Peiliang Kuan

Acetylcysteine protects against acute renal damage in patients with abnormal renal function undergoing a coronary procedure

OBJECTIVES We sought to evaluate the efficacy of the antioxidant acetylcysteine in limiting the nephrotoxicity after coronary procedures. BACKGROUND The increasingly frequent use of contrast-enhanced imaging for diagnosis or intervention in patients with coronary artery disease has generated concern about the avoidance of contrast-induced nephrotoxicity (CIN). Reactive oxygen species have been shown to cause CIN. METHODS We prospectively studied 121 patients with chronic renal insufficiency (mean [+/-SD] serum creatinine concentration 2.8 +/- 0.8 mg/dl) who underwent a coronary procedure. Patients were randomly assigned to receive either acetylcysteine (400 mg orally twice daily) and 0.45% saline intravenously, before and after injection of the contrast agent, or placebo and 0.45% saline. Serum creatinine and blood urea nitrogen were measured before, 48 h and 7 days after the coronary procedure. RESULTS Seventeen (14%) of the 121 patients had an increase in their serum creatinine concentration of at least 0.5 mg/dl at 48 h after administration of the contrast agent: 2 (3.3%) of the 60 patients in the acetylcysteine group and 15 (24.6%) of the 61 patients in the control group (p < 0.001). In the acetylcysteine group, the mean serum creatinine concentration decreased significantly from 2.8 +/- 0.8 to 2.5 +/- 1.0 mg/dl (p < 0.01) at 48 h after injection of the contrast medium, whereas in the control group, the mean serum creatinine concentration increased significantly from 2.8 +/- 0.8 to 3.1 +/- 1.0 mg/dl (p < 0.01). CONCLUSIONS Prophylactic oral administration of the antioxidant acetylcysteine, along with hydration, reduces the acute renal damage induced by a contrast agent in patients with chronic renal insufficiency undergoing a coronary procedure.

Intramyocardial injection of naked DNA encoding HIF-1α/VP16 hybrid to enhance angiogenesis in an acute myocardial infarction model in the rat

OBJECTIVES The therapeutic utility of hypoxia-inducible factor-1 (HIF-1) transcriptional regulatory system for ischemic hindlimb has been demonstrated. It is not yet known whether this transcriptional regulatory system can be used as a therapeutic strategy to enhance collateral vessel formation in myocardial tissues, where acute hypoxia occurs due to inadequate perfusion. We aimed to test the hypothesis that exogenous administration of HIF-1alpha/VP16 could enhance collateral vessel formation in a rat acute myocardial infarction model. METHODS Sprague-Dawley rats received ligation of the proximal left anterior descending coronary artery to induce acute myocardial infarction. Immediately after the ligation, 50 microg total plasmid DNA (control, plasmid encoding human vascular endothelial growth factor (pVEGF(165)), or pHIF-1alpha/VP16) was injected into the infarct area at three locations. RESULTS Reverse transcription-polymerase chain reaction (RT-PCR) showed the presence of HIF-1alpha and VEGF mRNA in the myocardium, but not in other organs at days 3 and 7. The infarct size significantly decreased from 37+/-4% (control) to 24+/-2% in the VEGF-treated group and 23+/-2% in the HIF-1alpha/VP16 treated group (P<0.05). Capillary density also significantly increased from 550+/-75/mm(2) (control) to 850+/-75/mm(2) in the VEGF group and 850+/-50/mm(2) in the HIF-1alpha/VP16-treated group (P<0.01). Combined therapy with HIF-1alpha/VP16 and VEGF resulted in higher capillary density (1230+/-50/mm(2)) than treatment with either therapy alone. Regional myocardial blood flow was also higher in the treated groups than in the control. Plasma levels of VEGF were also significantly higher in the HIF-1alpha/VP16 and VEGF-treated group than in the control group. CONCLUSIONS The HIF-1alpha/VP16 hybrid transcription factor is able to reduce infarct size and enhance neovascularization in an acute ischemic myocardium. The potency of VEGF and HIF-1alpha/VP16 hybrid as therapeutic angiogenic factors in acute hypoxic myocardium is similar.

