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1.
Acta Physiol (Oxf) ; 228(3): e13377, 2020 03.
Article in English | MEDLINE | ID: mdl-31512380

ABSTRACT

AIM: Dilated cardiomyopathy (DCM) is characterised by left ventricular dilation and associated with systolic dysfunction. Recent evidence has reported the high expression of latent transforming growth factor beta binding protein 2 (LTBP2) in heart diseases, which may play a role in regulating multiple biological functions of myocardial cells. Thus, this study set out to investigate the molecular mechanism and effects of LTBP2 in myocardial oxidative stress injury, fibrosis and remodelling in a rat model of DCM, with the involvement of NF-κB signalling pathway. METHODS: The rat model of DCM was treated with si-LTBP2 and/or activator of NF-κB signalling pathway to examine the haemodynamic indexes, cardiac functions, oxidative stress injury, fibrosis and remodelling. Moreover, in vitro experiments were conducted to verify the regulatory role of LTBP2 and NF-κB signalling pathway in DCM. RESULTS: LTBP2 was up-regulated in DCM rats. After LTBP2 was knocked down, haemodynamic indexes, HW/BW ratio, collagen volume fraction (CVF) level, positive expression of LTBP2, levels of reactive oxygen species (ROS), malondialdehyde (MDA), interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-α), tumour necrosis factor beta 1 (TGF-ß1) and brain natriuretic peptide (BNP) were all decreased. Meanwhile, levels of LTBP2, Col-I, Col-III, p65 and p52 were also reduced, while HW, BW and levels of SOD and TAOC were increased. In contrast, activation of NF-κB signalling pathway reversed effects of LTBP2 gene silencing. These findings were confirmed by in vivo experiments. CONCLUSIONS: LTBP2 silencing can attenuate myocardial oxidative stress injury, myocardial fibrosis and myocardial remodelling in DCM rats by down-regulating the NF-κB signalling pathway.


Subject(s)
Cardiomyopathy, Dilated/metabolism , Fibrosis/prevention & control , Latent TGF-beta Binding Proteins/metabolism , Myocardial Ischemia/prevention & control , Animals , Cardiomyopathy, Dilated/genetics , Cardiomyopathy, Dilated/pathology , Cells, Cultured , Disease Models, Animal , Fibrosis/etiology , Fibrosis/metabolism , Fibrosis/pathology , Gene Knockdown Techniques , Hemodynamics , Latent TGF-beta Binding Proteins/antagonists & inhibitors , Latent TGF-beta Binding Proteins/genetics , Male , Myocardial Ischemia/etiology , Myocardial Ischemia/metabolism , Myocardial Ischemia/pathology , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , NF-kappa B/genetics , NF-kappa B/metabolism , Oxidative Stress/physiology , RNA, Small Interfering/administration & dosage , RNA, Small Interfering/genetics , Rats , Signal Transduction , Vascular Remodeling
2.
Ann Transl Med ; 7(16): 386, 2019 Aug.
Article in English | MEDLINE | ID: mdl-31555700

ABSTRACT

BACKGROUND: The phenotypic transition of vascular smooth muscle cells (VSMCs) from a contractile to a proliferative state markedly affects the pathophysiology of cardiovascular diseases. The adventitial inflammation can promote neointimal formation and vascular remodeling. We used direct administration of lipopolysaccharide (LPS) into the periphery of the carotid artery to investigate the influence of transient adventitial inflammation on vascular remodeling and its potential mechanism. METHODS: Male 15-week-old Wistar rats were randomly assigned to four groups with six rats in each group. The rats of groups I and II were administered distilled water, and group III and IV were treated with fasudil and atorvastatin respectively. All treatments were given daily for 11 days. On day 8, the adventitia in group I was injected with 5 µL sterile saline, and the group II-IV were injected with 5 µL sterilized LPS. The carotid blood flow and femoral blood pressure were measured in vivo, and the thickness of vascular intima and middle layer was measured in vitro. Serum interleukin-6 (IL-6) and tumor necrosis factor α (TNFα) were determined using enzyme-linked immunosorbent assay (ELISA) assay. And the Rho-associated coiled-coil-containing protein kinase 2 (ROCK2), myosin phosphatase target subunit 1 (MYPT1), myosin light chain (MLC), myocardin, SM-α actin or glyceraldehyde-3-phosphate dehydrogenase (GAPDH) were detected by western blot. The comparisons were made by one-way analysis of variance with Bonferroni's post hoc test. A value of P<0.05 was considered to represent a statistically significant difference. RESULTS: Transient adventitial inflammation induced by LPS caused no obvious change in basal blood flow, but did lead to vascular hypersensitivity to serotonin. Morphological examinations revealed that the medial layer was the only domain affected, and showed VSMC proliferation and rearrangement. LPS increased serum IL-6 and TNFα contents, ROCK2 expression and activity, and caused changes in the expression levels of some stereotypical VSMC genes. Similar to the Rho-kinase inhibitor fasudil, atorvastatin completely restored the morphological alterations, even increased blood flow. CONCLUSIONS: Our study confirms the beneficial effect of atorvastatin on the vascular system in terms of morphology and function.

