AIM: To study the genesis of neointima formation in pulmonary hypertension(PH), we investigated the role of caveolin-1 and related proteins. METHODS: Male Sprague Dawley rats were given monocrotaline(M, 40 mg/kg) or s...AIM: To study the genesis of neointima formation in pulmonary hypertension(PH), we investigated the role of caveolin-1 and related proteins. METHODS: Male Sprague Dawley rats were given monocrotaline(M, 40 mg/kg) or subjected to hypobaric hypoxia(H) to induce PH. Another group was given M and subjected to H to accelerate the disease process(M + H). Right ventricular systolic pressure, right ventricular hypertrophy, lung histology for medial hypertrophy and the presence of neointimal lesions were examined at 2 and 4 wk. The expression of caveolin-1 and its regulatory protein peroxisome proliferator-activated receptor(PPAR) γ, caveolin-2, proliferative and antiapoptotic factors(PY-STAT3, p-Erk, Bcl-x L), endothelial nitric oxide synthase(e NOS) and heat shock protein(HSP) 90 in the lungs were analyzed, and the results from M + H group were compared with the controls, M and H groups. Double immunofluorescence technique was used to identify the localization of caveolin-1 in pulmonary arteries in rat lungs and in human PH lung tissue. RESULTS: In the M + H group, PH was more severe compared with M or H group. In the 4 wk M+H group, several arteries with reduced caveolin-1 expression in endothelial layer coupled with an increased expression in smooth muscle cells(SMC), exhibited neointimal lesions. Neointima was present only in the arteries exhibiting enhanced caveolin-1 expression in SMC. Lung tissue obtained from patients with PH also revealed neointimal lesions only in the arteries exhibiting endothelial caveolin-1 loss accompanied by an increased caveolin-1 expression in SMC. Reduction in e NOS and HSP90 expression was present in the M groups(2 and 4 wk), but not in the M + H groups. In both M groups and in the M + H group at 2 wk, endothelial caveolin-1 loss was accompanied by an increase in PPARγ expression. In the M + H group at 4 wk, increase in caveolin-1 expression was accompanied by a reduction in the PPARγ expression. In the H group, there was neither a loss of endothelial caveolin-1, eNOS or HSP 90, nor an increase in SMC caveolin-1 expression; or any alteration in PPARγ expression. Proliferative pathways were activated in all experimental groups. CONCLUSION: Enhanced caveolin-1 expression in SMC follows extensive endothelial caveolin-1 loss with subsequent neointima formation. Increased caveolin-1 expression in SMC, thus, may be a prelude to neointima formation.展开更多
Objective.The present study investigated the role of endogenous carbon monoxide(CO)in the pathogenesis of neointimal formation induced by balloon injury in rat. Method.Endothelial denudation ...Objective.The present study investigated the role of endogenous carbon monoxide(CO)in the pathogenesis of neointimal formation induced by balloon injury in rat. Method.Endothelial denudation of the left common carotid artery of rat was carried out by three passages of a Fogarty 2F balloon catheter.DNA,collagen and elastin contents of each intima media were estimated;and heme oxygenase(HO)activity and CO production in vascular smooth muscle cell(VSMC)were measured after administration of HO inhibitor. Result.Our data showed that neointima occurred in the rat on day 7 and day 21 after balloon injury,and at the same time HO activity and CO production in VSMC were markedly increased Administration of HO inhibitor,zinc deuteroporphyrin 2,4 bisglycol(ZnDPBG),could effectively inhibit HO activity and CO production,significantly enhance neointimal formation(aortic intima/media ratio were 21 4±1 8% vs 17 6±2 0%,P<0 05 on day 7;and 30 5±2 4% vs 23 0±2 2%,P<0 01 on day 21,respectively,compared with balloon alone group). Conclusion.We concluded that 1)inhibition of CO production may enhance neointimal formation induced by endothelial denudation,implying endogenous CO play an protective role in response to vascular injury,and 2)induction of HO activity may be applied clinically for preventing restenosis after angioplasty.展开更多
