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GW27-e0288 Ticagrelor Prevents Endothelial Dysfunction of Aortas in Apolipoprotein E-deficient Mice
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, VOL. 68, NO. 16, SUPPL S, 2016
(IL-6) and the tumor necrosis factor a (TNF-a) in the mouse serum are to be measured via ELISA; The senescent neuron was examined by the senescence-related beta galactosidase (SA-b-gal) staining. RESULTS Compared with the control group, the levels of IL-6 and TNF-a significantly increased, meanwhile the number of SA-b-galpositive cells significantly increased in the model group, However, after treated with Ginsenoside Rb1, the levels of IL-6 and TNF-a significantly decreased, meanwhile the number of SA-b-gal-positive cells significantly decreased. CONCLUSIONS Ginsenoside Rb1 could mitigate the intrinsic aging of mouse brain. The anti-aging mechanism of ginsenoside Rb1 is closely related to its resistance against oxidative damage. GW27-e0274 MicroRNA181a regulates Osteopontin expression and cardiac fibrosis in mice Jia Nan,1 Li Ren,1 Hong Wang,2 Kunfu Ouyang,2 Nan Jia1 1 Department of Cardiology, The Fourth People’s Hospital of Shenzhen; 2 Drug Discovery Center, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School OBJECTIVES Osteopontin (OPN) is a secreted glycophosphoprotin that has been shown to play an important role in cardiac fibrosis and remodeling. Here our objective was to determine whether microRNA181a would regulate OPN expression and cardiac fibrosis in mice. METHODS cardiac fibroblast cells isolated from adult mouse hearts were cultured and treated with microRNA181a mimics and inhibitor, and the expression of OPN and collagen I were examined by quantitative RT-PCR and protein analysis, respectively. Cardiac fibrosis was induced by Angiotensis-II infusion for 4 weeks via osmotic minipumps. MicroRNA181a agomir and negative control were injected via mouse tail vein, and cardiac fibrosis was assessed via optical microscopic imaging analysis. Cardiac expression of OPN and extracellular matrix proteins were assessed by quantitative RT-PCR.
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relaxation or contractile responses induced by L-NAME, indomethacin and 2-MeS-ADP in aortas of apolipoprotein E-deficient mices. P2Y13 receptor expression was significantly reduced but P2Y1 and P2Y12 protein expression was increased in aortas of apolipoprotein E-deficient mices. Endothelium-dependent relaxation by acetylcholinestimulation was reduced in vehicle-treament apolipoprotein E-deficient mices, and ticagrelor could improve endothelial function of aortas of apolipoprotein E-deficient mices. CONCLUSIONS Our data suggested that ticagrelor ameliorates aortic endothelium function of apolipoprotein E-deficient mices, but that mechanism was not clear. GW27-e0292 Activation of CD137 signaling accelerates vascular calcification in vivo and vitro Li Bo, Yao Chen, Juan Song, Zhongqun Wang, Wei Zhong, Jinchuan Yan Affiliated Hospital of Jiangsu University OBJECTIVES Vascular calcification is a characteristic feature of atherosclerosis and is considered as an independent predictor of cardiovascular morbidity and mortality. CD137 signaling, CD137CD137L interaction, has previously shown to be involved in atherosclerosis. However, the possible role of CD137 signaling in regulation of vascular calcification has not been reported. In this study, we aim to investigated the effect of CD137 signaling in vascular calcification in vivo and vitro. METHODS Vascular smooth muscle cells (VSMCs) were isolated from C57BL/6J. ApoE-/- mice (8 weeks) received a high fat diet for 4 weeks, after which the mice were randomly divided into the following groups: agonist-CD137 group, anti-CD137 group, and control group. Mice in each group were intraperitoneally injected with 200 m g agonist-CD137 antibody, 200mg anti-CD137 antibody þ 200mg agonist-CD137 antibody, or 200mg IgG 2b at 13, 15, and 17 weeks of age respectively.
RESULTS The expression of OPN and collagen I were significantly decreased in cultured cardiac fibroblast cells treated with microRNA181a mimics, whereas increased when the cells were treated with microRNA181a inhibitor. The mice injected with microRNA181a agomir exhibited less cardiac fibrosis when compared with those injected with negative control. Consistently, Injection of microRNA181a agomir also decreased the expression levels of OPN and collagen in vivo.