3.
J Cell Physiol ; 234(5): 6033-6041, 2019 05.
Article in English | MEDLINE | ID: mdl-30478832

ABSTRACT

Evidence has demonstrated that the microRNA (miR) may play a significant role in the development of congenital heart disease (CHD). Here, we explore the mechanism of microRNA-592 (miR-592) in heart development and CHD with the involvement of KCTD10 and Notch signaling pathway in a CHD mouse model. Cardiac tissues were extracted from CHD and normal mice. Immunohistochemistry staining was performed to detect positive expression rate of KCTD10. A series of inhibitor, activators, and siRNAs was introduced to verified regulatory functions for miR-592 governing KCTD10 in CHD. Furthermore, the effect of miR-592 on cell proliferation and apoptosis was also investigated. Downregulated positive rate of KCTD10 was observed in CHD mice. Downregulation of miR-592 would upregulate expression of KCTD10 and inhibit the activation of Notch signaling pathway, thus promote cell proliferation. This study demonstrates that downregulation of miR-592 prevents CHD and hypoplastic heart by inhibition of the Notch signaling pathway via negatively binding to KCTD10.


Subject(s)
Heart Defects, Congenital/prevention & control , MicroRNAs/metabolism , Myocardium/metabolism , Potassium Channels, Voltage-Gated/metabolism , Receptors, Notch/metabolism , 3' Untranslated Regions , Animals , Apoptosis , Basic Helix-Loop-Helix Transcription Factors/genetics , Basic Helix-Loop-Helix Transcription Factors/metabolism , Binding Sites , Cell Proliferation , Cells, Cultured , Disease Models, Animal , Down-Regulation , Female , Gene Expression Regulation, Developmental , Heart Defects, Congenital/genetics , Heart Defects, Congenital/metabolism , Heart Defects, Congenital/pathology , Jagged-1 Protein/genetics , Jagged-1 Protein/metabolism , Male , Mice , MicroRNAs/genetics , Myocardium/pathology , Potassium Channels, Voltage-Gated/genetics , Receptors, Notch/genetics , Repressor Proteins/genetics , Repressor Proteins/metabolism , Signal Transduction , Transcription Factor HES-1/genetics , Transcription Factor HES-1/metabolism
4.
J Cardiovasc Pharmacol ; 66(1): 9-15, 2015 Jul.
Article in English | MEDLINE | ID: mdl-26164718

ABSTRACT

BACKGROUND AND OBJECTIVE: Vasoconstriction and hypersensitivity to the vasoconstrictive action of serotonin occurs in the early stage of atherosclerosis. Vascular neural nitric oxide synthase (nNOS) plays an important role in the regulation of vascular tone and is vasoprotective against atherosclerosis. In this study, we intended to investigate the possible role of nNOS in mediating the effect of Chinese medicine Tongxinluo (TXL) to attenuate vasoconstriction induced by the chronic injury in the collared carotid artery. METHODS: Twenty-four male Wistar Kyoto rats were assigned to 2 treatments (n = 12): vehicle and TXL (400 mg·kg·d). After 2 weeks of treatment, adventitia injury was induced by placing a silicone collar around the left carotid artery for 2 weeks. Blood flow and vascular reactivity to serotonin were determined, and carotid arteries were harvested for morphometry, RT-PCR, and Western blotting analysis. Expression of nNOS and phosphorylated ERK1/2 was also analyzed in primary cultured vascular smooth muscle cells after TXL and/or ERK kinase inhibitor treatment. RESULTS: Adventitia injury induced by the placement of a silicone collar around the carotid artery for 2 weeks led to chronic vasoconstriction and vascular hypersensitivity to serotonin, which was attenuated by TXL treatment. TXL improved the carotid blood flow and normalized the vascular hypersensitivity to serotonin in collared carotid arteries. The expression of nNOS and phosphorylated ERK1/2 was increased by TXL treatment in both collared carotid artery and vascular smooth muscle cells indicating a possible contribution of ERK1/2 and nNOS signaling to the beneficial effects of TXL. Moreover, we showed that the effect of TXL to increase nNOS expression was mediated by the phosphorylated ERK1/2 since the effect could be abolished by the ERK kinase inhibitor PD98059. CONCLUSIONS: TXL increases nNOS expression in the collared carotid artery through activation of ERK1/2 signaling, which may have contributed to the attenuation of vasoconstriction induced by the collar-induced adventitia injury.


Subject(s)
Drugs, Chinese Herbal/pharmacology , Gene Expression Regulation, Enzymologic , MAP Kinase Signaling System/physiology , Nitric Oxide Synthase Type I/biosynthesis , Vasoconstriction/physiology , Animals , Cells, Cultured , Enzyme Activation/drug effects , Enzyme Activation/physiology , MAP Kinase Signaling System/drug effects , Male , Rats , Rats, Inbred WKY , Vasoconstriction/drug effects
5.
Mol Med Rep ; 12(1): 331-6, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25760256

ABSTRACT

Gap junction intercellular communication (GJIC) is important in mediating intercellular substance and signal transmission. Connexin (Cx)43 is a major component involved in GJIC in vascular tissue and its abnormal expression is closely associated with various vascular diseases. Insulin resistance is the central component of metabolic syndrome, and high doses of insulin can affect vascular function through multiple pathways, resulting in cardiovascular disease. However, the effects of insulin on GJIC function and connexin (Cx)43 expression in vascular smooth muscle cells (VSMCs) remain unclear. Following treatment of VSMCs with different doses of insulin, a fluorescence recovery after photobleaching (FRAP) assay was performed to evaluate GJIC function in treated VSMCs. The results showed that high­dose insulin suppressed GJIC function. Western blot assays further demonstrated that high­dose insulin induced the phosphorylation of Cx43 at s368 and downregulated the expression of Cx43. H2O2 release assays demonstrated that high­dose insulin treatment significantly elevated the cellular H2O2 level. In addition, compared with cells treated with high­dose insulin, pretreatment with catalase significantly restored the cellular GJIC function, decreased the phosphorylation level of Cx43 at s368, and enhanced Cx43 expression. In conclusion, these data indicate that high­dose insulin inhibits cellular GJIC function through the oxidative stress­activated signaling pathway. This phenomenon may also constitute a potential mechanism underlying the pathogenesis of insulin resistance and its complications.