Objective: Angiotensin Ⅱ is a growth-promoting factor for vascular smooth muscle cells in culture andin the intact animal. The biological effects of angiotensin Ⅱ are manifested only by binding to specific receptors...Objective: Angiotensin Ⅱ is a growth-promoting factor for vascular smooth muscle cells in culture andin the intact animal. The biological effects of angiotensin Ⅱ are manifested only by binding to specific receptors oncell membranes. In the study, we observed that the effect of rat antisense AT1B gene transfer mediated by adenoviral vector-on neointimal proliferation following rat carotid injury. Methods: Antisense AT1B gene was transductedinto the carotid by adenoviral vector after carotid bal1oon injury and the restenosis model was established in SD rat.We measured neointima/media area ratio in local artery at day 21 after gene transfer. Results: Rat antisense AT1Bgene was successfully transducted into local carotid after the carotid balloon injury. Neointima/media area ratiowas significantly reduced (47 %, P<0. 01) at day 21 after gene transfer compared with the control group. Conclusion: The results suggest it is possible that antisense AT1B gene transfer as a potential therapeutic approach prevent neointimal hyperplasia.展开更多
Objective Endothelial dysfunction is one candidate for triggering neointima formation after arteriovenous grafts(AVGs),but the factors mediating this process are unclear.The purpose of this study was to investigate th...Objective Endothelial dysfunction is one candidate for triggering neointima formation after arteriovenous grafts(AVGs),but the factors mediating this process are unclear.The purpose of this study was to investigate the role of endoplasmic reticulum stress(ERS)-induced endothelial dysfunction in neointima formation following AVGs in high-fat diet(HFD)mice.Methods CCAAT-enhancer-binding protein-homologous protein(CHOP)knockout(KO)mice were created.Mice were fed with HFD to produce HFD model.AVGs model were applied in the groups of WT ND,WT HFD,and CHOP KO HFD.Human umbilical vein endothelial cells(HUVECs)were cultured with oxidized low density lipoprotein(ox-LDL)(40 mg/L)for the indicated time lengths(0,6,12,24 h).ERS inhibitor tauroursodeoxycholic acid(TUDCA)was used to block ERS.Immunohistochemical staining was used to observe the changes of ICAM1.Changes of ERS were detected by real-time RT-PCR.Protein expression levels and ERS activation were detected by Western blotting.Endothellial cell function was determined by endothelial permeability assay and transendothelial migration assay.Results HFD increased neointima formation in AVGs associated with endothelial dysfunction.At the same time,ERS was increased in endothelial cells(ECs)after AVGs in mice consuming the HFD.In vitro,ox-LDL was found to stimulate ERS,increase the permeability of the EC monolayer,and cause endothelial dysfunction.Blocking ERS with TUDCA or CHOP siRNA reversed the EC dysfunction caused by ox-LDL.In vivo,knockout of CHOP(CHOP KO)protected the function of ECs and decreased neointima formation after AVGs in HFD mice.Conclusion Inhibiting ERS in ECs could improve the function of AVGs.展开更多
BACKGROUND Pulmonary hypertension(PH) is a progressive disease with a high morbidity and mortality rate; and neointima formation leads to the irreversibility of the disease.We have previously reported that in rats, mo...BACKGROUND Pulmonary hypertension(PH) is a progressive disease with a high morbidity and mortality rate; and neointima formation leads to the irreversibility of the disease.We have previously reported that in rats, monocrotaline(MCT) injection leads to progressive disruption of endothelial cells(EC), and endothelial caveolin-1(cav-1) loss, accompanied by the activation of pro-proliferative pathways leading to PH. Four weeks post-MCT, extensive endothelial cav-1 loss is associated with increased cav-1 expression in smooth muscle cells(SMC). Exposing the MCTtreated rats to hypoxia hastens the disease process; and at 4 wk, neointimal lesions and occlusion of the small arteries are observed.AIM To identify the alterations that occur during the progression of PH that lead to neointima formation.METHODS Male Sprague-Dawley rats(150-175 g) were divided in 4 groups(n = 6-8 per group): controls(C); MCT(M, a single sc injection 40 mg/kg); Hypoxia(H,hypobaric hypoxia); MCT + hypoxia(M+H, MCT-injected rats subjected to hypobaric hypoxia starting on day1). Four weeks later, right ventricular systolic pressure(RVSP), right ventricular hypertrophy(RVH), lung histology, and cav-1 localization using immunofluorescence technique were analyzed. In addition, the expression of cav-1, tyrosine 14 phosphorylated cav-1(p-cav-1), caveolin-2(cav-2), cavin-1, vascular