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ABSTRACT: Herein, we present a case of pneumoaorta and aortoduodenal fistula (ADF) caused by an endoluminal aortic prosthesis infection. An 82-year-old man underwent endovascular aneurysm repair with a stent graft to exclude a 5.1-cm abdominal aortic aneurysm. Three months after the index procedure, the patient was taken to the emergency department at a medical university hospital. He presented with a 2-d history of bloody diarrhea. An endoluminal aortic stent graft infection was diagnosed, and an ADF was identified. The patient died of septic shock despite emergency surgery and intensive care. When encountered, stent graft infections require appropriate antibiotics and graft explantation. The diagnosis of an ADF is important, and surgery remains the most effective management if septic shock presents despite conservative treatment.
World Journal of Gastroenterology 10/2012; 18(37):5309-11. · 2.47 Impact Factor
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ABSTRACT: Recent clinical evidence has failed to demonstrate the benefits of elevation of serum high-density lipoprotein (HDL), suggesting potential loss of protective effects of HDL at high concentrations. This study aimed to investigate the concentration-related effects of HDL on in vitro and in vivo functions of human endothelial progenitor cells (EPCs) and related angiogenesis.
Early and late outgrowth EPCs were generated from human circulating mononuclear cells. Oxidized low-density lipoprotein reduced viability of late outgrowth EPCs, which was reversed dose dependently by HDL. In the absence of oxidized low-density lipoprotein, HDL at low concentrations (5-50 μg/mL, equal to 0.5-5 mg/dL in human) enhanced EPC tube formation by activating phosphatidylinositol-3 kinase/Akt/endothelial NO synthase pathways. Moderate to high concentrations (400-800 μg/mL) of HDL paradoxically enhanced EPC senescence and impaired tube formation by activating Rho-associated kinase (ROCK) and inhibiting phosphatidylinositol-3 kinase/Akt and p38 mitogen-activated protein kinase pathways. Rho-associated kinase inhibitors, either Y27632 or statins, prevented high HDL-induced EPC senescence and improved in vitro tube formation, as well as in vivo capacity of angiogenesis of EPCs.
While protecting EPCs from the injury of oxidized low-density lipoprotein, moderate to high concentrations of HDL paradoxically impaired EPCs and related angiogenesis in the absence of oxidized low-density lipoprotein by activating Rho-associated kinase pathways, providing mechanistic evidence of potential hazard effects of HDL.
Arteriosclerosis Thrombosis and Vascular Biology 08/2012; 32(10):2405-17. · 6.37 Impact Factor
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Chun-Yao Huang,
Chun-Ming Shih,
Nai-Wen Tsao,
Yi-Wen Lin,
Po-Hsun Huang,
Shinn-Chih Wu,
Ai-Wei Lee,
Yung-Ta Kao, Nen-Chung Chang,
Hironori Nakagami,
Ryuichi Morishita,
Keng-Liang Ou,
Wen-Chi Hou,
Cheng-Yen Lin,
Kuo-Gi Shyu,
Feng-Yen Lin
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ABSTRACT: BACKGROUND AND PURPOSE: Current treatment modalities for critical limb ischemia (CLI) still make difficult progress, concepts on therapeutic vasculogenesis may open a new field on the treatment of CLI. This study is to study the DPP-4 inhibitor, sitagliptin, originally used as a hypoglycemic agent, in therapeutic potential of vasculogenesis in vivo. EXPERIMENTAL APPROACH: Sitagliptin were administered daily to C57CL/B6 mice and eGFP transgenic mouse bone marrow-transplanted ICR mice that had undergone hind limb ischemic surgery. Laser Doppler imaging and flowcytometry was used to evaluate the degree of neo-vasculogenesis and circulating levels of EPCs, respectively. Cell surface marker of EPCs and endothelial nitric oxide synthase (eNOS) in vessels were studies. KEY RESULTS: Mice that received sitagliptin with elevated plasma glucagon-like peptide-1 (GLP-1) levels, decreased plasma dipeptidyl peptidase-4 (DDP-4) concentration, as well as augmented ischemia induced increases in stromal cell-derived factor-1 (SDF-1) in a dose-dependent manner. Blood flow in the ischemic limb was significantly improved in mice treated with sitagliptin. Circulating levels of EPCs were also increased after sitagliptin treatment. Sitagliptin administration enhanced expression of CD 34 and eNOS in ischemia muscle. Additionally, sitagliptin promoted EPC mobilization and homing to ischemic tissue in eGFP transgenic mouse bone marrow-transplanted ICR mouse. CONCLUSIONS AND IMPLICATIONS: Circulating EPC levels and neo-vasculogenesis were augmented by DPP-4 inhibitor, which was dependent of eNOS-related pathway. The results indicate the therapeutic vasculogenesis potential of the DPP-4 inhibitor sitagliptin in a mouse hind limb ischemia model. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.