Subject(s)
Cell Communication/drug effects , Gap Junctions/metabolism , Insulin/pharmacology , Muscle, Smooth, Vascular/drug effects , Animals , Cells, Cultured , Connexin 43/metabolism , Fluorescence Recovery After Photobleaching , Gap Junctions/drug effects , Gap Junctions/pathology , Glucose/metabolism , Hydrogen Peroxide/metabolism , Hypoglycemic Agents/pharmacology , Immunohistochemistry , Muscle, Smooth, Vascular/cytology , Muscle, Smooth, Vascular/metabolism , Phosphorylation/drug effects , Rats , Rats, Sprague-Dawley
6.
Mol Med Rep ; 7(1): 105-9, 2013 Jan.
Article in English | MEDLINE | ID: mdl-23117913

ABSTRACT

Essential hypertension (EH) is an etiological risk factor that poses a serious threat to human health. The aim of this study therefore was to investigate the correlation between the two SNPs (rs1805067 and rs2397771) of the norepinephrine (NE) transporter gene in the sympathetic nervous system and essential hypertension (EH). A total of 96 hypertensive patients (EH group) and 96 normal subjects (control group) were selected by epidemiological investigation and the sequences at rs1805067 and rs2397771 in the two groups were investigated using polymerase chain reaction (PCR) and Sanger sequencing. In the EH group, systolic and diastolic blood pressure, body mass index (BMI), levels of creatinine, low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and the percentage of drinkers were found to be higher compared with those of the control group (P<0.05). The results of the analysis of the allele frequencies of rs1805067 (A/G) revealed that there was no difference between the two groups (P>0.05). The analysis results of the allele frequencies of rs2397771 (C/G) in the EH group revealed that G accounted for 48.96% and C for 51.04% of the patients, while in the control group, these values were 64.58 and 35.42%, respectively. These results indicated a significant difference between the two groups (P<0.05). In the population studied, the onset of EH may be correlated with BMI, TG, LDL-C and high-density lipoprotein cholesterol (HDL-C). EH may be related to the rs2397771 (C/G) C allele polymorphism of the NE transporter gene but not to rs1805067 (A/G).


Subject(s)
Genetic Predisposition to Disease , Hypertension/genetics , Norepinephrine Plasma Membrane Transport Proteins/genetics , Polymorphism, Genetic , Alleles , Case-Control Studies , Essential Hypertension , Gene Frequency , Genotype , Humans , Hypertension/epidemiology , Polymorphism, Single Nucleotide , Risk Factors , Sequence Analysis, DNA
7.
Mol Med Rep ; 5(3): 675-9, 2012 03.
Article in English | MEDLINE | ID: mdl-22159344

ABSTRACT

The present study was performed to elucidate the mechanism underlying the anti-atherogenic action of atorvastatin (ATV). We investigated the effect of ATV on intimal thickening of the rat carotid artery induced by collar placement and further examined the effect of ATV on the expression of C-type natriuretic peptide (CNP), cGMP-dependent protein kinase (PKG) Iα and PKG Iß in carotid arteries. The expression of CNP was examined by enzyme-linked immunosorbent assay (ELISA) and quantitative real-time RT-PCR. Western blotting was used to determine the expression of PKG Iα and PKG Iß. After 14 days, the collar placement induced a marked neointima formation and a reduction in CNP and PKG Iα expression. These effects were significantly reversed by ATV treatment. However, no obvious changes in PKG Iß expression were observed throughout the study. In conclusion, the present data suggest that elevation of CNP represents an additional mechanism by which ATV treatment may prevent the development and progression of atherosclerosis.


Subject(s)
Anticholesteremic Agents/pharmacology , Carotid Artery Injuries/drug therapy , Gene Expression Regulation/drug effects , Heptanoic Acids/pharmacology , Natriuretic Peptide, C-Type/metabolism , Pyrroles/pharmacology , Animals , Atorvastatin , Carotid Artery Injuries/metabolism , Cyclic GMP-Dependent Protein Kinase Type I , Cyclic GMP-Dependent Protein Kinases/metabolism , Male , Natriuretic Peptide, C-Type/genetics , Neointima/pathology , Rats
8.
Zhonghua Xin Xue Guan Bing Za Zhi ; 39(1): 73-8, 2011 Jan.
Article in Chinese | MEDLINE | ID: mdl-21418803

ABSTRACT

OBJECTIVE: Vasoconstriction and vascular hypersensitivity to serotonin were previously shown in animal models of adventitia injury. We investigated the contribution of angiotensin II (AngII)/AngII receptors and oxidative stress to vascular contractility and reactivity in this model. METHODS: Wistar Kyoto rats were divided into 3 groups: normal (n = 6, no any intervention, only for measuring the serum AngII concentration), vehicle (n = 12, collared), and valsartan (n = 12, collared + valsartan 30 mg×kg(-1)×d(-1)). After one week of treatment, adventitia injury was induced by positioning a silicone collar around the right carotid artery for one week. Blood flow and vascular reactivity to serotonin were determined one week after injury, the blood from left ventricle was taken to measure the serum AngII concentration by ELISA, and carotids were harvested for morphometry and Western blot analysis. RESULTS: Adventitia injury induced lumen cross-sectional area reduction (-44% vs. -5%), media diameter increase (62% vs. 10%), blood flow reduction [(2.79 ± 0.22) vs. (4.33 ± 0.84) ml/min] were significantly attenuated by valsartan. The increased vascular reactivity sensitivity to serotonin in vehicle group was also significantly reduced in valsartan group. Serum AngII concentration was significantly increased in vehicle group [(45.21 ± 4.52) pg/ml vs. (19.83 ± 0.5) pg/ml in normal rats, P = 0.0148] and the expression of AngII type 1 (AT(1)) receptor, AngII type 2 (AT(2)) receptor, as well as p22(phox) in collared arteries were significantly upregulated. Valsartan did not affect the AT(1) receptor expression but further increased serum AngII concentration [(89.73 ± 20.44) pg/ml vs. (45.21 ± 4.52) pg/ml, P = 0.001], and AT(2) receptor expression, while downregulated p22(phox) expressions. CONCLUSIONS: Collar-induced adventitia injury resulted in chronic vasoconstriction and vascular hypersensitivity to serotonin via increased serum AngII level, upregulated AngII receptors expression in the vascular well, and activated local oxidative stress. These changes could be blocked by valsartan suggesting a crucial role of AngII/AngII receptors on vascular contractility and reactivity changes in this model.