endothelial cadherin(VE-Cad) and p-ERK1/2 in the lungs were examined, and the results were compared with the controls.RESULTSSignificant PH and right ventricular hypertrophy were present in M and H groups [RVSP, mmHg, M 54±5~*, H 45±2~*, vs C 20±1, P < 0.05; RVH, RV/LV ratio M 0.57±0.02~*, H 0.50±0.03~*, vs C 0.23±0.007, P < 0.05]; with a further increase in M+H group [RVSP 69±9 mmHg, RV/LV 0.59±0.01 P < 0.05 vs M and H]. All experimental groups revealed medial hypertrophy; but only M+H group exhibited small occluded arteries and neointimal lesions. Immunofluorescence studies revealed endothelial cav-1 loss and increased cav-1 expression in SMC in M group; however, the total cav-1 level in the lungs remained low. In the M+H group, significant endothelial cav-1 loss was associated with increasing expression of cav-1 in SMC; resulting in near normalization of cav-1 levels in the lungs [cav-1, expressed as % control, C 100±0, M 22±4~*, H 96±7, M+H 77±6, ~* = P< 0.05 vs C]. The expression of p-cav-1 was observed in M and M+H groups [M314±4%, M+H 255±22% P < 0.05 vs C]. Significant loss of cav-2 [% control, C100±0, M 15±1.4~*, H 97±7, M+H 15±2~*; M and M+H vs C, ~* = P < 0.05], cavin-1 [%control, C 100±0, M 20±3~*, H 117±7, M+H 20±4~*; M and M+H vs C, P < 0.05] and VE-Cad [% control, C 100±0, M 17±4~*, H 96±9, M+H 8±3~*; M and M+H vs C, P <0.05] was present in M and M+H groups, confirming extensive disruption of EC.Hypoxia alone did not alter the expression of cav-1 or cav-1 related proteins.Expression of p-ERK1/2 was increased in all 3 PH groups [%control, C 100±0, M284±23~*, H 254±25~*, M+H 270±17~*; ~* = P < 0.05 vs C].CONCLUSION Both cavin-1 loss and p-cav-1 expression are known to facilitate cell migration;thus, these alterations may in part play a role in neointima formation in PH.展开更多
Drug-eluting stents have been successful in reducing in-stent restenosis but are not suitable for all lesion types and have been implicated in causing late stent thrombosis due to incomplete regeneration of the endoth...Drug-eluting stents have been successful in reducing in-stent restenosis but are not suitable for all lesion types and have been implicated in causing late stent thrombosis due to incomplete regeneration of the endothelial cell layer. In this study we implanted stents coated with cicaprost, a prostacyclin analogue with a long plasma half-life and antiproliferative effects on vascular smooth muscle cells, into the iliac arteries of rabbits. At 28-day follow-up we compared neointima formation within the stented vessels and vascular function in adjacent vessels, to assess if cicaprost could reduce restenosis without impairing vessel function. Arteries implanted with cicaprost eluting stents had significantly more neointima compared to bare metal stents. In adjacent segments of artery, endothelium-dependent relaxation was impaired by the cicaprost-eluting stent but vasodilation to an endothelium-independent vasodilator was maintained. We conclude that the presence of the polymer and sub-optimal release of cicaprost from the stent may be responsible for the increased neointma and impaired functional recovery of the endothelium observed. Further experiments should be aimed at optimising release of cicaprost and exploring different stent polymer coatings.展开更多
Objective To examine antisense and decoy oligonucleotides of nuclear factor kappa B in vivo effects on intima proliferation and balloon-injured monocytes chemotactic protein-1 （ MCP-1 ） and extraceUular signal regul...Objective To examine antisense and decoy oligonucleotides of nuclear factor kappa B in vivo effects on intima proliferation and balloon-injured monocytes chemotactic protein-1 （ MCP-1 ） and extraceUular signal regulated kinase-2 （ERK2） κexpression in the carotid artery of rats. Methods Sprague-Dawley rats underwent balloon-dilation injury of the left carotid artery. Rats are divided into 7 groups （ n = 18 ） and each group includes6 time points （6 h, 1, 3, 5, 7, 14 d） （n =3）. Uninjured right carotid artery of the same rat was used as controls. Results In model group, sense group and scramble group, vessel intima area , media area and intima/media ratio increased after 5 d and reached the maximum after 7 d. The effect of antisense plus decoy group on intimal hyperplasia was more obvious than that of antisense group and decoy group alone. MCP-1 mRNA expression was increased expression continuously at 3, 5 and 7 d and decreased at 14 d. Compared with model group, sense group and scramble group, antisense group, decoy group and antisense plus decoy group had lowered MCP-1 mRNA expression in each time point （ P 〈 0. 