Intramuscular vascular endothelial growth factor gene therapy in patients with chronic critical leg ischemia

We sought to investigate the safety and efficacy of intramuscular gene therapy with vascular endothelial growth factor (VEGF) in patients with chronic critical leg ischemia.Gene transfer was performed in 24 limbs of 21 patients with rest pain, some of whom also had nonhealing ischemic ulcers (n = 16) due to occlusive peripheral arterial disease. Between 400 microg and 2000 microg of phVEGF(165) (400 microg, n = 2; 800 microg, n = 4; 1200 microg, n = 4; 1600 microg, n = 6; and 2000 microg, n = 8) was injected directly into the muscles of the ischemic limb; the same dose was injected 4 weeks later. The ratio of blood pressures at the ankle and brachial artery was measured before and after treatment. Mean (+/- SD) plasma levels of VEGF increased significantly from 26 +/- 31 pg/mL to 63 +/- 56 pg/mL (P <0.005), and the ankle-brachial index improved significantly from 0.58 +/- 0.24 to 0.72 +/- 0.28 (P <0.001). Magnetic resonance angiography showed qualitative evidence of improved distal flow in 19 limbs (79%). Ischemic ulcers healed or improved markedly in 12 limbs (75%). Rest pain was relieved or improved markedly in 20 limbs (83%). Amputation was performed in two limbs because of wound infection. Complications were limited to transient leg edema in six limbs. Intramuscular gene therapy with VEGF(165) for patients with chronic critical leg ischemia is safe, feasible, and effective.

Induction of matrix metalloproteinases-14 and -2 by cyclical mechanical stretch is mediated by tumor necrosis factor-α in cultured human umbilical vein endothelial cells

OBJECTIVE Mechanical forces have profound effects on endothelial cells. This study was undertaken to examine the hypothesis that tumor necrosis factor-alpha (TNF-alpha) is a potential mediator of stretch-induced effects on matrix metalloproteinase (MMP). METHODS Human umbilical vein endothelial cells (HUVECs) grown on a flexible membrane base were stretched by vacuum to 20% of maximum elongation, at 60 cycles/min. We used the TNF-alpha monoclonal antibody and c-Jun N-terminal kinase (JNK) inhibitor, SP600125, to investigate the cyclical stretch-induced expression of MMP-14 and -2 in cultured HUVECs. RESULTS Cyclical mechanical stretch significantly increased protein synthesis and mRNA expression for MMP-14 and -2 from 2 to 24 h. The increased MMP-14 and-2 proteins after stretch were completely blocked after the addition of TNF-alpha monoclonal antibody (5 microg/ml) or SP600125 (20 microM) 30 min before stretch. By zymography, MMP-2 expression was induced by cyclical stretch and was attenuated by TNF-alpha monoclonal antibody and SP600125. Cyclical stretch increased the immunohistochemical labeling of MMP-14 and -2 and significantly increased release of TNF-alpha into the culture media from 120+/-2 to 331+/-2 pg/ml (P<0.001) after stretch for 12 h. Cyclical stretch increased and SP600125 decreased the phosphorylated JNK. Gel-shifting assay showed that DNA-protein binding activity of AP-1 increased after cyclical stretch and TNF-alpha monoclonal antibody and SP600125 abolished the binding activity induced by cyclical stretch. CONCLUSION These findings indicate that cyclical stretch augments TNF-alpha production and MMP genes expression in HUVECs. TNF-alpha mediates the stretch-induced MMP genes expression, at least in part, through the JNK pathway.

Regulation of hypoxia-inducible factor-1α by cyclical mechanical stretch in rat vascular smooth muscle cells

Vascular smooth muscle cells (VSMCs) are exposed to hormonal and mechanical stress in vivo. Hormonal factors have been shown to affect hypoxia-inducible factor-1alpha (HIF-1alpha). How mechanical stress affects the regulation of HIF-1alpha in VSMCs has not been reported previously, and therefore we sought to investigate the regulation of HIF-1alpha by cyclical mechanical stretch in cultured rat VSMCs. Rat VSMCs grown on a flexible membrane base were stretched by vacuum to 20% of the maximum elongation at 60 cycles/min. The levels of HIF-1alpha protein began to increase as early as 2 h after stretch was applied and reached a maximum of 2.8-fold over the control by 4 h. Real-time PCR showed that the levels of HIF-1alpha mRNA increased 2.1-fold after cyclical stretch for 4 h. Cyclical mechanical stretch also increased the immunohistochemical labelling of HIF-1alpha in VSMCs after cyclical stretch for 4 h. The phosphorylation of p42/p44 mitogen-activated protein kinase (MAP kinase) increased after stretch and this was inhibited by the MAP kinase kinase inhibitors PD98059 and U0126. PD98059 and U0126 also blocked HIF-1alpha gene expression induced by cyclical stretch. In conclusion, cyclical mechanical stretch activates the gene expression of HIF-1alpha in cultured VSMCs and this mechanical effect is possibly mediated by the p42/p44 MAP kinase kinase pathway.