British Journal of Pharmacology 07/2012; · 4.41 Impact Factor
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ABSTRACT: We have demonstrated that activation of ATP-sensitive potassium (K(ATP)) channels can attenuate sympathetic hyperinnervation. Sildenafil, a phosphodiesterase-5 inhibitor, has been shown to provide a preconditioning-like cardioprotective effect via opening of K(ATP) channels. The aim of this study was to investigate whether chronic administration of sildenafil attenuates cardiac sympathetic hyperinnervation after myocardial infarction through activation of K(ATP) channels and to compare it with the nitric oxide donor isosorbide dinitrate. Male Wistar infarcted rats induced by ligation of the anterior descending artery were randomized to either vehicle, nicorandil, sildenafil, isosorbide dinitrate, glibenclamide, or a combination of nicorandil and glibenclamide, or sildenafil and glibenclamide. Myocardial norepinephrine levels revealed a significant elevation in vehicle-treated rats compared with sham-operated rats, consistent with sympathetic hyperinnervation after infarction assessed by immunohistochemical analysis for tyrosine hydroxylase, growth associated factor 43 and neurofilament and by protein expression and mRNA of nerve growth factor. Sympathetic hyperinnervation was reduced after administering either nicorandil or sildenafil. Arrhythmic scores during programmed stimulation in the sildenafil-treated rats were significantly lower than those treated with the vehicle. Furthermore, the beneficial effects of sildenafil-induced were reversed by the addition of either glibenclamide or 5-hydroxydecanoate, implicating mitochondrial K(ATP) channels as the relevant target. Isosorbide dinitrate failed to confer similar antiarrhythmia. 1H-[1,2,4]oxadiazolo[4,3-α]quinoxalin-1-one, a soluble guanylyl cyclase inhibitor, did not influence the effect of sildenafil on the nerve growth factor. These data indicate that sildenafil after infarction attenuated sympathetic hyperinnervation and arrhythmias by activation of mitochondrial K(ATP) channels through a guanylyl cyclase-cGMP-independent pathway.
European journal of pharmacology 06/2012; 690(1-3):124-32. · 2.59 Impact Factor
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Nai-Wen Tsao,
Chun-Ming Shih,
Jong-Shiuan Yeh,
Yung-Ta Kao,
Ming-Hsiung Hsieh,
Keng-Liang Ou,
Jaw-Wen Chen,
Kou-Gi Shyu,
Zen-Chung Weng, Nen-Chung Chang,
Feng-Yen Lin,
Chun-Yao Huang
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ABSTRACT: The aim of this study was to evaluate the impact of extracorporeal membrane oxygenation (ECMO) assistance on the clinical outcome of patients with acute myocardial infarction (AMI) that is complicated by profound cardiogenic shock (CS) who received primary percutaneous coronary intervention (PCI).
We collected patients from January 2004 through December 2006 (stage 1); 25 patients who presented with AMI and received primary PCI and had profound CS were enrolled in the study. Intraaortic balloon counterpulsation (IABP) was the only modality for extracorporeal support in our hospital. From January 2007 through December 2009 (stage 2), 33 patients who presented with AMI and received primary PCI and had profound CS were enrolled; for this stage; both intra-aortic balloon counter-pulsation and ECMO support were available in our facility.
A Kaplan-Meier survival analysis displayed significantly improved survival for patients in stage 2 (P = .001; 1-year survival in stage 1 vs 2; 24% vs 63.64%). Patients presenting with either STEMI (ST segment elevation myocardial infarction) or NSTEMI (Non-ST segment elevation myocardial infarction) benefited from ECMO-assisted PCI (P < .05). In stage 1, patients with refractory ventricular tachycardia/ventricular fibrillation had a very low survival rate; however, in stage 2, the survival rate of patients with and without refractory ventricular tachycardia/ventricular fibrillation was similar (P = .316).
Extracorporeal membrane oxygenation-assisted PCI for patients with AMI that is complicated by profound CS may improve the 30-day and 1-year survival rates.