05 ）. NF-KB p65 was dispersed positive stain 6 h after injury and increased after 1 d and peaked at 7 d, but the protein expression was weak at 14 d. ERK2 protein synthesis increased at I d and reached the peak at 7 d, while protein expression after 14 d was similar to that at 7 d. Treatment of antisense group, decoy group and antisense plus decoy group inhibited protein synthesis more significantly than those of model group, sense group and scramble group（ P 〈 0. 05）. Conclusion NF-KB modulates genes expression and protein synthesis of MCP-1 and ERK2. Celluar proliferation in vessel wall was dynamically changed after balloon angioplasty injury. Antisense and decoy oligonucleotide of NF-KB by local lipofectaraine transfer inhibit NF-KB activating gene modulation and neointimal hyperplasia.展开更多
Optical coherence tomography （OCT） is a new imaging modality with resolution of approximately 10 pm and can be employed to visualize intracoronary characteristics. Sirolimus-eluting stents （SES） are susceptible to...Optical coherence tomography （OCT） is a new imaging modality with resolution of approximately 10 pm and can be employed to visualize intracoronary characteristics. Sirolimus-eluting stents （SES） are susceptible to late thrombosis due to delayed reendothelialization over the stent struts, which may result in acute myocardial infarction or death. This study was designed to evaluate the re-endothelialization and neointimal coverage of SES with OCT 6 months and 12 months after implantation.Methods A total of 36 patients enrolled in the study underwent OCT examination 6 months （17 patients） and 12 months （19 patients） after SES implantation, The strut apposition to the vessel wall and neointimal coverage on SES struts were evaluated by OCT, Results Forty-six SES and 6561 struts were analyzed, At 6 months, 3041 struts （98.7%） were well-apposed and 39 struts （1,3%） were malapposed, At 12 months, 3434 struts （98,6%） were well-apposed and 47 struts （1,4%） were malapposed, Furthermore, only 4 SES at 6 months （18,2%） and 10 SES at 12 months （41,7%） were fully covered by neointimal growth, The average neointimal thicknesses covering the analyzed struts at 6 months and 12 months were （42±28） μm and （88±32） μm, respectively, There were 1989 struts at 6 months （72,1%） and 1461 struts at 12 months （45,6%） with neointimal thickness 〈100 μm, Conclusions OCT was able to visualize the strut apposition to the vessel wall and neointimal coverage on SES struts, At 6-month and 12-month follow-up examinations most struts were covered with thin neointima, but few of the entire SES showed full coverage. To prevent late-stent thrombosis in the presence of uncovered stent struts, longer dual antiplatelet drugs therapy should be recommended,展开更多
Background： Endothelial cell damage is an important pathophysiological step of restenosis after angioplasty and stenting. Cell transplantation has great therapeutic potential for endothelial recovery. We investigated...Background： Endothelial cell damage is an important pathophysiological step of restenosis after angioplasty and stenting. Cell transplantation has great therapeutic potential for endothelial recovery. We investigated the effect of transplanting endothelial progenitor cells （EPCs） derived from human early fetal aortas in rat injured arteries. Methods： The carotid arterial endothelium of Sprague-Dawley rats was damaged by dilatation with a 1.5 F balloon catheter, and then EPCs derived from human early fetal aortas （〈14 weeks） were injected into the lumen of the injured artery in transplanted rats, with an equal volume of normal saline injected into control rats. Rats were sacrificed at 2 and 4 weeks after treatment and transplanted cells were identified by immunohistochemical staining with anti-human CD31 and anti-human mitochondria antibodies. Arterial cross-sections were analyzed by pathology, immunohistochemistry, and morphometry. Results： Green fluorescence-labeled EPCs could be seen in the endovascular surface of balloon-injured vessels after transplantation. The intimal area and intimal/medial area ratio were significantly smaller in the transplanted group than in the control （P 〈 0.05） and the residual lumen area was larger （P 〈 0.05）. After EPC transplantation, a complete vascular endothelial layer was formed, which was positive for human yon Willebrand factor after immunohistochemical staining, and immunohistochemical staining revealed many CD31- and mitochondria-positive cells in the re-endothelialized endothelium with EPC transplantation but not control treatment. Conclusion： EPCs derived from human early fetal aorta were successfully transplanted into injured vessels and might inhibit neointimal hyperplasia after vascular injury.展开更多