RESULTS Agonist-CD137 demonstrated increased areas of vascular calcification, as well as increased bone morphogenic proteins 2 (BMP2), runt-related transcription factor 2 (Runx2) expression. In vitro, activation of CD137 signaling with agonist-CD137 aggravated VSMCs calcification, while blocking CD137 signaling with additionally anti-CD137 alleviated agonist-CD137 induced VSMCs calcification. Consistent with this, the levels of calcium, BMP2 and Runx2 were significant elevated in agonist-CD137 group.
CONCLUSIONS Our data demonstrated that microRNA181a regulates OPN expression in vitro and in vivo, and increased microRNA181a expression could reduce cardiac fibrosis.
CONCLUSIONS Activation of CD137 accelerates vascular calcification in vivo and vitro, and that CD137 signaling plays an important role in differentiation of VSMCs to osteogenic cells.
GW27-e0288 Ticagrelor Prevents Endothelial Dysfunction of Aortas in Apolipoprotein E-deficient Mice
GW27-e0293 CD137 promotes angiogenesis in atherosclerosis by modulating endothelial Smad1/5-NFATc1 signaling
Xiaoyan Li,1 Erhong Zhang,2 Jiaojie Xue,1 Yu Du,2 Jingwen Xie1 1 The Sixth Affiliated Hospital of Sun Yat-sen University; 2The Third Affiliated Hospital of Sun Yat-sen University
Li Bo, JiaYi Weng, CuiPing Wang, Zhongqun Wang, Wei Zhong, Jinchuan Yan Affiliated Hospital of Jiangsu University
OBJECTIVES Cardiovascular disease due to atherosclerosis is the leading cause of death worldwide. Platelets have a fundamental role in atherothrombosis, but their role in atherogenesis is unclear. Herein, the purpose of this study was to determine anti-platelet drug ticagrelor on function of the aortas in apolipoprotein E-deficient mice.
OBJECTIVES Angiogenesis is a key feature of vulnerable atherosclerotic plaques prone to rupture, and is the consequence of inappropriate angiogenic signaling. The costimulatory molecules of the tumor necrosis factor receptor (TNFR) superfamily such as CD40/CD40L were shown to be pluripotent in both angiogenesis and atheroscletotic development. CD137, the immunologic mediator of the TNF superfamily members is expressed in human atherosclerotic lesions, by endothelial. Here, we aim to investigate the role and the mechanism of CD137 in atherosclerostic angiogenesis.
METHODS Apolipoprotein E-deficient mices were made atherosclerosis by feeding a high cholesterol diet, and simultaneously treated with ticagrelor (10 mg/kg ig.q24h) or vehicle from 0 day to 8 week. Blood samples were collected and serum levels of total cholesterol(TC), triglyceride(TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) were measured at 0 day, 1,4, and 8 week. Western blot was used to exam the expression of P2Y1 and P2Y12 protein of aortas of mice,histopathological changes of aortas were detected at 8 Week. Endothelium-dependent relaxation induced by 2-MeS-ADP (selective P2Y1/12 -receptor agonist) was examined in aorta rings of mice at 8 week. RESULTS Ticagrelor and vehicle did not decreased serum levels of TC, TG, HDL-C, LDL-C in the apolipoprotein E-deficient mices. Endothelium-dependent relaxations induced by 2-MeS-ADP were decreased in aortas of vehicle-treament apolipoprotein E-deficient mices comparing to vehicle-treament wild mices. In the same time, indomethacin and L-NAME augmented 2-MeS-ADP induced contraction in vehicle-treament apolipoprotein E-deficient mices comparing to vehicle-treament wild mices. Ticagrelor treament did not normalize
METHODS In vivo, Apolipoprotein E-deficient (ApoE-/) mouse was used as model. Masson and Immunohistochemical analysis of atherosclerotic plaques and matrigel plug assay were assessed. In ex vivo and vivo, human umbilical vein endothelial cells (HUVEC) and mouse brain endothelial cells were used as models. Matrigel tube formation assay, mouse aortic ring angiogenesis assay and migration and proliferation assay were assessed. Western blot was used to detect protein expression. RESULTS In vivo, we found that activating CD137 signaling induced neovessel formation in ApoE-/mouse atherosclerotic plaques. In ex vivo and in vitro, we demonstrated that the supplementation with agonist-CD137 antibody could induce angiogenesis, endothelial proliferation and endothelial migration. CD137 activates the pro-angiogenic Smad1/5 pathway, induces the phosphorylation of Smad1/5 and promotes nuclear translocation of P-Smad1/5, which results in the