Combined cord blood stem cells and gene therapy enhances angiogenesis and improves cardiac performance in mouse after acute myocardial infarction

Background  Gene and stem cell therapies hold promise for the treatment of ischaemic cardiovascular disease. However, combined stem cell and angiogenic growth factor gene therapy for acute ischaemic myocardium has not been previously reported. This study hypothesized that combined stem cell and gene therapy would not only augment new vessels formation but also improve myocardial function in acute ischaemic myocardium.

The role of P wave in prediction of atrial fibrillation after coronary artery surgery.

Atrial fibrillation (AF) is a common arrhythmia after coronary artery bypass surgery (CABG). The purpose of this study was to determine the role of P wave duration, amplitude and dispersion in the prediction of AF after CABG. This study included 120 patients undergoing elective CABG. Clinical characteristics, 12-lead electrocardiogram (ECG), echocardiogram and coronary angiogram were obtained in all patients. We measured P wave duration, amplitude and dispersion from 12-lead ECG in each patient. After CABG, all patients were continuously monitored for AF attacks in the intensive care unit and ordinary ward. Our results showed that age greater than 60 years was the strongest predictor of postoperative AF (p<0.01), with a 3.7-fold greater likelihood of developing postoperative AF compared to ages less than 60 years. Gender was another independent predictor of postoperative AF, with men being 3.0 times more likely to develop postoperative AF compared to women (p = 0.03). The presence of prolonged P wave duration (> or =100 ms in lead II) was also an independent predictor (p = 0.04), with 2.9-fold greater risk of developing postoperative AF compared to a P wave duration of less than 100 ms. The P wave dispersion was similar between patients with and without postoperative AF (29+/-15 vs. 33+/-15 mm, p = NS). In conclusion, old age, male gender and prolonged P wave duration were independent predictors of AF after CABG. However, P wave dispersion and amplitude did not provide significant information in the prediction of postoperative AF.

Regulation of Discoidin Domain Receptor 2 by Cyclic Mechanical Stretch in Cultured Rat Vascular Smooth Muscle Cells

Discoidin domain receptor 2 (DDR2) plays potential roles in the regulation of collagen turnover mediated by smooth muscle cells in atherosclerosis. How mechanical stretch affects the regulation of DDR2 in smooth muscle cells is not fully understood. We sought to investigate the cellular and molecular mechanisms of regulation of DDR2 by cyclic stretch in smooth muscle cells. Rat vascular smooth muscle cells grown on a flexible membrane base were stretched by vacuum to 20% of maximum elongation, at 60 cycles/min. Cyclic stretch significantly increased DDR2 protein and mRNA expression after stretch. Cyclic stretch also significantly increased DNA–protein binding activity of Myc-Max. Addition of SB203580, transforming growth factor-β1 (TGF-β1) monoclonal antibody, p38 small interfering RNA (siRNA), and c-myc siRNA 30 minutes before stretch inhibited the induction of DDR2 protein and abolished the DNA–protein binding activity induced by cyclic stretch. Cyclic stretch increased, whereas SB203580 abolished the phosphorylated p38 protein. Conditioned medium from stretched smooth muscle cells and exogenous administration of angiotensin II and TGF-β1 recombinant proteins to the nonstretched cells increased DDR2 protein expression similar to that seen after stretch. In conclusion, cyclic mechanical stretch enhances DDR2 expression in cultured rat smooth muscle cells. The stretch-induced DDR2 is mediated by angiotensin II and TGF-β1, at least in part, through p38 mitogen-activated protein kinase and Myc pathway.

Acute ST-elevation myocardial infarction in young patients: 15 Years of experience in a single center

There have been few studies done regarding young patients with ST‐elevation myocardial infarction (STEMI). The purpose of this study was to investigate the clinical characteristics and coronary angiographic features in young patients with STEMI.

Mechanism of the inhibitory effect of atorvastatin on endoglin expression induced by transforming growth factor‐β1 in cultured cardiac fibroblasts

Transforming growth factor‐β1 (TGF‐β1) and endoglin play a causal role in promoting cardiac fibrosis. Atorvastatin has been shown to have an inhibitory effect on cardiac fibroblasts in vitro. However, the effects of statins on TGF‐β1 and endoglin are poorly understood. We therefore sought to investigate the molecular mechanisms of atorvastatin on endoglin expression after TGF‐β1 stimulation in cardiac fibroblasts.