基金Supported by Funds from NYMC Research Endowment Fund under the College’s intramural support program(RM)the National Institutes of Health(JEL,R01 HL111259)K23 HL098743(EDA)
文摘AIM: To study the genesis of neointima formation in pulmonary hypertension(PH), we investigated the role of caveolin-1 and related proteins. METHODS: Male Sprague Dawley rats were given monocrotaline(M, 40 mg/kg) or subjected to hypobaric hypoxia(H) to induce PH. Another group was given M and subjected to H to accelerate the disease process(M + H). Right ventricular systolic pressure, right ventricular hypertrophy, lung histology for medial hypertrophy and the presence of neointimal lesions were examined at 2 and 4 wk. The expression of caveolin-1 and its regulatory protein peroxisome proliferator-activated receptor(PPAR) γ, caveolin-2, proliferative and antiapoptotic factors(PY-STAT3, p-Erk, Bcl-x L), endothelial nitric oxide synthase(e NOS) and heat shock protein(HSP) 90 in the lungs were analyzed, and the results from M + H group were compared with the controls, M and H groups. Double immunofluorescence technique was used to identify the localization of caveolin-1 in pulmonary arteries in rat lungs and in human PH lung tissue. RESULTS: In the M + H group, PH was more severe compared with M or H group. In the 4 wk M+H group, several arteries with reduced caveolin-1 expression in endothelial layer coupled with an increased expression in smooth muscle cells(SMC), exhibited neointimal lesions. Neointima was present only in the arteries exhibiting enhanced caveolin-1 expression in SMC. Lung tissue obtained from patients with PH also revealed neointimal lesions only in the arteries exhibiting endothelial caveolin-1 loss accompanied by an increased caveolin-1 expression in SMC. Reduction in e NOS and HSP90 expression was present in the M groups(2 and 4 wk), but not in the M + H groups. In both M groups and in the M + H group at 2 wk, endothelial caveolin-1 loss was accompanied by an increase in PPARγ expression. In the M + H group at 4 wk, increase in caveolin-1 expression was accompanied by a reduction in the PPARγ expression. In the H group, there was neither a loss of endothelial caveolin-1, eNOS or HSP 90, nor an increase in SMC caveolin-1 expression; or any alteration in PPARγ expression. Proliferative pathways were activated in all experimental groups. CONCLUSION: Enhanced caveolin-1 expression in SMC follows extensive endothelial caveolin-1 loss with subsequent neointima formation. Increased caveolin-1 expression in SMC, thus, may be a prelude to neointima formation.
文摘Objective.The present study investigated the role of endogenous carbon monoxide(CO)in the pathogenesis of neointimal formation induced by balloon injury in rat. Method.Endothelial denudation of the left common carotid artery of rat was carried out by three passages of a Fogarty 2F balloon catheter.DNA,collagen and elastin contents of each intima media were estimated;and heme oxygenase(HO)activity and CO production in vascular smooth muscle cell(VSMC)were measured after administration of HO inhibitor. Result.Our data showed that neointima occurred in the rat on day 7 and day 21 after balloon injury,and at the same time HO activity and CO production in VSMC were markedly increased Administration of HO inhibitor,zinc deuteroporphyrin 2,4 bisglycol(ZnDPBG),could effectively inhibit HO activity and CO production,significantly enhance neointimal formation(aortic intima/media ratio were 21 4±1 8% vs 17 6±2 0%,P<0 05 on day 7;and 30 5±2 4% vs 23 0±2 2%,P<0 01 on day 21,respectively,compared with balloon alone group). Conclusion.We concluded that 1)inhibition of CO production may enhance neointimal formation induced by endothelial denudation,implying endogenous CO play an protective role in response to vascular injury,and 2)induction of HO activity may be applied clinically for preventing restenosis after angioplasty.