(IL-6) and the tumor necrosis factor a (TNF-a) in the mouse serum are to be measured via ELISA; The senescent neuron was examined by the senescence-related beta galactosidase (SA-b-gal) staining. RESULTS Compared with the control group, the levels of IL-6 and TNF-a significantly increased, meanwhile the number of SA-b-galpositive cells significantly increased in the model group, However, after treated with Ginsenoside Rb1, the levels of IL-6 and TNF-a significantly decreased, meanwhile the number of SA-b-gal-positive cells significantly decreased. CONCLUSIONS Ginsenoside Rb1 could mitigate the intrinsic aging of mouse brain. The anti-aging mechanism of ginsenoside Rb1 is closely related to its resistance against oxidative damage. GW27-e0274 MicroRNA181a regulates Osteopontin expression and cardiac fibrosis in mice Jia Nan,1 Li Ren,1 Hong Wang,2 Kunfu Ouyang,2 Nan Jia1 1 Department of Cardiology, The Fourth People’s Hospital of Shenzhen; 2 Drug Discovery Center, Key Laboratory of Chemical Genomics, Peking University Shenzhen Graduate School OBJECTIVES Osteopontin (OPN) is a secreted glycophosphoprotin that has been shown to play an important role in cardiac fibrosis and remodeling. Here our objective was to determine whether microRNA181a would regulate OPN expression and cardiac fibrosis in mice. METHODS cardiac fibroblast cells isolated from adult mouse hearts were cultured and treated with microRNA181a mimics and inhibitor, and the expression of OPN and collagen I were examined by quantitative RT-PCR and protein analysis, respectively. Cardiac fibrosis was induced by Angiotensis-II infusion for 4 weeks via osmotic minipumps. MicroRNA181a agomir and negative control were injected via mouse tail vein, and cardiac fibrosis was assessed via optical microscopic imaging analysis. Cardiac expression of OPN and extracellular matrix proteins were assessed by quantitative RT-PCR.
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relaxation or contractile responses induced by L-NAME, indomethacin and 2-MeS-ADP in aortas of apolipoprotein E-deficient mices. P2Y13 receptor expression was significantly reduced but P2Y1 and P2Y12 protein expression was increased in aortas of apolipoprotein E-deficient mices. Endothelium-dependent relaxation by acetylcholinestimulation was reduced in vehicle-treament apolipoprotein E-deficient mices, and ticagrelor could improve endothelial function of aortas of apolipoprotein E-deficient mices. CONCLUSIONS Our data suggested that ticagrelor ameliorates aortic endothelium function of apolipoprotein E-deficient mices, but that mechanism was not clear. GW27-e0292 Activation of CD137 signaling accelerates vascular calcification in vivo and vitro Li Bo, Yao Chen, Juan Song, Zhongqun Wang, Wei Zhong, Jinchuan Yan Affiliated Hospital of Jiangsu University OBJECTIVES Vascular calcification is a characteristic feature of atherosclerosis and is considered as an independent predictor of cardiovascular morbidity and mortality. CD137 signaling, CD137CD137L interaction, has previously shown to be involved in atherosclerosis. However, the possible role of CD137 signaling in regulation of vascular calcification has not been reported. In this study, we aim to investigated the effect of CD137 signaling in vascular calcification in vivo and vitro. METHODS Vascular smooth muscle cells (VSMCs) were isolated from C57BL/6J. ApoE-/- mice (8 weeks) received a high fat diet for 4 weeks, after which the mice were randomly divided into the following groups: agonist-CD137 group, anti-CD137 group, and control group. Mice in each group were intraperitoneally injected with 200 m g agonist-CD137 antibody, 200mg anti-CD137 antibody þ 200mg agonist-CD137 antibody, or 200mg IgG 2b at 13, 15, and 17 weeks of age respectively.
RESULTS The expression of OPN and collagen I were significantly decreased in cultured cardiac fibroblast cells treated with microRNA181a mimics, whereas increased when the cells were treated with microRNA181a inhibitor. The mice injected with microRNA181a agomir exhibited less cardiac fibrosis when compared with those injected with negative control. Consistently, Injection of microRNA181a agomir also decreased the expression levels of OPN and collagen in vivo.
