ischemia were enrolled. Pre-procedure serum resistin, inflammatory and metabolic biomarkers were measured. All participants were followed for seven years for MACEs, including cardiovascular death, recurrent nonfatal myocardial infarction, and re-PCI. RESULTS: Patients with ACS (n = 69) had significantly higher resistin levels than those without coronary artery disease (CAD) (n = 37) (4.61 (1.79 - 10.80) ng/ml vs. 2.36 (0.85 - 4.15) ng/ml, P = 0.002). Correlation analysis revealed positive correlations between resistin levels and inflammatory and metabolic factors (P < 0.05). A follow-up of a mean of 83.4 months showed that patients with ACS suffered more MACEs than those without (13.0% vs. 2.7%, P = 0.05). Adjusted for cardiovascular risks, inflammatory and metabolic factors, multiple Logistic regression analysis indicated that an elevated resistin level was an independent predictor of ACS onset (OR = 1.139, 95%CI 1.024 - 1.268, P = 0.017) and of MACEs after PCI (OR = 1.099, 95%CI 1.015 - 1.189, P = 0.019). To clarify the association between resistin levels and MACEs, ACS patients were divided into two subgroups on the basis of resistin levels. Compared with the low resistin subgroup (≤ 4.35 ng/ml, n = 32), patients in the high resistin subgroup (> 4.35 ng/ml, n = 37) were more prone to suffer MACEs (21.6% vs. 3.1%, P = 0.015). Kaplan-Meier analysis showed a significantly lower event-free survival rate in ACS patients with high resistin levels than in the low resistin subgroup (78.4% vs. 96.9%, Log rank 5.594, P = 0.018). CONCLUSION: An elevated serum resistin level is associated with ACS and cardiovascular events and acts as a predictor in progression of ACS in postmenopausal women.

Coronary flow velocity reserve is improved by PPAR-α agonist fenofibrate in patients with hypertriglyceridemia.

INTRODUCTION: Fenofibrate, an agonist of peroxisome proliferator-activated receptor-α (PPAR-α), has a vascular protective effect. AIMS: We investigated the effect of the PPAR-α agonist on coronary artery endothelial function in patients with hypertriglyceridemia. METHODS: Fifty-eight patients with hypertriglyceridemia were divided into two groups: control (no treatment; n = 23) and fenofibrate treatment (n = 35), 200 mg/d, for 6 months. The patients had undergone rest and adenosine treatment to induce hyperemia for quantification of coronary flow velocity reserve (CFVR) by noninvasive Doppler echocardiography before treatment and at 6-month follow-up. Pulse wave velocity (PWV) was measured before treatment and at 6-month follow-up. RESULTS: CFVR was significantly improved with fenofibrate treatment as compared with baseline level and control group (3.14 ± 0.36 vs. 2.80 ± 0.58 and 2.79 ± 0.65, P < 0.01 and 0.05, respectively), with no difference between baseline levels and untreated controls. In addition, at 6 months, plasma level of homocysteine was significantly increased with fenofibrate treatment as compared with at baseline and control group (median 18.13 [range 14.46-22.02]µmol/L vs. 14.09 [12.01-18.81] and 13.34 [9.69-17.06]µmol/L, P < 0.001 and 0.01, respectively). Furthermore, at 6 months, PWV was significantly decreased with fenofibrate treatment as compared with control group (1446 ± 136 cm/s vs. 1570 ± 203 cm/s, P < 0.05). CONCLUSIONS: Treatment with PPAR-α agonist fenofibrate significantly improved CFVR and arterial stiffness in patients with hypertriglyceridemia. This endothelial protective effect may be reduced in part by the side effect of increasing homocysteine.

[Correlation of large artery stiffness and coronary flow velocity reserve].