Journal of critical care 05/2012; 27(5):530.e1-530.e11. · 2.13 Impact Factor
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ABSTRACT: Sympathetic activities are elevated in the central SNSs (sympathetic nervous systems) of hypertensive animals, but it is not known whether sympathetic innervation is also elevated in the heart. Sympathetic hyper-responsiveness in hypertension may result from oxidative stress. The aim of the present study was to investigate sympathetic hyperinnervation in DOCA (deoxycorticosterone acetate)-salt hypertensive rats with established hypertension. At 4 weeks after the start of DOCA-salt treatment and uninephrectomization, male Wistar rats were randomized into three groups for 8 weeks: vehicle, NAC (N-acetylcysteine) and triple therapy (hydralazine, hydrochlorothiazide and reserpine). DOCA-salt was associated with increased oxidant release. DOCA-salt produced concentric left ventricular hypertrophy and cardiomyocyte hypertrophy. Sympathetic hyperinnervation was observed in DOCA-salt rats, as assessed by myocardial noradrenaline levels, immunofluorescent analysis of tyrosine hydroxylase, growth-associated factor 43 and neurofilament and Western blotting and real-time quantitative RT-PCR (reverse transcription-PCR) of NGF (nerve growth factor). Arrhythmic scores during programmed stimulation in DOCA-salt rats were significantly higher than those in the control rats. Triple therapy, despite being effective on BP (blood pressure), offered neither attenuated cardiomyocyte hypertrophy nor anti-arrhythmia. The effects of DOCA-salt treatment on NGF expression, sympathetic hyperinnervation and arrhythmias were attenuated by NAC. Furthermore, the effects of NAC on NGF were abolished by administering BSO (L-buthionine sulfoximine), an inhibitor of glutamate-cysteine ligase. In conclusion, DOCA-salt treatment contributes to up-regulation of NGF proteins probably through a free radical-dependent pathway in a BP-independent manner. DOCA-salt rats treated with NAC attenuate sympathetic hyperinnervation and thus show a beneficial effect on arrhythmogenic response to programmed electrical stimulation.
Clinical Science 04/2012; 123(7):445-57. · 4.61 Impact Factor
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Chun-Yao Huang,
Chun-Ming Shih,
Nai-Wen Tsao,
Yung-Hsiang Chen,
Chi-Yuan Li,
Yu-Jia Chang, Nen-Chung Chang,
Keng-Liang Ou,
Cheng-Yen Lin,
Yi-Wen Lin,
Chih-Hao Nien,
Feng-Yen Lin
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ABSTRACT: The expression of vascular adhesion molecule-1 (VCAM-1) by endothelial cells may play a major role in atherogenesis. The actual mechanisms of chlamydia pneumoniae (C. pneumoniae) relate to atherogenesis are unclear. We investigate the influence of VCAM-1 expression in the GroEL1 from C. pneumoniae-administered human coronary artery endothelial cells (HCAECs) and hypercholesterolemic rabbits. In this study, we constructed the recombinant GroEL1 from C. pneumoniae. The HCAECs/THP-1 adhesion assay, tube formation assay, western blotting, enzyme-linked immunosorbent assay, actinomycin D chase experiment, luciferase reporter assay, and immunohistochemical stainings were performed. The results show that GroEL1 increased both VCAM-1 expression and THP-1 cell adhesives, and impaired tube-formation capacity in the HCAECs. GroEL1 significantly increased the VCAM-1 mRNA stability and cytosolic AU-binding factor 1 (AUF1) level. Overexpression of the p37(AUF1) significantly increased VCAM-1 gene expression in GroEL1-induced bovine aortic endothelial cells (BAECs). GroEL1 prolonged the stability of VCAM-1 mRNA by increasing both p37(AUF1) and the regulation of the 5' untranslated region (UTR) of the VCAM-1 mRNA in BAECs. In hypercholesterolemic rabbits, GroEL1 administration enhanced fatty-streak and macrophage infiltration in atherosclerotic lesions, which may be mediated by elevated VCAM-1 expression. In conclusion, GroEL1 induces VCAM-1 expression by p37(AUF1) in endothelial cells and enhances atherogenesis in hypercholesterolemic rabbits.