RESULTS Agonist-CD137 demonstrated increased areas of vascular calcification, as well as increased bone morphogenic proteins 2 (BMP2), runt-related transcription factor 2 (Runx2) expression. In vitro, activation of CD137 signaling with agonist-CD137 aggravated VSMCs calcification, while blocking CD137 signaling with additionally anti-CD137 alleviated agonist-CD137 induced VSMCs calcification. Consistent with this, the levels of calcium, BMP2 and Runx2 were significant elevated in agonist-CD137 group.
CONCLUSIONS Our data demonstrated that microRNA181a regulates OPN expression in vitro and in vivo, and increased microRNA181a expression could reduce cardiac fibrosis.
CONCLUSIONS Activation of CD137 accelerates vascular calcification in vivo and vitro, and that CD137 signaling plays an important role in differentiation of VSMCs to osteogenic cells.
GW27-e0288 Ticagrelor Prevents Endothelial Dysfunction of Aortas in Apolipoprotein E-deficient Mice
GW27-e0293 CD137 promotes angiogenesis in atherosclerosis by modulating endothelial Smad1/5-NFATc1 signaling
Xiaoyan Li,1 Erhong Zhang,2 Jiaojie Xue,1 Yu Du,2 Jingwen Xie1 1 The Sixth Affiliated Hospital of Sun Yat-sen University; 2The Third Affiliated Hospital of Sun Yat-sen University
Li Bo, JiaYi Weng, CuiPing Wang, Zhongqun Wang, Wei Zhong, Jinchuan Yan Affiliated Hospital of Jiangsu University
OBJECTIVES Cardiovascular disease due to atherosclerosis is the leading cause of death worldwide. Platelets have a fundamental role in atherothrombosis, but their role in atherogenesis is unclear. Herein, the purpose of this study was to determine anti-platelet drug ticagrelor on function of the aortas in apolipoprotein E-deficient mice.
OBJECTIVES Angiogenesis is a key feature of vulnerable atherosclerotic plaques prone to rupture, and is the consequence of inappropriate angiogenic signaling. The costimulatory molecules of the tumor necrosis factor receptor (TNFR) superfamily such as CD40/CD40L were shown to be pluripotent in both angiogenesis and atheroscletotic development. CD137, the immunologic mediator of the TNF superfamily members is expressed in human atherosclerotic lesions, by endothelial. Here, we aim to investigate the role and the mechanism of CD137 in atherosclerostic angiogenesis.
METHODS Apolipoprotein E-deficient mices were made atherosclerosis by feeding a high cholesterol diet, and simultaneously treated with ticagrelor (10 mg/kg ig.q24h) or vehicle from 0 day to 8 week. Blood samples were collected and serum levels of total cholesterol(TC), triglyceride(TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) were measured at 0 day, 1,4, and 8 week. Western blot was used to exam the expression of P2Y1 and P2Y12 protein of aortas of mice,histopathological changes of aortas were detected at 8 Week. Endothelium-dependent relaxation induced by 2-MeS-ADP (selective P2Y1/12 -receptor agonist) was examined in aorta rings of mice at 8 week. RESULTS Ticagrelor and vehicle did not decreased serum levels of TC, TG, HDL-C, LDL-C in the apolipoprotein E-deficient mices. Endothelium-dependent relaxations induced by 2-MeS-ADP were decreased in aortas of vehicle-treament apolipoprotein E-deficient mices comparing to vehicle-treament wild mices. In the same time, indomethacin and L-NAME augmented 2-MeS-ADP induced contraction in vehicle-treament apolipoprotein E-deficient mices comparing to vehicle-treament wild mices. Ticagrelor treament did not normalize
METHODS In vivo, Apolipoprotein E-deficient (ApoE-/) mouse was used as model. Masson and Immunohistochemical analysis of atherosclerotic plaques and matrigel plug assay were assessed. In ex vivo and vivo, human umbilical vein endothelial cells (HUVEC) and mouse brain endothelial cells were used as models. Matrigel tube formation assay, mouse aortic ring angiogenesis assay and migration and proliferation assay were assessed. Western blot was used to detect protein expression. RESULTS In vivo, we found that activating CD137 signaling induced neovessel formation in ApoE-/mouse atherosclerotic plaques. In ex vivo and in vitro, we demonstrated that the supplementation with agonist-CD137 antibody could induce angiogenesis, endothelial proliferation and endothelial migration. CD137 activates the pro-angiogenic Smad1/5 pathway, induces the phosphorylation of Smad1/5 and promotes nuclear translocation of P-Smad1/5, which results in the