Background We hypothesize that increased atrial oxidative stress and inflammation may play an important role in atrial nerve sprouting and heterogeneous sympathetic hyperinnervation during atrial fibrillation （AF）. ...Background We hypothesize that increased atrial oxidative stress and inflammation may play an important role in atrial nerve sprouting and heterogeneous sympathetic hyperinnervation during atrial fibrillation （AF）. To test the hypothesis, we examined whether the antioxidant and anti-inflammatory treatment with probucol attenuates atrial autonomic remodeling in a canine model of AF produced by prolonged rapid right atrial pacing.Methods Twenty-one dogs were divided into a sham-operated group, a control group and a probucol group. Dogs in the control group and probucol group underwent right atrial pacing at 400 beats per minute for 6 weeks, and those in the probucol group received probucol 1 week before rapid atrial pacing until pacing stopped. After 6-week rapid atrial pacing, general properties including left atrial structure and function, atrial hemodynamics and the inducibility and duration of AF were measured in all the groups. Atrial oxidative stress markers and serum C-reactive protein （CRP） concentration were estimated. The degree of nerve sprouting and sympathetic innervation at the right atrial anterior wall （RAAW） and the left atrial anterior wall （LAAW） were quantified by immunohistochemistry, atrial norepinephrine contents were also detected. Atrial beta-nerve growth factor （beta-NGF） mRNA and protein expression at the RAAW and LAAW were assessed by real-time quantitative RT-PCR and Western blotting respectively.Results Atrial tachypacing induced significant nerve sprouting and heterogeneous sympathetic hyperinnervation, and the magnitude of nerve sprouting and hyperinnervation was higher in the RAAW than in the LAAW. Atrial beta-NGF mRNA and protein levels were significantly increased at the RAAW and LAAW, and the upregulation of beta-NGF expression was greater at the RAAW than at the LAAW in the control group. The beta-NGF protein level was positively correlated with the density of sympathetic nerves in all groups. Probucol decreased the increase of CRP concentration and attenuated atrial oxidative stress caused by atrial tachypacing. In addition, probucol could effectively inhibit atrial beta-NGF upregulation, significantly attenuate atrial nerve sprouting and heterogeneous sympathetic hyperinnervation, and dramatically reduce the inducibility and duration of AF.Conclusions The atrial over-expression of beta-NGF possibly caused by increased oxidative stress and inflammation may be the main mechanism underlying atrial autonomic remodeling during AF. Probucol attenuates atrial autonomic remodeling possibly by its antioxidant and anti-inflammatory actions.展开更多
Background Experimental autoimmune myocarditis （EAM） in rats is a T-cell-mediated disorder. The initiation and maintenance of autoimmune responses in EAM depend on the maturation state of dendritic cells. IL-10 is a...Background Experimental autoimmune myocarditis （EAM） in rats is a T-cell-mediated disorder. The initiation and maintenance of autoimmune responses in EAM depend on the maturation state of dendritic cells. IL-10 is a pleiotrophic immunomodulatory cytokine that functions at different levels of the immune response, so it has emerged as a promising therapeutic factor for the treatment of autoimmune/inflammatory diseases. This study was designed to test the hypothesis that IL-10 gene modified bone marrow-derived immature dendritic cells （iDCs） ameliorate EAM and to explore the underlying mechanisms. Methods EAM was induced using the methods of cardiac myosin immunization on day 0 and day 7. Immature and mature bone marrow-derived dendritic cells （BMDCs） were generated without or with the stimulation by lipopolysaccharide （LPS） and the phenotype was analyzed by flow cytometry. Some of the iDCs were transfected by pcDNA3-IL-10 plasmid. 2× 10^6/per rat mature DC （mDC）, immature DC （iDC）, pcDNA3 transfected iDC, pcDNA3-IL-10 transfected iDC or phosphate buffered saline （PBS） were injected intravenously for treatment 5 days after the first immunization. On day 21, HE staining was performed to detect the myocardial inflammation and T lymphocyte proliferation assay was used to determine the effects of IL-10 gene transfected iDC on autoreactive T cell proliferation. Expression of IκB, the inhibitor of NF-κB pathway, was determined by Western blot. Results BMDCs generated in a medium supplemented with granulocyte-macrophage-colony-stimulating factor （GM-CSF） were relatively immature, as determined by flow cytometry. However, stimulation with LPS induced these cells to become mature （m）DCs with higher levels of surface major histocompatibility complex （MHC）-Ⅱ and costimulatory molecules. Intravenous administration of iDCs, especially pcDNA3-IL-10 transfected iDC, ameliorated the histopathological severity of the myosin induced-EAM, and the effect was lost after the DCs underwent maturation induced by in vitro exposure to LPS. IL-10 gene modified iDC inhibited the antigen specific T cell responses towards cardiac myosin. IκB protein was up-regulated significantly in the IL-10 gene modified iDC group. Conclusions IL-10 gene modified iDC induced antigen-specific tolerance in EAM. The underlying mechanisms may be related to costimulatory molecules down-regulation and NF-κB pathway inhibition.展开更多
The use of intense anticoagulation and antiplatelet therapy in acute myocardial infarction （AMI）potentially increases the risk of bleeding complications during percutaneous coronary intervention （PCI） via the tran...The use of intense anticoagulation and antiplatelet therapy in acute myocardial infarction （AMI）potentially increases the risk of bleeding complications during percutaneous coronary intervention （PCI） via the transfemoral approach. Recently, the transradial access has been increasingly employed as an alternative means for diagnostic and interventional procedures. Low incidence of vascular access site bleeding complications suggests the transradial approach as a safe alternative to the femoral technique in AMI, particularly under an aggressive anticoagulation/antiplatelet regimen.Nevertheless, the safety and feasibility of employing the transradial approach for primary PCI in AMI has not been thoroughly investigated so far.展开更多