文摘Objective: Angiotensin Ⅱ is a growth-promoting factor for vascular smooth muscle cells in culture andin the intact animal. The biological effects of angiotensin Ⅱ are manifested only by binding to specific receptors oncell membranes. In the study, we observed that the effect of rat antisense AT1B gene transfer mediated by adenoviral vector-on neointimal proliferation following rat carotid injury. Methods: Antisense AT1B gene was transductedinto the carotid by adenoviral vector after carotid bal1oon injury and the restenosis model was established in SD rat.We measured neointima/media area ratio in local artery at day 21 after gene transfer. Results: Rat antisense AT1Bgene was successfully transducted into local carotid after the carotid balloon injury. Neointima/media area ratiowas significantly reduced (47 %, P<0. 01) at day 21 after gene transfer compared with the control group. Conclusion: The results suggest it is possible that antisense AT1B gene transfer as a potential therapeutic approach prevent neointimal hyperplasia.
基金funded by the National Natural Science Foundation of China(No.81770413)Hubei Provincial Natural Science Foundation of China(No.2017CFB669).
文摘Objective Endothelial dysfunction is one candidate for triggering neointima formation after arteriovenous grafts(AVGs),but the factors mediating this process are unclear.The purpose of this study was to investigate the role of endoplasmic reticulum stress(ERS)-induced endothelial dysfunction in neointima formation following AVGs in high-fat diet(HFD)mice.Methods CCAAT-enhancer-binding protein-homologous protein(CHOP)knockout(KO)mice were created.Mice were fed with HFD to produce HFD model.AVGs model were applied in the groups of WT ND,WT HFD,and CHOP KO HFD.Human umbilical vein endothelial cells(HUVECs)were cultured with oxidized low density lipoprotein(ox-LDL)(40 mg/L)for the indicated time lengths(0,6,12,24 h).ERS inhibitor tauroursodeoxycholic acid(TUDCA)was used to block ERS.Immunohistochemical staining was used to observe the changes of ICAM1.Changes of ERS were detected by real-time RT-PCR.Protein expression levels and ERS activation were detected by Western blotting.Endothellial cell function was determined by endothelial permeability assay and transendothelial migration assay.Results HFD increased neointima formation in AVGs associated with endothelial dysfunction.At the same time,ERS was increased in endothelial cells(ECs)after AVGs in mice consuming the HFD.In vitro,ox-LDL was found to stimulate ERS,increase the permeability of the EC monolayer,and cause endothelial dysfunction.Blocking ERS with TUDCA or CHOP siRNA reversed the EC dysfunction caused by ox-LDL.In vivo,knockout of CHOP(CHOP KO)protected the function of ECs and decreased neointima formation after AVGs in HFD mice.Conclusion Inhibiting ERS in ECs could improve the function of AVGs.