OBJECTIVE: Coronary flow velocity reserve (CFVR) is an important indicator of coronary endothelial functions and microcirculation. Pulse wave velocity (PWV) reflects the degree of aortic sclerosis and it is an independent predictor of cardiovascular events. The present study was designed to evaluate the correlation of large artery stiffness and CFVR. METHODS: A total of 101 consecutive subjects were enrolled to measure the brachial-ankle pulse wave velocity (baPWV). According to the presence or absence of higher baPWV (> 1400 cm/s), they were divided into 2 groups. Transthoracic echocardiography was employed to measure coronary flow velocity in coronary left anterior descending (LAD). Then after an intravenous infusion of adenosine triphosphate, the velocity of blood flow was measured when the vessel was in maximal dilation. The ratio of flow velocity of those in maximal dilation to those at rest was CFVR. RESULTS: The subjects with a higher baPWV (> 1400 cm/s) were markedly elder and had higher risks of hypertension and diabetes. Thus age, hypertension and diabetes contributed to arteriosclerosis. More importantly, the subjects with a higher baPWV (> 1400 cm/s) had a much lower level of CFVR (2.66 ± 0.74 vs 2.95 ± 0.76; P < 0.01) than those with a lower baPWV (< 1400 cm/s). Furthermore correlation analysis showed that CFVR and baPWV levels were significantly negatively correlated (r = -0.35, P < 0.01). CONCLUSIONS: A negative correlation exists between artery stiffness and coronary flow velocity reserve. The increased vascular stiffness may impair coronary endothelial function, cause the dysfunction of coronary microcirculation and raise the risks of cardiovascular events.

Rad GTPase induces cardiomyocyte apoptosis through the activation of p38 mitogen-activated protein kinase.

Rad is a member of a subclass of small GTP-binding proteins, the RGK family. In the present study we investigated the role of Rad protein in regulating cardiomyocyte viability. DNA fragmentation and TUNEL assays demonstrated that Rad promoted rat neonatal cardiomyocyte apoptosis. Rad silencing fully blocked serum deprivation induced apoptosis, indicating Rad is necessary for trigger cardiomyocyte apoptosis. Rad overexpression caused a dramatic decrease of the anti-apoptotic molecule Bcl-x(L), whereas Bcl-x(L) overexpression protected cardiomyocytes against Rad-induced apoptosis. Rad-triggered apoptosis was mediated by the activation of p38 MAPK. The p38 blocker SB203580 effectively protected cardiomyocytes against Rad-evoked apoptosis.

[Effects of advanced glycation end products on the secretion of proinflammatory chemokines in vascular smooth muscle cells].

OBJECTIVE: To investigate the effects of advanced glycation end products (AGEs) on the secretion of monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8) in vascular smooth muscle cells (VSMCs) and explore its possible intracellular signaling mechanism. METHODS: Primary rat VSMCs were isolated and identified. VSMCs were treated with glycation serum albumin (GSA), an important component of AGEs, in series of concentrations and time. The role of MAPK and NF-κB inhibitors was confirmed. The levels of MCP-1 and IL-8 were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: VSMCs were treated with GSA at the doses of 10 µg/ml, 100 µg/ml and 500 µg/ml respectively. In comparison with the control group, the levels of MCP-1 (13.01 ng/ml ± 0.12 ng/ml vs 7.02 ng/ml ± 0.26 ng/ml, P < 0.05) and IL-8 (12.6 ng/ml ± 0.86 ng/ml vs 3.07 ng/ml ± 0.35 ng/ml, P < 0.05) increased in the GSA-treated group, especially at the concentration of 100 µg/ml. After adjustment for cells proliferation, the levels of MCP-1 and IL-8 were still higher in the GSA-treated group. After a pretreatment of PDTC (10 µmol/L), SB203580 (5 µmol/L) and MG132 (10 µmol/L), the levels of MCP-1 and IL-8 decreased. However, it had no change when pretreated with PD98059 (20 µmol/L). CONCLUSION: GSA promotes the secretion of MCP-1 and IL-8 in VSMCs. Such an effect is not dependent on cellular proliferation. It may be realized through an activation of NF-κB by p38MAPK-sensitive intracellular signaling pathway.

Homocysteine impairs coronary artery endothelial function by inhibiting tetrahydrobiopterin in patients with hyperhomocysteinemia.

Hyperhomocysteinemia (HHcy) has been associated with impaired vascular endothelial function. Our previous study demonstrated significantly higher secretion of the chemokine monocyte chemoattractant protein-1 from monocytes in response to lipopolysaccharide in patients with HHcy. In the present study, we investigated whether coronary endothelial function was damaged in patients with chronic HHcy (plasma level of homocysteine >15 µmol/l) and, if so, whether this impaired endothelial function is induced by the uncoupling of endothelial nitric oxide synthase (eNOS). When tetrahydrobiopterin levels are inadequate, eNOS is no longer coupled to l-arginine oxidation, which results in reactive oxygen species rather than nitric oxide production, thereby inducing vascular endothelial dysfunction. The 71 participants were divided into two groups, control (n = 50) and HHcy (n = 21). Quantification of coronary flow velocity reserve (CFVR) was after rest and after adenosine administration done by noninvasive Doppler echocardiography. Plasma levels of nitric oxide and tetrahydrobiopterin were significantly lower in patients with HHcy than in controls (99.54 ± 32.23 vs. 119.50 ± 37.68 µmol/l and 1.43 ± 0.46 vs. 1.73 ± 0.56 pmol/ml, all P < 0.05). Furthermore, CFVR was significantly lower in the HHcy than the control group (2.76 ± 0.49 vs. 3.09 ± 0.52, P < 0.05). In addition, plasma level of homocysteine was negatively correlated with CFVR. Chronic HHcy may contribute to coronary artery disease by inducing dysfunction of the coronary artery endothelium. The uncoupling of eNOS induced by HHcy in patients with chronic HHcy may explain this adverse effect in part.