PLoS ONE 01/2012; 7(8):e42808. · 4.09 Impact Factor
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Chun-Yao Huang,
Chun-Ming Shih,
Nai-Wen Tsao,
Yung-Hsiang Chen,
Chi-Yuan Li,
Yu-Jia Chang, Nen-Chung Chang,
Keng-Liang Ou,
Cheng-Yen Lin,
Yi-Wen Lin,
Chih-Hao Nien,
Feng-Yen Lin
PLoS ONE 01/2012; 7(8). · 4.09 Impact Factor
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Feng-Yen Lin,
Yi-Ting Tsai,
Chung-Yi Lee,
Chih-Yuan Lin,
Yi-Wen Lin,
Chi-Yuan Li,
Chun-Ming Shih,
Chun-Yao Huang, Nen-Chung Chang,
Jui-Chi Tsai,
Ta-Liang Chen,
Chien-Sung Tsai
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ABSTRACT: Thrombomodulin (TM) is expressed on the surface of monocytes and is a key regulator of actual immune capacity. Propofol is an anesthetic agent that exerts anti-inflammatory effects. The objective of this study was to determine whether propofol could modulate TM in TNF-α-stimulated monocytes. THP-1 cells and male New Zealand rabbits were used in this study. The results showed that TNF-α decreases the TM expression by mediating posttranscriptional modification, and this inhibition may be repressed by treatment with propofol. Immunofluorescence, immunoprecipitation, and pull-down assays were used to demonstrate that Rac1-dependent nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, Cdc42, and p38 mitogen-activated protein kinase activation, as well as tristetraprolin (TTP) expression, all contributed to the downregulation of TM in TNF-α-treated cells. Propofol reversed the effects of TNF-α on TM downregulation. Propofol mediated the expression of intracellular TTP and the distribution of cytosolic human antigen R (HuR) and changed their interactions with the 3'-untranslated region of TM mRNA regulating by Cdc42 and Rac1. In addition, the animal study showed that propofol regulates TM, TTP, and HuR expression on monocytes in TNF-α-treated rabbits. In conclusion, the inhibition of TM expression in TNF-α-treated monocytes was mediated by the activation of NADPH oxidase and the expression of TTP. Propofol may inhibit the downregulation of TM by mediating NADPH oxidase and TTP inactivation and through the activation of HuR in vitro and in vivo. Utilizing TTP and HuR to control TM expression may be a promising approach for controlling systemic inflammation, and propofol may possess potential implications for the clinical immunity of monocytes after anesthesia or surgery.
Shock (Augusta, Ga.) 05/2011; 36(3):279-88. · 2.87 Impact Factor
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ABSTRACT: Lectin-like oxidized low-density lipoprotein receptor 1 (LOX-1) plays a major role in oxidized low-density lipoprotein-induced vascular inflammation. Chlamydia pneumoniae has been found in atherosclerotic lesions and is related to atherosclerotic pathogenesis, although its specific mechanism remains unknown. This study was conducted to investigate the mechanisms of LOX-1 expression in GroEL1 (a heat shock protein from C. pneumoniae)-administered human coronary artery endothelial cells (HCAECs) and atherogenesis in hypercholesterolemic rabbits. We demonstrated that in the hypercholesterolemic rabbit model, GroEL1 administration enhanced fatty streak and macrophage infiltration in atherosclerotic lesions, which may be mediated by elevated LOX-1 expression. In in vitro study using HCAECs, stimulation with GroEL1 increased TLR4 and LOX-1 expression. Increased LOX-1 expression was downregulated by Akt activation and PI3K-mediated endothelial NO synthase activation. PI3K inhibitor and NO synthase inhibitor induced LOX-1 mRNA production, whereas the NO donor ameliorated the increasing effect of LOX-1 mRNA in GroEL1-stimulated HCAECs. LOX-1 expression was regulated by NADPH oxidase, which mediates reactive oxygen species production and intracellular MAPK signaling pathway in GroEL1-stimulated HCAECs. Treatment with polyethylene-glycol-conjugated superoxide dismutase, apocynin, or diphenylene iodonium significantly decreased GroEL1-induced LOX-1 expression, as did the knockdown of Rac1 gene expression by RNA interference. In conclusion, the GroEL1 protein may induce LOX-1 expression in endothelial cells and atherogenesis in hypercholesterolemic rabbits. The elevated level of LOX-1 in vitro may be mediated by the PI3K-Akt signaling pathway, endothelial NO synthase activation, NADPH oxidase-mediated reactive oxygen species production, and MAPK activation in GroEL1-stimulated HCAECs. The GroEL1 protein of C. pneumoniae may contribute to vascular inflammation and cardiovascular disorders.