文摘Background We hypothesize that increased atrial oxidative stress and inflammation may play an important role in atrial nerve sprouting and heterogeneous sympathetic hyperinnervation during atrial fibrillation （AF）. To test the hypothesis, we examined whether the antioxidant and anti-inflammatory treatment with probucol attenuates atrial autonomic remodeling in a canine model of AF produced by prolonged rapid right atrial pacing.Methods Twenty-one dogs were divided into a sham-operated group, a control group and a probucol group. Dogs in the control group and probucol group underwent right atrial pacing at 400 beats per minute for 6 weeks, and those in the probucol group received probucol 1 week before rapid atrial pacing until pacing stopped. After 6-week rapid atrial pacing, general properties including left atrial structure and function, atrial hemodynamics and the inducibility and duration of AF were measured in all the groups. Atrial oxidative stress markers and serum C-reactive protein （CRP） concentration were estimated. The degree of nerve sprouting and sympathetic innervation at the right atrial anterior wall （RAAW） and the left atrial anterior wall （LAAW） were quantified by immunohistochemistry, atrial norepinephrine contents were also detected. Atrial beta-nerve growth factor （beta-NGF） mRNA and protein expression at the RAAW and LAAW were assessed by real-time quantitative RT-PCR and Western blotting respectively.Results Atrial tachypacing induced significant nerve sprouting and heterogeneous sympathetic hyperinnervation, and the magnitude of nerve sprouting and hyperinnervation was higher in the RAAW than in the LAAW. Atrial beta-NGF mRNA and protein levels were significantly increased at the RAAW and LAAW, and the upregulation of beta-NGF expression was greater at the RAAW than at the LAAW in the control group. The beta-NGF protein level was positively correlated with the density of sympathetic nerves in all groups. Probucol decreased the increase of CRP concentration and attenuated atrial oxidative stress caused by atrial tachypacing. In addition, probucol could effectively inhibit atrial beta-NGF upregulation, significantly attenuate atrial nerve sprouting and heterogeneous sympathetic hyperinnervation, and dramatically reduce the inducibility and duration of AF.Conclusions The atrial over-expression of beta-NGF possibly caused by increased oxidative stress and inflammation may be the main mechanism underlying atrial autonomic remodeling during AF. Probucol attenuates atrial autonomic remodeling possibly by its antioxidant and anti-inflammatory actions.
基金This study was supported by Harbin Medical University Postgraduate Creation Foundation (2005).
文摘Background Experimental autoimmune myocarditis （EAM） in rats is a T-cell-mediated disorder. The initiation and maintenance of autoimmune responses in EAM depend on the maturation state of dendritic cells. IL-10 is a pleiotrophic immunomodulatory cytokine that functions at different levels of the immune response, so it has emerged as a promising therapeutic factor for the treatment of autoimmune/inflammatory diseases. This study was designed to test the hypothesis that IL-10 gene modified bone marrow-derived immature dendritic cells （iDCs） ameliorate EAM and to explore the underlying mechanisms. Methods EAM was induced using the methods of cardiac myosin immunization on day 0 and day 7. Immature and mature bone marrow-derived dendritic cells （BMDCs） were generated without or with the stimulation by lipopolysaccharide （LPS） and the phenotype was analyzed by flow cytometry. Some of the iDCs were transfected by pcDNA3-IL-10 plasmid. 2× 10^6/per rat mature DC （mDC）, immature DC （iDC）, pcDNA3 transfected iDC, pcDNA3-IL-10 transfected iDC or phosphate buffered saline （PBS） were injected intravenously for treatment 5 days after the first immunization. On day 21, HE staining was performed to detect the myocardial inflammation and T lymphocyte proliferation assay was used to determine the effects of IL-10 gene transfected iDC on autoreactive T cell proliferation. Expression of IκB, the inhibitor of NF-κB pathway, was determined by Western blot. Results BMDCs generated in a medium supplemented with granulocyte-macrophage-colony-stimulating factor （GM-CSF） were relatively immature, as determined by flow cytometry. However, stimulation with LPS induced these cells to become mature （m）DCs with higher levels of surface major histocompatibility complex （MHC）-Ⅱ and costimulatory molecules. Intravenous administration of iDCs, especially pcDNA3-IL-10 transfected iDC, ameliorated the histopathological severity of the myosin induced-EAM, and the effect was lost after the DCs underwent maturation induced by in vitro exposure to LPS. IL-10 gene modified iDC inhibited the antigen specific T cell responses towards cardiac myosin. IκB protein was up-regulated significantly in the IL-10 gene modified iDC group. Conclusions IL-10 gene modified iDC induced antigen-specific tolerance in EAM. The underlying mechanisms may be related to costimulatory molecules down-regulation and NF-κB pathway inhibition.
文摘The use of intense anticoagulation and antiplatelet therapy in acute myocardial infarction （AMI）potentially increases the risk of bleeding complications during percutaneous coronary intervention （PCI） via the transfemoral approach. Recently, the transradial access has been increasingly employed as an alternative means for diagnostic and interventional procedures. Low incidence of vascular access site bleeding complications suggests the transradial approach as a safe alternative to the femoral technique in AMI, particularly under an aggressive anticoagulation/antiplatelet regimen.Nevertheless, the safety and feasibility of employing the transradial approach for primary PCI in AMI has not been thoroughly investigated so far.