Thorombolytic therapy with rescue percutaneous coronary intervention versus primary percutaneous coronary intervention in patients with acute myocardial infarction: a multicenter randomized clinical trial.

BACKGROUND: Although thrombolytic therapy with rescue percutaneous coronary intervention (PCI) is a common treatment strategy for ST-segment elevation acute myocardial infarction (STEMI), scant data are available on its efficacy relative to primary PCI, and comparison was therefore the aim of this study. METHODS: This multicenter, open-label, randomized, parallel trial was conducted in 12 hospitals on patients (age < or = 70 years) with STEMI who presented within 12 hours of symptom onset (mean interval > 3 hours). Patients were randomized to three groups: primary PCI group (n = 101); recombinant staphylokinase (r-Sak) group (n = 104); and recombinant tissue-type plasminogen activator (rt-PA) group (n = 106). For all patients allocated to the thrombolytic therapy arm, coronary angiography was performed at 90 minutes after drug therapy to confirm infarct-related artery (IRA) patency; rescue PCI was performed in cases with TIMI flow grade < or = 2. Bare-metal stent implantation was planned for all patients. RESULTS: After randomization it required an average of 113.4 minutes to start thrombolytic therapy (door-to-needle time) and 141.2 minutes to perform first balloon inflation in the IRA (door to balloon time). Rates of IRA patency (TIMI flow grade 2 or 3) and TIMI flow grade 3 were significantly lower in the thrombolysis group at 90 minutes after drug therapy than in the primary PCI group at the end of the procedure (70.5% vs. 98.0%, P < 0.0001, and 53.0% vs. 85.9%, P < 0.0001, respectively). Rescue PCI with stenting was performed in 117 patients (55.7%) in the thrombolytic therapy arm. Rates of patency and TIMI flow grade 3 were still significantly lower in the rescue PCI than in the primary PCI group (88.9% vs. 97.9%, P = 0.0222, and 68.4% vs. 85.0%, P = 0.0190, respectively). At 30 days post-therapy, mortality rate was significantly higher in the thrombolysis combined with rescue PCI group than in primary PCI group (7.1% vs. 0, P = 0.0034). Rates of death/MI and bleeding complications were significantly higher in the thrombolysis with rescue PCI group than in the primary PCI group (10.0% vs. 1.0%, P = 0.0380, and 28.10% vs. 8.91%, P = 0.0001, respectively). CONCLUSIONS: Thrombolytic therapy with rescue PCI was associated with significantly lower rates of coronary patency and TIMI flow grade 3, but with significantly higher rates of mortality, death/MI and hemorrhagic complications at 30 days, as compared with primary PCI in this group of Chinese STEMI patients with late presentation and delayed treatments.

Assessment of coronary artery flow velocity pattern as a long-term predictor of left ventricular function and cardiac events after percutaneous coronary intervention in anterior acute myocardial infarction.

BACKGROUND: Coronary flow velocity (CFV) can be used to assess short-term left ventricular function recovery and the clinical prognosis of patients with acute myocardial infarction (AMI). We evaluated CFV as a predictor of long-term left ventricular function recovery and cardiac events in patients with anterior wall AMI. METHODS AND RESULTS: CFV pattern of the distal left anterior descending (LAD), wall motion score index (WMSI) and left ventricular ejection fraction (LVEF) were recorded at the points of time within 24 hours, 3 days, 6 months, and 3 years after percutaneous coronary intervention (PCI) in 50 consecutive patients with anterior wall AMI. The clinical data were collected. Patients were divided into two groups based on diastolic deceleration time (DDT) 3 days after PCI. Compared with 3 days, LVEF and WMSI in group A (DDT>600 ms, n=20) improved in 6 months and 3 years (p<0.01), but they were unchanged in group B (DDT< or =600 ms, n=30). The incidence of cardiac events was higher in group B than in group A during 6 months (p<0.01).With a 3-year follow up, the incidence of chronic heart failure was higher in group B than in group A (p=0.009). CONCLUSION: CFV could be used as a predictor of long-term left ventricular function recovery and cardiac events in patients with anterior wall AMI.