The Journal of Immunology 03/2011; 186(7):4405-14. · 5.79 Impact Factor
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ABSTRACT: The Xue-Fu-Zhu-Yu decoction (XFZYD) is a well-known traditional Chinese medicine for treating cardiovascular diseases. The therapeutic effects of this XFZYD have been well documented especially in treating of atherosclerosis and hyperlipidemia. Since this decoction can induce endothelial progenitor cell angiogenesis, it can provide experimental evidence for the treatment of ischemic diseases. Patients who are admitted to the hospital with acute ischemic stroke are initially considered candidates for the recombinant tissue plasminogen activator (rt-PA). However, rt-PA therapy is still lesser than ideal due to its major side effect of hemorrhaging. Therefore, medical research has been devoted to finding an alternative and/or complementary therapy for ischemic stroke. In the present study, we evaluated the protective effect of the combination of XFZYD with or without rt-PA in a rat model of thromboembolic stroke.
A cerebral thromboembolic stroke animal model and immunoblotting analysis were used to assess the effects of XFZYD and rt-PA.
Treatment with rt-PA (8 mg/kg) or XFZYD (1.5 and 3.0 g/kg/day) alone showed slight reductions in the infarct volume compared to solvent-treated rats. However, XFZYD (1.5 and 3.0 g/kg/day) obviously potentiated rt-PA-mediated reduction in the infarct volume in cerebral ischemic regions. In addition, treatment with rt-PA significantly reduced both tumor necrosis factor (TNF)-α and inducible nitric oxide synthase (iNOS) but not hypoxia-inducible factor (HIF)-1 α or active caspase-3 expressions in ischemic regions, whereas treatment with XFZYD (3.0 g/kg/day) significantly reduced all of these protein expressions in ischemic regions. Moreover, treatment with XFZYD (1.5 and 3.0 g/kg/day) obviously potentiated rt-PA-mediated reductions in TNF-α, iNOS, HIF-1 α, and active caspase-3 expressions.
Results of this study suggest that XFZYD potentiated rt-PA-mediated neuroprotection against thromboembolic stroke in rats. This neuroprotection is probably mediated by the inhibition of HIF-1 α and TNF-α, followed by the inhibition of inflammatory responses (i.e., iNOS) and apoptosis (active caspase-3). These results provide a better understanding of the scientific validation of the therapeutic value of the combination of XFZYD with rt-PA in ischemic stroke.
Journal of ethnopharmacology 02/2011; 134(3):824-30. · 2.32 Impact Factor
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ABSTRACT: Ursolic acid (UA), a triterpenoid compound found in plants, is used in the human diet and in medicinal herbs and possesses a wide range of biological benefits including antioxidative, anti-inflammatory, and anticarcinogenic effects. Endothelial expression of allograft inflammatory factor-1 (AIF-1) mediates vasculogenesis, and nitric oxide (NO) produced by endothelial NO (eNOS) represents a mechanism of vascular protection. It is unclear whether UA affects the neovascularization mediated by AIF-1 and eNOS expression. This study investigated the effects and mechanisms of UA on angiogenesis in vivo in hind limb ischemic animal models and in vitro in human coronary artery endothelial cells (HCECs). This study explored the impact of UA on endothelial cell (EC) activities in vitro in HCECs, vascular neovasculogenesis in vivo in a mouse hind limb ischemia model, and the possible role of AIF-1 in vasculogenesis. The results demonstrate that UA enhances collateral blood flow recovery through induction of neovascularization in a hind limb ischemia mouse model. In vitro data showed that UA increases tube formation and migration capacities in human endothelial cells, and exposing HCECs to UA increased AIF-1 expression through a NO-related mechanism. Moreover, UA administration increased capillary density and eNOS and AIF-1 expression in ischemic muscle. These findings suggest that UA may be a potential therapeutic agent in the induction of neovascularization and provide a novel mechanistic insight into the potential effects of UA on ischemic vascular diseases.
Journal of Agricultural and Food Chemistry 11/2010; 58(24):12941-9. · 2.82 Impact Factor
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ABSTRACT: Endothelin-1 (ET-1) has been implicated in the pathogenesis of renal impairment. The current study was undertaken to assess the effect of pravastatin on the progression of renal impairment in deoxycorticosterone acetate (DOCA)-salt hypertensive rats.