Subject(s)
Carotid Arteries/drug effects , Connective Tissue/pathology , Tetrazoles/pharmacology , Valine/analogs & derivatives , Vasoconstriction/drug effects , Angiotensin II/metabolism , Animals , Carotid Arteries/metabolism , Carotid Arteries/pathology , Male , Oxidative Stress , Rats , Rats, Inbred WKY , Receptors, Angiotensin/metabolism , Valine/pharmacology , Valsartan
9.
Int J Cardiol ; 148(2): 168-73, 2011 Apr 14.
Article in English | MEDLINE | ID: mdl-19942308

ABSTRACT

BACKGROUND: Vasoconstriction and vascular hypersensitivity to serotonin has been described previously in animal models of adventitia injury. The present study was undertaken to investigate the contribution of the RhoA/Rho-kinase pathway to the collar-induced the change of vascular contractility and reactivity in rat carotid artery. METHODS: Wistar Kyoto rats were assigned to 4 treatments (n=12): vehicle, fasudil, valsartan, and fasudil plus valsartan. After 1 week of treatment, adventitia injury was induced by positioning a silicone collar around the right carotid artery for 1 week. Blood flow and vascular reactivity to serotonin was determined 1 week after injury, and carotids were harvested for morphometry and biochemical analysis. RESULTS: Adventitia injury leaded to histological changes of vasoconstriction with the percent lumen patency of 54.5 ± 4.3% (p<0.001) decreasing, accompanying by the reduction of the blood flow (2.79 ± 0.22 ml/min vs. 3.67 ± 0.26 mi/min/p<0.001) when compared to contralateral arteries. The increase of vascular reactivity sensitivity to serotonin was observed in the collared artery when compared with the contralateral artery. Treatment with valsartan and fasudil prevented the development of vasoconstriction, improved the carotid blood flow and normalized the hypersensitivity to serotonin. Injury increased Angiotensin II type 1(AT(1)receptor, Rho-kinase, and p-MYPT1(Thr696) expression. Valsartan lowered the Rho-kinase and p-MYPT1(Thr696) expression. Fasudil inhibited the p-MYPT1(Thr696) expression. CONCLUSIONS: Collar-induced adventitia injury resulted in the enhancement of vascular contractility and reactivity. The activation of RhoA/Rho-kinase signal pathway, stimulated by AT(1) receptor, plays an important role in the collar-induced the change of vascular contractility and reactivity.


Subject(s)
Carotid Artery Diseases/metabolism , Carotid Artery Diseases/physiopathology , Serotonin/pharmacology , Vasoconstriction/physiology , rho-Associated Kinases/metabolism , 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/analogs & derivatives , 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/pharmacology , Angiotensin II Type 1 Receptor Blockers/pharmacology , Animals , Carotid Artery Diseases/drug therapy , Cerebrovascular Circulation/drug effects , Cerebrovascular Circulation/physiology , Disease Models, Animal , Male , Protein Kinase Inhibitors/pharmacology , Rats , Rats, Inbred WKY , Receptor, Angiotensin, Type 1/metabolism , Silicones , Tetrazoles/pharmacology , Valine/analogs & derivatives , Valine/pharmacology , Valsartan , Vasoconstriction/drug effects , rho-Associated Kinases/antagonists & inhibitors , rhoA GTP-Binding Protein/metabolism
10.
Chin Med J (Engl) ; 123(17): 2405-9, 2010 Sep.
Article in English | MEDLINE | ID: mdl-21034557