基金Supported in part by Cardiovascular Medical Research and Education Fund
文摘BACKGROUND Pulmonary hypertension(PH) is a progressive disease with a high morbidity and mortality rate; and neointima formation leads to the irreversibility of the disease.We have previously reported that in rats, monocrotaline(MCT) injection leads to progressive disruption of endothelial cells(EC), and endothelial caveolin-1(cav-1) loss, accompanied by the activation of pro-proliferative pathways leading to PH. Four weeks post-MCT, extensive endothelial cav-1 loss is associated with increased cav-1 expression in smooth muscle cells(SMC). Exposing the MCTtreated rats to hypoxia hastens the disease process; and at 4 wk, neointimal lesions and occlusion of the small arteries are observed.AIM To identify the alterations that occur during the progression of PH that lead to neointima formation.METHODS Male Sprague-Dawley rats(150-175 g) were divided in 4 groups(n = 6-8 per group): controls(C); MCT(M, a single sc injection 40 mg/kg); Hypoxia(H,hypobaric hypoxia); MCT + hypoxia(M+H, MCT-injected rats subjected to hypobaric hypoxia starting on day1). Four weeks later, right ventricular systolic pressure(RVSP), right ventricular hypertrophy(RVH), lung histology, and cav-1 localization using immunofluorescence technique were analyzed. In addition, the expression of cav-1, tyrosine 14 phosphorylated cav-1(p-cav-1), caveolin-2(cav-2), cavin-1, vascular endothelial cadherin(VE-Cad) and p-ERK1/2 in the lungs were examined, and the results were compared with the controls.RESULTSSignificant PH and right ventricular hypertrophy were present in M and H groups [RVSP, mmHg, M 54±5~*, H 45±2~*, vs C 20±1, P < 0.05; RVH, RV/LV ratio M 0.57±0.02~*, H 0.50±0.03~*, vs C 0.23±0.007, P < 0.05]; with a further increase in M+H group [RVSP 69±9 mmHg, RV/LV 0.59±0.01 P < 0.05 vs M and H]. All experimental groups revealed medial hypertrophy; but only M+H group exhibited small occluded arteries and neointimal lesions. Immunofluorescence studies revealed endothelial cav-1 loss and increased cav-1 expression in SMC in M group; however, the total cav-1 level in the lungs remained low. In the M+H group, significant endothelial cav-1 loss was associated with increasing expression of cav-1 in SMC; resulting in near normalization of cav-1 levels in the lungs [cav-1, expressed as % control, C 100±0, M 22±4~*, H 96±7, M+H 77±6, ~* = P< 0.05 vs C]. The expression of p-cav-1 was observed in M and M+H groups [M314±4%, M+H 255±22% P < 0.05 vs C]. Significant loss of cav-2 [% control, C100±0, M 15±1.4~*, H 97±7, M+H 15±2~*; M and M+H vs C, ~* = P < 0.05], cavin-1 [%control, C 100±0, M 20±3~*, H 117±7, M+H 20±4~*; M and M+H vs C, P < 0.05] and VE-Cad [% control, C 100±0, M 17±4~*, H 96±9, M+H 8±3~*; M and M+H vs C, P <0.05] was present in M and M+H groups, confirming extensive disruption of EC.Hypoxia alone did not alter the expression of cav-1 or cav-1 related proteins.Expression of p-ERK1/2 was increased in all 3 PH groups [%control, C 100±0, M284±23~*, H 254±25~*, M+H 270±17~*; ~* = P < 0.05 vs C].CONCLUSION Both cavin-1 loss and p-cav-1 expression are known to facilitate cell migration;thus, these alterations may in part play a role in neointima formation in PH.
文摘Drug-eluting stents have been successful in reducing in-stent restenosis but are not suitable for all lesion types and have been implicated in causing late stent thrombosis due to incomplete regeneration of the endothelial cell layer. In this study we implanted stents coated with cicaprost, a prostacyclin analogue with a long plasma half-life and antiproliferative effects on vascular smooth muscle cells, into the iliac arteries of rabbits. At 28-day follow-up we compared neointima formation within the stented vessels and vascular function in adjacent vessels, to assess if cicaprost could reduce restenosis without impairing vessel function. Arteries implanted with cicaprost eluting stents had significantly more neointima compared to bare metal stents. In adjacent segments of artery, endothelium-dependent relaxation was impaired by the cicaprost-eluting stent but vasodilation to an endothelium-independent vasodilator was maintained. We conclude that the presence of the polymer and sub-optimal release of cicaprost from the stent may be responsible for the increased neointma and impaired functional recovery of the endothelium observed. Further experiments should be aimed at optimising release of cicaprost and exploring different stent polymer coatings.