Four weeks after the start of DOCA-salt treatment and uninephrectomization, male Wistar rats were treated with one of the following therapies for 8 weeks: vehicle; a nonselective endothelin receptor antagonist bosentan; pravastatin; or hydralazine.
Treatment with bosentan or pravastatin was associated with reductions in blood pressure and renal medullary hydroxyproline content, and improvement in glomerular filtration rate, urinary protein excretion, macrophage infiltration, tubular injury, and vascular injury, but not glomerulosclerosis. The renal medullary ET-1 protein levels and preproET-1 mRNA assessed by western blotting and real-time quantitative reverse transcription-PCR were significantly decreased (both P < 0.001) in the pravastatin-treated rats compared with vehicle, which was also confirmed by immunohistochemical analysis. However, there were no significant differences of ET-1 levels in the renal cortex among the DOCA-salt groups. The nephroprotective effects of pravastatin were not associated with its antihypertensive action because hydralazine despite reducing blood pressure failed to improve renal function and disorder.
These results suggest a crucial role of renal endothelin system in the pathogenesis of renal functional and structural alterations in the DOCA-salt hypertensive rats. Pravastatin administration ameliorates the impairment of renal function and structures by attenuating medullary ET-1 expression, independent of systemic blood pressure.
Journal of hypertension 10/2009; 27(11):2232-43. · 4.02 Impact Factor
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ABSTRACT: The purpose of this study was to determine whether N-acetylcysteine (NAC) attenuates cardiac sympathetic hyperinnervation through replenishment of glutathione in infarcted rats.
After ligation of the coronary artery, male Wistar rats were randomized to either vehicle, NAC, or vitamins C + E groups for 4 weeks. Post-infarction was associated with increased oxidant release, as measured by tissue isoprostane and myocardial glutathione. Measurement of myocardial norepinephrine levels revealed a significant elevation in vehicle-treated infarcted rats compared with sham-operated rats. Sympathetic hyperinnervation was blunted after administering NAC, as assessed by immunofluorescent analysis of tyrosine hydroxylase and western blotting and real-time quantitative RT-PCR of nerve growth factor. Arrhythmic scores during programmed stimulation in the vehicle-treated infarcted rats were significantly higher than those in animals treated with NAC. Although NAC and vitamins showed similar effects on ventricular remodelling, only NAC demonstrated beneficial effects on sympathetic hyperinnervation. Furthermore, the effects of NAC on nerve growth factor were abolished by administering l-buthionine sulfoximinem, an inhibitor of gamma-glutamylcysteine ligase.
Chronic use of NAC, but not vitamins, after infarction is associated with down-regulation of nerve growth factor proteins, probably through a glutathione-dependent pathway, and thus plays a critical role in the beneficial effect on the arrhythmogenic response to programmed electrical stimulation.
Cardiovascular research 09/2009; 85(1):137-46. · 5.80 Impact Factor
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ABSTRACT: Granulocyte colony-stimulating factor (G-CSF) has been used for the repair of infarcted myocardium, but concerns have been raised regarding its proarrhythmic potential. We analyzed the influence of G-CSF treatment on sympathetic nerve remodeling and the expression of nestin in a rat model of experimental myocardial infarction (MI). Twenty-four hours after ligation of the anterior descending artery, male Wistar rats were randomized to receive either saline (MI/C) or G-CSF (MI/G) for 5 days. At 56 days after infarction, MI/G rats had a significantly higher left ventricular ejection fraction accompanied by a significant decrease in the left ventricular end-diastolic dimension than the MI/C group. Myocardial norepinephrine levels revealed a significant elevation in MI/G rats in the border zone compared with MI/C rats. Immunohistochemical analysis for tyrosine hydroxylase, growth-associated protein 43, and neurofilament also confirmed the changes of myocardial norepinephrine. At 5 days after infarction, MI/G rats had increased numbers of tissue-infiltrated CD34(+) cells, although a similar increase in circulating neutrophil counts between sham-operated rats treated with G-CSF and MI/G rats was observed. Compared with MI/C rats, MI/G rats showed an increase of nestin and nerve growth factor expression, as assessed by protein expression and mRNA levels. The arrhythmia scores during programmed stimulation were significantly higher in MI/G rats than in MI/C rats, suggesting proarrhythmic potential. These findings suggest that, although G-CSF administration after infarction improved myocardial function, it resulted in the activation of nestin and nerve growth factor expression and increased sympathetic reinnervation, which may increase the arrhythmogenic response to programmed electrical stimulation.