ABSTRACT

BACKGROUND: Coronary artery in-stent restenosis (ISR) and late stent thrombosis remain as important complications of stenting. The inflammation reactions to sirolimus and paclitaxel-eluting stents were investigated in a swine stenosis model induced by interleukin (IL)-1ß. METHODS: Mini pigs (n = 12; 2-3 months old and weighing 25-30 kg) were subjected to thoracotomy. Segments (10 mm) of the mid left anterior descending coronary artery and left circumflex coronary artery were exposed and aseptically wrapped with a cotton mesh soaked with IL-1ß (5 µg). After 2 weeks, the animals were anesthetized and quantitative coronary arteriography (QCA) was performed. The stenosis sites were randomized into three groups for stent insertion: a sirolimus-eluting stent (SES) group (Firebird(TM), n = 7), a paclitaxel-eluting stent (PES) group (TAXUS(TM), n = 9), and a bare-metal stent (BMS) group (YINYITM, Dalian Yinyi Biomaterials Development Co., Ltd, China, n = 8). The three different stents were randomly implanted into stenosis segments. Expression of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), P-selectin and vascular cell adhesion molecule-1 (VCAM-1) was determined by reverse transcription-coupled polymerase chain reaction (RT-PCR). RESULTS: QCA showed severe stenosis in IL-1ß treated segments. The SES and PES groups showed lower 1-month angiographic late lumen loss (LLL) within the stent and the lesion compared with BMS (P < 0.05) by follow-up QCA. The SES showed lower LLL than that of PES in reducing 1-month inflammation lesions in pigs by follow-up QCA ((0.15 ± 0.06) mm vs. (0.33 ± 0.01) mm, P < 0.0001). The neointimal hyperplasia areas in SES and PES showed lower than those of BMS (SES (11.6 ± 1.7) mm(2), PES (27.2 ± 1.6) mm(2) vs. BMS (76.2 ± 1.3) mm(2), P < 0.0001). The mRNA expression of MCP-1 by RT-PCR in SES and PES showed lower than that of BMS at 30 days after stenting (SES 0.20 ± 0.03, PES 0.48 ± 0.49 vs. BMS 0.58 ± 0.07, P < 0.05). Levels of VCAM-1 in SES were significantly lower than those of PES and BMS (SES 0.35 ± 0.08 vs. PES 0.65 ± 0.13, BMS 0.70 ± 0.06, P < 0.05). Histochemical immunostaining of vessel walls showed lower inflammatory chemokine MCP-1 expression in the SES and PES groups compared with BMS. CONCLUSION: SESs were superior in reducing 1-month angiographic LLL in inflammation lesions in pigs, strongly suggesting that SESs can suppress inflammatory reactions in ISR at multiple points.


Subject(s)
Angioplasty, Balloon, Coronary/adverse effects , Coronary Restenosis/prevention & control , Drug-Eluting Stents/adverse effects , Inflammation/prevention & control , Interleukin-1beta/pharmacology , Paclitaxel/administration & dosage , Sirolimus/administration & dosage , Animals , Male , Swine
11.
Chin Med J (Engl) ; 123(11): 1365-72, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20819587

ABSTRACT

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.


Subject(s)
Angioplasty, Balloon, Coronary , Myocardial Infarction/therapy , Thrombolytic Therapy , Aged , Coronary Angiography , Female , Fibrinolytic Agents/therapeutic use , Humans , Male , Middle Aged , Myocardial Infarction/drug therapy
12.
Mol Cell Biochem ; 338(1-2): 59-68, 2010 May.
Article in English | MEDLINE | ID: mdl-19949838

ABSTRACT

The large conductance Ca(2+)-activated K(+) (BK) channel, abundantly expressed in vascular smooth muscle cells, plays a critical role in controlling vascular tone. Activation of BK channels leads to membrane hyperpolarization and promotes vasorelaxation. BK channels are activated either by elevation of the intracellular Ca(2+) concentration or by membrane depolarization. It is also regulated by a diversity of vasodilators and vasoconstrictors. Interleukin-1beta (IL-1beta) is one of the cytokines that play important roles in the development and progression of a variety of cardiovascular diseases. The effects of IL-1beta on vascular reactivity are controversial, and little is known about the modulation of BK channel function by IL-1beta. In this study, we investigated how IL-1beta modulates BK channel function in cultured arterial smooth muscle cells (ASMCs), and examined the role of H(2)O(2) in the process. We demonstrated that IL-1beta had biphasic effects on BK channel function and membrane potential of ASMCs, that is both concentration and time dependent. IL-1beta increased BK channel-dependent K(+) current and hyperpolarized ASMCs when applied for 30 min. While long-term (24-48 h) treatment of IL-1beta resulted in decreased expression of alpha-subunit of BK channel, suppressed BK channel activity, decreased BK channel-dependent K(+) current and depolarization of the cells. H(2)O(2) scavenger catalase completely abolished the early effect of IL-1beta, while it only partly diminished the long-term effect of IL-1beta. These results may provide important molecular mechanisms for therapeutic strategies targeting BK channel in inflammation-related diseases.


Subject(s)
Hydrogen Peroxide/pharmacology , Interleukin-1beta/pharmacology , Large-Conductance Calcium-Activated Potassium Channels/metabolism , Myocytes, Smooth Muscle/drug effects , Myocytes, Smooth Muscle/metabolism , Reactive Oxygen Species/metabolism , Animals , Aorta/cytology , Aorta/drug effects , Catalase/metabolism , Cells, Cultured , Large-Conductance Calcium-Activated Potassium Channels/genetics , Membrane Potentials/drug effects , Membrane Potentials/physiology , Muscle, Smooth, Vascular/cytology , Muscle, Smooth, Vascular/drug effects , Myocytes, Smooth Muscle/cytology , Oxidants/pharmacology , Patch-Clamp Techniques , Rats
13.
Zhongguo Zhong Xi Yi Jie He Za Zhi ; 28(7): 627-31, 2008 Jul.
Article in Chinese | MEDLINE | ID: mdl-18822914