文摘Objective To examine antisense and decoy oligonucleotides of nuclear factor kappa B in vivo effects on intima proliferation and balloon-injured monocytes chemotactic protein-1 （ MCP-1 ） and extraceUular signal regulated kinase-2 （ERK2） κexpression in the carotid artery of rats. Methods Sprague-Dawley rats underwent balloon-dilation injury of the left carotid artery. Rats are divided into 7 groups （ n = 18 ） and each group includes6 time points （6 h, 1, 3, 5, 7, 14 d） （n =3）. Uninjured right carotid artery of the same rat was used as controls. Results In model group, sense group and scramble group, vessel intima area , media area and intima/media ratio increased after 5 d and reached the maximum after 7 d. The effect of antisense plus decoy group on intimal hyperplasia was more obvious than that of antisense group and decoy group alone. MCP-1 mRNA expression was increased expression continuously at 3, 5 and 7 d and decreased at 14 d. Compared with model group, sense group and scramble group, antisense group, decoy group and antisense plus decoy group had lowered MCP-1 mRNA expression in each time point （ P 〈 0. 05 ）. NF-KB p65 was dispersed positive stain 6 h after injury and increased after 1 d and peaked at 7 d, but the protein expression was weak at 14 d. ERK2 protein synthesis increased at I d and reached the peak at 7 d, while protein expression after 14 d was similar to that at 7 d. Treatment of antisense group, decoy group and antisense plus decoy group inhibited protein synthesis more significantly than those of model group, sense group and scramble group（ P 〈 0. 05）. Conclusion NF-KB modulates genes expression and protein synthesis of MCP-1 and ERK2. Celluar proliferation in vessel wall was dynamically changed after balloon angioplasty injury. Antisense and decoy oligonucleotide of NF-KB by local lipofectaraine transfer inhibit NF-KB activating gene modulation and neointimal hyperplasia.
文摘Optical coherence tomography （OCT） is a new imaging modality with resolution of approximately 10 pm and can be employed to visualize intracoronary characteristics. Sirolimus-eluting stents （SES） are susceptible to late thrombosis due to delayed reendothelialization over the stent struts, which may result in acute myocardial infarction or death. This study was designed to evaluate the re-endothelialization and neointimal coverage of SES with OCT 6 months and 12 months after implantation.Methods A total of 36 patients enrolled in the study underwent OCT examination 6 months （17 patients） and 12 months （19 patients） after SES implantation, The strut apposition to the vessel wall and neointimal coverage on SES struts were evaluated by OCT, Results Forty-six SES and 6561 struts were analyzed, At 6 months, 3041 struts （98.7%） were well-apposed and 39 struts （1,3%） were malapposed, At 12 months, 3434 struts （98,6%） were well-apposed and 47 struts （1,4%） were malapposed, Furthermore, only 4 SES at 6 months （18,2%） and 10 SES at 12 months （41,7%） were fully covered by neointimal growth, The average neointimal thicknesses covering the analyzed struts at 6 months and 12 months were （42±28） μm and （88±32） μm, respectively, There were 1989 struts at 6 months （72,1%） and 1461 struts at 12 months （45,6%） with neointimal thickness 〈100 μm, Conclusions OCT was able to visualize the strut apposition to the vessel wall and neointimal coverage on SES struts, At 6-month and 12-month follow-up examinations most struts were covered with thin neointima, but few of the entire SES showed full coverage. To prevent late-stent thrombosis in the presence of uncovered stent struts, longer dual antiplatelet drugs therapy should be recommended,
文摘Background： Endothelial cell damage is an important pathophysiological step of restenosis after angioplasty and stenting. Cell transplantation has great therapeutic potential for endothelial recovery. We investigated the effect of transplanting endothelial progenitor cells （EPCs） derived from human early fetal aortas in rat injured arteries. Methods： The carotid arterial endothelium of Sprague-Dawley rats was damaged by dilatation with a 1.5 F balloon catheter, and then EPCs derived from human early fetal aortas （〈14 weeks） were injected into the lumen of the injured artery in transplanted rats, with an equal volume of normal saline injected into control rats. Rats were sacrificed at 2 and 4 weeks after treatment and transplanted cells were identified by immunohistochemical staining with anti-human CD31 and anti-human mitochondria antibodies. Arterial cross-sections were analyzed by pathology, immunohistochemistry, and morphometry. Results： Green fluorescence-labeled EPCs could be seen in the endovascular surface of balloon-injured vessels after transplantation. The intimal area and intimal/medial area ratio were significantly smaller in the transplanted group than in the control （P 〈 0.05） and the residual lumen area was larger （P 〈 0.05）. After EPC transplantation, a complete vascular endothelial layer was formed, which was positive for human yon Willebrand factor after immunohistochemical staining, and immunohistochemical staining revealed many CD31- and mitochondria-positive cells in the re-endothelialized endothelium with EPC transplantation but not control treatment. Conclusion： EPCs derived from human early fetal aorta were successfully transplanted into injured vessels and might inhibit neointimal hyperplasia after vascular injury.