AJP Heart and Circulatory Physiology 07/2009; 297(2):H512-22. · 3.71 Impact Factor
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ABSTRACT: Although the acute administration of ATP-sensitive potassium (K(ATP)) channel agonists provides a neuroprotection, it is unclear whether similar benefits are found by modulating sympathetic innervation in chronic settings after myocardial infarction. We assessed whether K(ATP) channel agonists can attenuate the sprouting of cardiac sympathetic nerves after infarction. Male Wistar rats after ligating coronary artery were randomized to either saline, nicorandil, pinacidil, glibenclamide, or a combination of 1) nicorandil and glibenclamide or 2) pinacidil and glibenclamide for 4 wk. To elucidate the role of mitochondrial K(ATP) channels in modulating nerve growth factor, 5-hydroxydecanoate was assessed in an in vitro model. The measurement of myocardial norepinephrine levels revealed a significant elevation in saline-treated infarcted rats compared with sham-operated rats, consistent with excessive sympathetic innervation. Excessive sympathetic innervation was blunted after giving the rats either nicorandil or pinacidil, compared with saline, as assessed by the immunohistochemical analysis of tyrosine hydroxylase, growth associated protein-43, and neurofilament and Western blot analysis and real-time quantitative RT-PCR of nerve growth factor. The arrhythmic scores during programmed stimulation in the saline- or glibenclamide-treated infarcted rats were significantly higher than those of rats treated with K(ATP) channel agonists. In contrast, the beneficial effects of nicorandil and pinacidil were abolished by administering either glibenclamide or 5-hydroxydecanoate. The sympathetic hyperinnervation after infarction is attenuated by the activation of mitochondrial K(ATP) channels. The chronic use of mitochondrial K(ATP) channel agonists after infarction may attenuate the arrhythmogenic response to programmed electrical stimulation.
AJP Heart and Circulatory Physiology 05/2009; 296(6):H1949-59. · 3.71 Impact Factor
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ABSTRACT: Proteinuria is an important risk factor for cardiovascular and renal morbidity and mortality. The effect of nicorandil on proteinuria in hypertensive patients well controlled by antihypertensive agents containing a low dose of valsartan has not been studied.
A total of 136 proteinuric (300-3000 mg/day), valsartan-treated hypertensive patients with blood pressure less than 140/90 mmHg were randomized into three groups to receive placebo, isosorbide dinitrate (30 mg/day), or nicorandil (15 mg/day) for 6 months.
The average dose of valsartan given to the patients was similar in the three groups. Creatinine clearance remained stable throughout the study in the three groups. Nicorandil, but not isosorbide dinitrate, significantly reduced proteinuria by 44% after 6 months (P < 0.0001). Urinary endothelin-1 levels significantly decreased after administration of nicorandil (P = 0.002), whereas placebo and isosorbide dinitrate had no effect. Urinary excretion of endothelin-1 was significantly correlated with improvement in urinary protein excretion in nicorandil-treated patients (r = 0.69, P < 0.0001). The urinary excretion of retinol-binding protein decreased after nicorandil administration, probably reflecting an improvement in tubular function. In contrast, the urinary excretion of immunoglobulin G did not change significantly throughout the study in the three groups. Multivariate analysis revealed that proteinuria was only significantly correlated with the use of nicorandil (model adjusted r = 0.35, P < 0.0001).
The addition of nicorandil to treatment for patients with well controlled hypertension may have an additive effect on reducing proteinuria independent of hemodynamics and nitric oxide effects, possibly through inhibiting renal endothelin-1 synthesis and improving tubular function.
Journal of hypertension 03/2009; 27(3):618-25. · 4.02 Impact Factor
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ABSTRACT: PH (pulmonary hypertension) often complicates the disease course of patients with COPD (chronic obstructive pulmonary disease) and is an indication of a worse prognosis. In the present study, we assessed whether pravastatin administration was effective in improving PH and exercise capacity in COPD patients with PH, and whether the pulmonary protection was mediated by inhibiting ET-1 (endothelin-1) production. In a double-blind parallel design, 53 COPD patients with PH were randomly assigned to receive either placebo or pravastatin (40 mg/day) over a period of 6 months at a medical centre. Baseline characteristics were similar in both groups. The exercise time remained stable throughout the study in the placebo group. After 6 months, the exercise time significantly increased 52% from 660+/-352 to 1006+/-316 s (P<0.0001) in pravastatin-treated patients. With pravastatin, echocardiographically derived systolic PAP (pulmonary artery pressure) decreased significantly from 47+/-8 to 40+/-6 mmHg. There was significant improvement in the Borg dyspnoea score after administering pravastatin. Despite unchanged plasma ET-1 levels throughout the study, urinary excretion of the peptide was decreased and significantly correlated with an improvement in exercise time in pravastatin-treated patients (r=-0.47, P=0.01). In conclusion, pravastatin significantly improved exercise tolerance, and decreased PH and dyspnoea during exercise in COPD patients with PH, probably by inhibiting ET-1 synthesis.