ABSTRACT

OBJECTIVE: To observe the inhibitory effect of Tongxinluo (TXL) on coronary vaso spasm in small swine in vivo, and to investigate its possible acting mechanism. METHODS: The model of coronary atherosclerosis in 16 male small swines was established by left thoracotomy after anesthesia, isolated the sections of left anterio-descending branch and proximal end of rotator branch with similar outer diameter, and encapsulated them with paper-towel holding 2.5 microg interleukin-1beta. Two weeks later, the condition of coronary vasospasm induced by catheter intra-coronary injection of 5-hydroxytryptamine (5-HT, 10 microg/kg) was observed through coronary artery contrast examination. The 12 swines with successfully formed coronary vaso spasm were randomly divided into 2 groups, the TXL group and the control group. They were fed with special diet, but TXL 1 g/(kg d) was administered additionally to the TXL group for 4 weeks. The observation on coronary vasospasm was repeated 1 week after discontinuation of TXL treatment, then the animals were sacrificed, their vascular sections enclosed with IL-1beta was taken to conduct the pathologic examination and to detect the expressions of Rho kinase mRNA and its substrate myosin- binding subunit phosphorylation (MBS-P) by RT-PCR and Western blot method. RESULTS: Coronary artery contrast showed that local coronary stenosis occurred in the 12 model swines to different extents (20% - 30%, and vascular spasm on them could be induced by 5-HT. At the time of repeating examination, 11 vascular sections in the control group still maintain their positive spasm reaction to 5-HT, but only 2 in the TXL group did so, the reaction turned to negative in 1 and 10 in the two groups respectively. Pathological examination showed that different degrees of macrophage aggregation could be found in both groups. The degree of lumen stricture and endometrial hyperplasia in the TXL group was obviously attenuated than those in the control group. The expressions of Rho kinase mRNA and MBS-P in the control group were up-regulated obviously. As compared with those in the control group, they were inhibited significantly in the TXL group, as (71.5 +/- 2.4) vs (98.2 +/- 7.7)% and 16,633 +/- 1,390 vs 25,818 +/- 4,745, respectively (all P < 0.05). CONCLUSION: TXL could obviously inhibit the coronary intimal hyperplasia mediated by IL-1beta and coronary vasospasm induced by 5-HT, one of its mechanisms is possibly the inhibition on the intracellular Rho kinase mRNA expression in the IL-1beta enclosed vascular section to decrease the level of MBS-P.


Subject(s)
Coronary Vasospasm/drug therapy , Coronary Vasospasm/metabolism , Drugs, Chinese Herbal/therapeutic use , Interleukin-1beta/metabolism , Serotonin/adverse effects , Animals , Coronary Vasospasm/chemically induced , Coronary Vasospasm/genetics , Disease Models, Animal , Gene Expression/drug effects , Humans , Interleukin-1beta/genetics , Male , Random Allocation , Swine , rho-Associated Kinases/genetics , rho-Associated Kinases/metabolism
14.
Arch Med Res ; 39(1): 52-60, 2008 Jan.
Article in English | MEDLINE | ID: mdl-18067996

ABSTRACT

BACKGROUND: AMP-activated protein kinase (AMPK) activation plays an essential role in glucose metabolism of the heart. This study aimed at investigating whether AMPK was involved in glucose transporter-4 (GLUT-4) translocation induced by azide-induced chemical hypoxia in primary cultured neonatal rat cardiomyocytes. METHODS: With or without adenine 9-beta-D-arabinofuranoside (ara A, AMPK inhibitor) preincubation, primary cultured rat cardiomyocytes were randomized to several groups as incubated with azide (the respiratory chain inhibitor), insulin, or 5-aminoimidazole-4-carboxyamide-1-beta-D-ribofuranoside (AICAR, an AMPK activator). Glucose uptake was measured through gamma-scintillation and GLUT-4 protein was detected by Western blot for each group. RESULTS: Azide-induced chemical hypoxia and AICAR both increased glucose uptake and GLUT-4 translocation in cardiomyocytes, and AICAR had an additive effect on insulin action. Ara A decreased AICAR- and azide-induced glucose uptake and GLUT-4 translocation but did not affect basal or insulin-stimulated glucose uptake. CONCLUSIONS: Azide-induced chemical hypoxia increased glucose uptake and GLUT-4 translocation in neonatal rat cardiomyocytes through a mechanism that at least was partially mediated by AMPK activation.


Subject(s)
Glucose Transporter Type 4/metabolism , Multienzyme Complexes/metabolism , Myocytes, Cardiac/metabolism , Protein Kinases/metabolism , Protein Serine-Threonine Kinases/metabolism , AMP-Activated Protein Kinase Kinases , AMP-Activated Protein Kinases , Aminoimidazole Carboxamide/analogs & derivatives , Aminoimidazole Carboxamide/pharmacology , Animals , Animals, Newborn , Cell Hypoxia , Hypoglycemic Agents/pharmacology , Multienzyme Complexes/antagonists & inhibitors , Myocytes, Cardiac/drug effects , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Transport/drug effects , Rats , Rats, Wistar , Ribonucleotides/pharmacology , Sodium Azide/toxicity
15.
Zhonghua Xin Xue Guan Bing Za Zhi ; 34(5): 445-9, 2006 May.
Article in Chinese | MEDLINE | ID: mdl-16776964

ABSTRACT

OBJECTIVE: To observe the effects of rapamycin on the expressions of Rho-kinase and p27 mRNA during vascular intimal proliferation in a porcine model of coronary stenosis induced by interleukin-1beta (IL-1beta). METHODS: The proximal segments of LAD and LCX were wrapped with cotton mesh that had absorbed sepharose bead solution with or without IL-1beta. Selective coronary angiography was performed two weeks later and the animals were killed for collecting the samples for histopathology and RT-PCR analyzing of Rho-kinase and p27 mRNA. RESULTS: The expressions of Rho-kinase and p27 mRNA could be visualized in normal coronary wall. The expression of Rho-kinase mRNA was significantly enhanced and the expression of p27 mRNA was significantly decreased during the process of intimal proliferation induced by IL-1beta. Rapamycin significantly inhibited the intimal proliferation, reduced the infiltration of inflammatory cells, reduced the expression of Rho-kinase mRNA and increased the expression of p27 mRNA. CONCLUSIONS: The expression of Rho-kinase mRNA is upregulated and p27 mRNA downregulated in coronary artery stenosis induced by IL-1beta and these effects could be abolished by cotreatment with rapamycin.