Antidiabetic rosiglitazone reduces soluble intercellular adhesion molecule-1 level in type 2 diabetic patients with coronary artery disease.

Background. We investigated the level of soluble adhesion molecules in diabetic patients and the effect of the peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist rosiglitazone on plasma levels of adhesion molecules and an inflammation marker in type 2 diabetic patients with coronary artery disease (CAD) after percutaneous coronary intervention (PCI). Methods. A total of 116 diabetic patients with CAD who had undergone PCI were randomized to receive rosiglitazone (4 mg/d) or not for 6 months. Plasma levels of soluble intercellular adhesion molecules (sICAM-1) and P-selectin (sP-selectin) were measured on ELISA. Results. After 6-month rosiglitazone treatment, plasma levels of sICAM-1 were lower than baseline and control group levels (370.4 (332.4-421.9) pg/mL versus 423.5 (327.4-500.3) pg/mL and 404.6 (345.2-483.4) pg/mL, P < .001). In addition, plasma levels of C-reactive protein were significantly reduced from baseline levels. However, plasma level of sP-selectin was not significantly lowered with rosiglitazone treatment than with control treatment after 6-month follow-up. Conclusions. Rosiglitazone reduces chronic inflammatory responses and improves levels of markers of endothelial dysfunction in patients with diabetes and CAD. PPAR-gamma agonist may have a beneficial effect on the vascular endothelium through its anti-inflammatory mechanism and may be useful as therapy in patients undergoing PCI.

Peroxisome proliferator-activated receptor gamma agonist improves arterial stiffness in patients with type 2 diabetes mellitus and coronary artery disease.

Arterial stiffness is an independent risk factor for cardiovascular events in diabetic patients, and it can be assessed by measuring pulse wave velocity (PWV). We investigated the degree of arterial stiffness in diabetic patients with coronary artery disease (CAD) and the effect of the proliferator-activated receptor gamma (PPAR-gamma) agonist rosiglitazone on arterial stiffness in the potential mechanism of anti-arteriosclerosis in patients with type 2 diabetes mellitus and CAD. The 123 participants were divided into 3 groups: healthy controls (n = 36), diabetic patients (n = 41), and diabetic patients with CAD (n = 46). Forty-six diabetic patients with CAD were randomly divided into 2 groups: untreated diabetic patients with CAD and diabetic patients with CAD treated with 4 mg/d of rosiglitazone (n = 25) for 12 weeks. Pulse wave velocity was measured before treatment and at 12-week follow-up. Baseline PWV was significantly higher in patients with diabetes, diabetes and CAD, and diabetes and CAD with treatment as compared with the healthy control group (1,633 +/- 37.3, 1,669 +/- 53.8, 1,615 +/- 44.4, and 1,360 +/- 39.9 cm/s, respectively, P < .001). Pulse wave velocity in the rosiglitazone-treated group was significantly reduced, from 1,615 +/- 44.4 to 1,525 +/- 43.1 cm/s, after 12-week treatment, Furthermore, PWV was significantly decreased in the rosiglitazone-treated group compared with untreated group after 12 weeks (1525 +/- 43.1 and 1,670 +/- 41.3 cm/s, respectively). Pulse wave velocity in the untreated group did not differ from baseline levels after 12 weeks. In addition, plasma C-reactive protein level was decreased significantly in the rosiglitazone-treated group compared with values at baseline and for the untreated group after 12 weeks (0.73 +/- 0.09, 1.71 +/- 0.24, and 1.33 +/- 0.29 mg/L, respectively). Plasma level of monocyte chemoattractant protein 1 was decreased in the rosiglitazone group compared with the level at baseline (392 +/- 42 and 273 +/- 40 pg/mL, respectively). Moreover, the decrease in PWV was associated linearly both with improved homeostasis model assessment of insulin resistance and with decreased C-reactive protein level after PPAR-gamma agonist treatment. In conclusion, PPAR-gamma agonist rosiglitazone treatment may significantly decrease arterial stiffness in diabetic patients with CAD. Proliferator-activated receptor gamma agonists may play an important role in protecting against arteriosclerosis by normalizing the metabolic disorders and depressing chronic inflammation of the vascular system in patients with type 2 diabetes mellitus and serious vascular disease.