Clinical Science 10/2008; 116(6):497-505. · 4.61 Impact Factor
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ABSTRACT: Coronary artery disease (CAD) is an important etiology of atrial fibrillation (AF). Coronary artery calcification is a marker of coronary atherosclerosis and coronary events. The purpose of this study was to investigate whether larger left atrium (LA) and pulmonary veins (PVs) were seen by multidetector computed tomography (MDCT) scans in those patients with higher coronary calcium scores.
A total of 166 patients undergoing MDCT for general check-up (n = 128, 77%) or suspected CAD (n = 38, 23%) were enrolled and divided into a control (calcium score = 0, n = 60), medium calcium score (calcium score = 100 approximately 400, n = 47), and high calcium score (calcium score >400, n = 59) groups. Diameters and areas of the LA, left atrial appendage (LAA), and PVs were measured by MDCT. The high calcium score group had significantly larger PVs diameters, LAA orifice area (1.9 +/- 1.4 cm(2), 0.9 +/- 0.5 cm(2), 0.8 +/- 0.4 cm(2), P < 0.005), LA anterior-posterior distance (32.2 +/- 6.8 mm, 30.4 +/- 6.5 mm, 27.3 +/- 6.0 mm, P < 0.05), and transverse distance (52.6 +/- 7.3 mm, 50.2 +/- 9 mm, 49.5 +/- 4.6 mm, P < 0.05) than the medium calcium score and control groups. Six (3.6%) patients with paroxysmal AF had higher calcium scores and larger diameters of LA, LAA, and PVs than those (96.4%) without paroxysmal AF. Two patients in the high calcium score group had calcified PVs localized to the right upper and left upper PVs. The incidence of calcified PVs was 1.2% for the total patients and 3.3% for the high calcium score patients.
In the presence of high calcium scores in this patient population, the LA, LAA, and PVs were enlarged.
Journal of Cardiovascular Electrophysiology 10/2008; 20(2):153-8. · 3.06 Impact Factor
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ABSTRACT: The purpose of this study was to determine whether ATP-sensitive potassium (K(ATP)) channel agonists exert a beneficial effect on the structural, functional, and molecular features of the remodeling heart in infarcted rats.
Myocardial K(ATP) channels have been implicated in the ventricular remodeling after myocardial infarction by inhibition of 70-kDa S6 (p70S6) kinase.
Male Wistar rats after induction of myocardial infarction were randomized to either vehicle, agonists of K(ATP) channels nicorandil and pinacidil, an antagonist of K(ATP) channels glibenclamide, or a combination of nicorandil and glibenclamide or pinacidil and glibenclamide for 4 weeks. To verify the role of p70S6 kinase in ventricular remodeling, rapamycin was also assessed.
Significant ventricular hypertrophy was detected by increased myocyte size at the border zone isolated by enzymatic dissociation after infarction. Increased synthesis of p70S6 kinase messenger ribonucleic acid after infarction in vehicle-treated rats was confirmed by reverse transcription-polymerase chain reaction, consistent with the results of immunohistochemistry and Western blot for phosphorylated p70S6 kinase. Rats in the nicorandil- and pinacidil-treated groups significantly attenuated cardiomyocyte hypertrophy and phosphorylated p70S6 kinase expression with similar potency, as compared with vehicle. The beneficial effects of nicorandil and pinacidil were abolished by administering either glibenclamide or 5-hydroxydecanoate. Addition of rapamycin attenuated ventricular remodeling and did not have additional beneficial effects compared with those seen in rats treated with either nicorandil or pinacidil alone.
Activation of K(ATP) channels by either nicorandil or pinacidil can attenuate ventricular remodeling, probably through a p70S6 kinase-dependent pathway after infarction.
Journal of the American College of Cardiology 05/2008; 51(13):1309-18. · 14.16 Impact Factor