Subject(s)
Coronary Vessels/drug effects , Interleukin-1beta/pharmacology , Sirolimus/pharmacology , Tunica Intima/drug effects , rho-Associated Kinases/metabolism , Animals , Coronary Angiography , Coronary Vessels/metabolism , Coronary Vessels/pathology , Disease Models, Animal , Male , RNA, Messenger/metabolism , Swine , Tunica Intima/metabolism , Tunica Intima/pathology
16.
Zhonghua Xin Xue Guan Bing Za Zhi ; 34(3): 252-6, 2006 Mar.
Article in Chinese | MEDLINE | ID: mdl-16630464

ABSTRACT

OBJECTIVE: We investigated the effects of pitavastatin on angiogenesis and perfusion in C3H/He mice with unilateral hind limb ischemia. METHODS: C3H/He mice treated with saline (n = 15) or pitavastatin (1 mg.kg(-1).d(-1), n = 15) per gavage for 1 week underwent unilateral hind limb ischemia surgery and were treated for another 5 weeks. Hind-limb blood flow was measured by Laser Doppler perfusion imager (LDPI, ischemic/nonischemic limb, %) at baseline, immediately after ischemia and weekly thereafter for 5 weeks. Endpoints included local vessel counts by immunofluorescence, phospho-Akt positive cell counts by immunoenzyme histochemical technique, vascular endothelial growth factors (VEGFs) expression in ischemic limbs by Western blot and serum nitric oxide metabolite (NOx) by chrome dioxide Griess method. RESULTS: Lower extremity perfusion was significantly improved in pitavastatin treated mice vs. controls as measured by LDPI% at 1 week post ischemia and thereafter (P < 0.05). Pitavastatin treatment was associated with significantly increased capillary count [(47 +/- 11) vs. (26 +/- 14)/per high-power field (x 200), P < 0.05] and greater percentage of phospho-Akt positive cells [(6 +/- 1) vs. (2 +/- 0)/per high-power field (x 200), P < 0.05] in ischemic limbs. Serum NOx [(77.3 +/- 21.8) vs. (52.1 +/- 11.2) mol/L, P < 0.05) and VEGF protein expression in ischemic limbs were also significantly increased in pitavastatin group than those in control group. CONCLUSIONS: Pitavastatin enhances angiogenesis and perfusion in CsH/He mice with limb ischemia.


Subject(s)
Ischemia/physiopathology , Lower Extremity/blood supply , Neovascularization, Physiologic/drug effects , Quinolines/pharmacology , Animals , Disease Models, Animal , Male , Mice , Mice, Inbred C3H , Nitric Oxide/blood , Vascular Endothelial Growth Factors/metabolism
17.
Zhonghua Xin Xue Guan Bing Za Zhi ; 34(1): 50-3, 2006 Jan.
Article in Chinese | MEDLINE | ID: mdl-16626550

ABSTRACT

OBJECTIVE: Phosphorylation of myosin light chain (MLC) is one of the most important steps for vascular smooth muscle contraction and Rho-kinase is involved in this process. We investigated the role of Rho-kinase in a porcine coronary artery spasm model with interleukin-1beta. METHODS: Segments of left coronary artery adventitia were surrounded by normal saline (n = 8) or IL-1beta agarose microne (n = 8) for 2 weeks. Vasospastic responses to intracoronary serotonin or histamine then studied at the saline or IL-1beta-treated site. The Rho-kinase mRNA expression in the treated site was measured by reverse transcription-polymerase chain reaction analysis (RT-PCR). The extent of phosphorylation of myosin-binding subunit of myosin phosphates (MBS, one of the major substrates of Rho-kinase) were quantified by Western blot analysis. RESULTS: Intracoronary serotonin or histamine repeatedly induced coronary artery spasm and coronary arterial stenosis was evidenced at IL-1beta-treated site. Expression of Rho-kinase mRNA in IL-1beta-treated site was significantly increased compared to saline treated site (98.20% +/- 7.66% vs. 63.70% +/- 4.26%, P < 0.05). Western blot analysis showed that during the serotonin-induced contractions the extent of phosphorylation of MBS was also significantly increased in the spastic site (25,485 +/- 4745 vs. 6510 +/- 779, P < 0.05). CONCLUSION: Rho-kinase upregulation at the spastic site and increased phosphorylation of myosin-binding subunit of myosin phosphates are key players in inducing vascular smooth muscle hypercontraction in this porcine model.


Subject(s)
Coronary Vasospasm/metabolism , Interleukin-1beta/adverse effects , Myosin Light Chains/metabolism , rho-Associated Kinases/metabolism , Animals , Coronary Vasospasm/pathology , Disease Models, Animal , Interleukin-1beta/metabolism , Male , Phosphorylation , RNA, Messenger/metabolism , Swine
18.
Article in Chinese | MEDLINE | ID: mdl-21162230

ABSTRACT

AIM: To discuss the effect of Pitavastatin on angiogenesis in vivo and its mechanism in Klotho heterozygous deficient mice. METHODS: The heterozygous deficient Klotho mice (kl +/-) and wild mice (kl +/+) from the same litter were used to establish the animal model of hind-limb ischemia and grouped into control and Pitavastatin group, respectively. Hind-limb blood flow was evaluated using Laser Doppler perfusion imager (LDPI) before treatment and after operation of hind-limbs. The capillaries in muscle of limbs were counted by means of CD-31 labeled immuno-fluorescence. The phosphorylation of Akt (Protein kinase B) in cells was measured by direct immunohistochemical technique. The expression of vascular endothelial growth factors (VEGFs) in muscle of limbs was assessed using Western blotting. RESULTS: After treatment of Pitavastatin, the blood flow in ischemic limbs of the Kl +/- and wild mice improved obviously, the ratio of blood flow area in ischemic limb to that in non-ischemic limb increased and the density of capillaries increased in ischemic limbs of the Kl +/- and wild mice. Pitavastatin enhanced the phosphorylation of Akt and the expression of VEGF in ischemic limbs of the Kl +/- and wild mice. CONCLUSION: Pitavastatin has the pro-angiogenesis effect in vivo and the VEGF-p-Akt-NO pathway may be involved in the mechanism of the effect of Pitavastatin.