Mesenchymal stem cells modified with angiopoietin-1 improve remodeling in a rat model of acute myocardial infarction.

We used human angiopoietin-1 (hAng1)-modified mesenchymal stem cells (MSCs) to treat acute myocardial infarction (AMI) in rats. The hAng1 gene was transfected into cultured rat MSCs using an adenoviral vector. Five million hAng-transfected MSCs (MSC(Ang1)) or green fluorescent protein transfected MSCs (MSC(GFP)) or PBS only (PBS group) were injected intramyocardially into the inbred Lewis rat hearts immediately after myocardial infarction. MSC(Ang1) survived in the infarcted myocardium, and expressed hAng1 at both mRNA and protein levels. The vascular density was higher in the MSC(Ang1) and MSC(GFP) groups than in the PBS group. The measurements of infarcted ventricular wall thickness, infarction area, and left ventricular diameter indicated that heart remodeling was inhibited and heart function was improved in both the MSC(Ang1) and MSC(GFP) groups. However, in contrast to the MSC(GFP) group, the MSC(Ang1) group showed enhanced angiogenesis and arteriogenesis (by 11-35%), infarction area was reduced by 30% and the left ventricular wall was 46% thicker (P<0.05). The results indicated that hAng1-modified MSCs improved heart function, followed by angiogenic effects in salvaging ischemic myocardium and reduced cardiac remodeling.

[Anti-apoptotic effects of mesenchymal stem cells on cardiac myocytes: in vitro study with rats].

OBJECTIVE: To investigate the anti-apoptotic effects of mesenchymal stem cells (MSCs) on hypoxia-injured cardiac myocytes. METHODS: MSCs were isolated from the bone marrow of 6 - 8 week-old Sprague-Dawley rats. Cardiac myocytes from neonatal rat were cultured under hypoxia, then the hypoxia-injured cardiac myocytes were divided into 3 groups: cultured alone (control group), co-cultured with the MSCs, or co-cultured in MSC-conditioned media in conditions of anoxia (95% N(2) + 5% CO(2), continuous hypoxia group) or normoxia [hypoxia/reoxygen (H/R) group] for 72 hours. The cell apoptosis was measured by Hoechst staining, and Western blotting was used to test the protein expression of Bcl-2 and Bax in the cardiac myocytes. RESULTS: The apoptotic rate of the cardiac myocytes cultured under hypoxia was 51.6% +/- 2.4%, significantly higher than those of the cardiac myocytes co-cultured with MSCs and MSC-conditioned media respectively (15.1% +/- 5.4% and 24.0% +/- 4.2% respectively, both P < 0.001). The apoptotic rate of the H/R group was 20.9% +/- 2.7%, significant higher than that of the MSC group (11.5% +/- 3.7%, P < 0.05), however, not significantly different from that of the MSC-conditioned media group (20.1% +/- 4.2%, P > 0.05). The protein expression of Bcl-2 was not significantly different among different groups. The Bax protein expression of the MSC group and MSC-conditioned media group were 2.28 +/- 0.46 and 3.01 +/- 0.26 respectively, both significantly lower than that of the control group (7.62 +/- 1.28, both P < 0.05). The decreased expression of Bax in the cardiac myocytes was greatly related to the decreasing of apoptosis. CONCLUSION: Co-cultured MSCs show significant anti-apoptotic effects on cardiac myocytes both in continuous hypoxia and in H/R conditions with the possible mechanism of direct cell to cell interaction and paracrine of cytokines which effect the expression of Bax in the myocytes.

Synergistic proliferation induced by insulin and glycated serum albumin in rat vascular smooth muscle cells.

Hyperglycemia, advanced glycation end products (AGEs), hyperinsulinemia and dyslipidemia may play roles in the development of diabetes-associated atherosclerosis and post-angioplasty restenosis. Clinically, their effects seem to be synergic. However, few studies have focused on the synergistic action of these factors. In the present study, we investigated whether glycated serum albumin (GSA) has a synergistic effect with insulin on the proliferation of vascular smooth muscle cells (VSMCs). VSMCs were isolated from rat thoracic aortas and cultured in fetal bovine serum (FBS)-free medium for 24 h, then exposed to GSA, insulin or GSA + insulin for 48 h with or without pretreatment of mitogen-activated protein kinase (MAPK) inhibitors or the antioxidant N-acetylcysteine (NAC). Cell growth rate was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay or cell counting. The changes of phosphorylated-p38 MAPK and phosphorylated-C-Jun N-terminal kinase 1/2 (JNK1/2) were measured by Western blot analysis. The results showed that only p38 MAPK, but not JNK was activated by GSA and insulin co-incubation. VSMC proliferation was increased by insulin (10-1000 nmol/L) or GSA (10, 100 microg/mL). Co-incubation of insulin (100 nmol/L) and GSA (100 mug/mL) caused a more potent increase in VSMC proliferation than insulin or GSA incubation alone. p38 MAPK inhibitor, SB203580, as well as NAC, could inhibit the VSMC proliferation induced by co-incubation of GSA and insulin. The results show that insulin enhances GSA-induced VSMC proliferation, which may be mediated through a reactive oxygen species (ROS)-p38 MAPK pathway. The synergism of AGEs and insulin may play a detrimental role in the pathogenesis of diabetic atherosclerosis and post-angioplasty restenosis.

[Folic acid attenuates homocysteine induced human monocytes chemokine secretion via reducing NADPH oxidase activity].

OBJECTIVE: To investigate the effect of folic acid on homocysteine (Hcy)-induced chemokine secretion and NADPH oxidase activity in human monocytes. METHODS: Human monocytes from healthy volunteers were incubated with Hcy (100 micromol/L) with or without folic acid (5 micromol/L) for 24 h; MCP-1 and IL-8 were assessed by ELISA. DCFH-DA was added to monitor intracellular ROS production on confocal microscopy. A cytochrome c reduction assay was used to measure NADPH oxidase activity. RESULTS: The Hcy-induced secretion of MCP-1 and IL-8 was significantly reduced by folic acid [(1.88 +/- 0.51) ng/ml vs. (4.36 +/- 0.72) ng/ml vs. (2.40 +/- 0.60) ng/ml and (4.9 +/- 1.9) ng/ml vs. (12.7 +/- 1.5) ng/ml vs. (7.2 +/- 1.9) ng/ml, all P < 0.05]. The Hcy-induced production of ROS was also significantly attenuated by folic acid. Moreover, the Hcy-induced NADPH oxidase activity increase was significantly inhibited by cotreatment with folic acid. CONCLUSION: Folic acid may attenuate oxidative stress induced by Hcy by reducing NADPH oxidase activity in monocytes.

[Prediction of 2-year outcome by combining TIMI myocardial perfusion grading with sum ST segment resolution in patients with acute myocardial infarction].

OBJECTIVE: To evaluate the value of combining TIMI myocardial perfusion (TMP) grading with sum ST segment resolution (sumSTR) in prediction of the 2-year outcome and heart function in patients with acute myocardial infarction (AMI) after emergency percutaneous intervention (PCI). METHODS: Seventy-seven consecutive patients of AMI with elevated ST segment, 62 males and 15 females, aged 63 +/- 12 (30-91), underwent PCI. TMP grading was used in combination of electrocardiography to calculate the sumSTR so as to evaluate the effect of myocardial reperfusion. The patients with TMP grade 2-3 and sumSTR > or = 30% were included in the group of better perfusion, and those with the TMP grade 0-1 and sumSTR < 30% were included in the group of lower perfusion. The cardiac events, including death, reinfarction, revascularization, angina pectoris, and heart failure were recorded. The left ventricular end-diastolic dimension (LVEDD) and left ventricular ejection fraction (LVEF) were measured by echocardiography 72 hours and 2 years after the PCI. RESULTS: There were 37 patients in the lower perfusion group and 39 patients in the better perfusion group. Cos regression showed that TMP grade 0-1 associated with sumSTR < 30% was an independent factor for 2-year cardiac events (RR = 13.186, 95% CI 2.149 - 80.917, P = 0.005). The LVEDD 2 years after PCI was 60 mm +/- 4 mm, significantly higher than that 72 hours after PCI (53 mm +/- 4 mm. P < 0.01) in the lower perfusion group. The LVEDD increased by 7.1 mm +/- 1.9 mm two years after PCI in the lower perfusion group, significantly more than that in the better perfusion group (1.5 mm +/- 1.2 mm, P < 0.01). The myocardial perfusion after PCI was closely correlated with the extent of heart function improvement 2 years after (chi(2) = 50.58, P < 0.01). CONCLUSION: TMP grading combined with sumSTR helps predict the 2-year outcome and heart function in the patients with AMI after emergency PCI.