Subject(s)
Angiogenesis Inducing Agents/pharmacology , Ischemia , Quinolines/pharmacology , Vascular Endothelial Growth Factor A/metabolism , Animals , Heterozygote , Male , Mice , Mice, Knockout
19.
Zhonghua Xin Xue Guan Bing Za Zhi ; 33(1): 73-6, 2005 Jan.
Article in Chinese | MEDLINE | ID: mdl-15924788

ABSTRACT

OBJECTIVE: To study the expression of Rho/Rho kinase of cardiac muscle in heart failure rats caused by pressure overload and the effects of fasudil on heart failure. METHODS: The heart failure models were successfully induced by coarctation of ascending aorta after 20 weeks in this study. Thirty female Wistar operated rats were divided randomly into three groups (n = 10) for 4 week treatment. (1) Sham operation group: normal saline, 0.1 ml, i.p,Bid. (2) Heart failure group: normal saline, 0.1 ml,i.p,Bid. (3) Fasudil group: fasudil 5 mg/kg, i.p, Bid. The hemodynamic parameters, the ratio of LV weight to body weight, the expressions of RhoA and Rho kinase mRNA, and the concentration of calcium ion same as [Ca(2+)](i) were investigated in the three groups. RESULTS: Hemodynamic parameters were significantly changed in heart failure group than those in sham operation group, such as left ventricular diastolic end pressure increased [(13.00 +/- 0.30) mm Hg vs (3.78 +/- 0.31) mm Hg, P < 0.01], left ventricular systolic pressure decreased [(97.20 +/- 7.21) mm Hg vs (129.45 +/- 7.52) mm Hg, P < 0.01]. Those results could be significantly changed by use of fasudil, P < 0.01. The ratio of LV weight to body weight was significantly increased in heart failure group than that in sham operation group [(4.77 +/- 0.08) mg/g vs (2.51 +/- 0.12) mg/g, P < 0.01]. Fasudil could significantly decrease the ratio of LV weight to body weight compared with that in heart failure group [(4.05 +/- 0.08) mg/g vs (4.77 +/- 0.08) mg/g, P < 0.01]. Cardiac muscle RhoA, Rho kinase mRNA level and [Ca(2+)](i) were higher in heart failure group than those in sham operation group [Ca(2+)](i) (475.93 +/- 28.22) nmol/L vs (79.25 +/- 3.33) nmol/L, P < 0.01. Compared with those in heart failure group, the expressions of RhoA, Rho kinase mRNA level decreased significantly, P < 0.01, and the levels of cardiomyocyte [Ca(2+)](i) had no change in fasudil group [(462.78 +/- 16.72) nmol/L vs (475.93 +/- 28.22) nmol/L, P > 0.05]. CONCLUSIONS: These results indicated that heart failure was probably related to activating of RhoA, Rho kinase. Fasudil may contribute to the observed beneficial effects on heart failure such as the decrease of RhoA, Rho kinase mRNA expression and not increase of [Ca(2+)](i) level. Rho/Rho kinase may be a novel, potent signaling of heart failure.


Subject(s)
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/analogs & derivatives , Heart Failure/metabolism , Myocardium/metabolism , Protein Kinase Inhibitors/pharmacology , rho-Associated Kinases/metabolism , 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/pharmacology , Animals , Female , Heart Failure/physiopathology , Rats , Rats, Wistar
20.
Zhongguo Wei Zhong Bing Ji Jiu Yi Xue ; 15(8): 469-71, 2003 Aug.
Article in Chinese | MEDLINE | ID: mdl-12919646

ABSTRACT

OBJECTIVE: To observe the changes in mitogen-activated protein kinase (MAPK) activity and gene expression after coronary artery balloon injury in rat. METHODS: Forty Wistar rats were randomly divided into control group (without coronary artery balloon injury), and 3, 7 and 14 days after coronary artery balloon injury groups (n=10, respectively). The activity of MAPK was measured by biochemical method and the gene expression was examined by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: MAPK activity and gene expression of MAPK in the coronary artery balloon injury in rat after 3, 7 and 14 days were significantly higher than that of normal control, especially 3 days after injury [MAPK activity: (17.32+/-2.17) pmol x mg(-1) x min(-1);MAPK protein: ERK1 was 194.7+/-8.6, ERK2 was 175.8+/-7.9; MAPK gene expression: ERK1 was 1.15+/-0.21, ERK2 was 1.13+/-0.14 ]. CONCLUSION: The increase activity and mRNA of MAPK may be involved in the restenosis process after coronary balloon injury.


Subject(s)
Angioplasty, Balloon, Coronary/adverse effects , Coronary Vessels/enzymology , Mitogen-Activated Protein Kinase 1/metabolism , Mitogen-Activated Protein Kinase 3/metabolism , Animals , Coronary Restenosis , Gene Expression , Random Allocation , Rats , Rats, Wistar
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