BACKGROUND The accumulation of advanced glycation end products(AGEs)have been implicated in the development and progression of diabetic vasculopathy.However,the role of profilin-1 as a multifunctional actin-binding pr...BACKGROUND The accumulation of advanced glycation end products(AGEs)have been implicated in the development and progression of diabetic vasculopathy.However,the role of profilin-1 as a multifunctional actin-binding protein in AGEs-induced atherosclerosis(AS)is largely unknown.AIM To explore the potential role of profilin-1 in the pathogenesis of AS induced by AGEs,particularly in relation to the Janus kinase 2(JAK2)and signal transducer and activator of transcription 3(STAT3)signaling pathway.METHODS Eighty-nine individuals undergoing coronary angiography were enrolled in the study.Plasma cytokine levels were detected using ELISA kits.Rat aortic vascular smooth muscle cells(RASMCs)were incubated with different compounds for different times.Cell proliferation was determined by performing the MTT assay and EdU staining.An AGEs-induced vascular remodeling model was established in rats and histological and immunohistochemical analyses were performed.The mRNA and protein levels were detected using real-time PCR and Western blot analysis,respectively.In vivo,shRNA transfection was performed to verify the role of profilin-1 in AGEs-induced proatherogenic mediator release and aortic remodeling.Statistical analyses were performed using SPSS 22.0 software.RESULTS Compared with the control group,plasma levels of profilin-1 and receptor for AGEs(RAGE)were significantly increased in patients with coronary artery disease,especially in those complicated with diabetes mellitus(P<0.01).The levels of profilin-1 were positively correlated with the levels of RAGE(P<0.01);additionally,the levels of both molecules were positively associated with the degree of coronary artery stenosis(P<0.01).In vivo,tail vein injections of AGEs induced the release of proatherogenic mediators,such as asymmetric dimethylarginine,intercellular adhesion molecule-1,and the N-terminus of procollagen III peptide,concomitant with apparent aortic morphological changes and significantly upregulated expression of the profilin-1 mRNA and protein in the thoracic aorta(P<0.05 or P<0.01).Downregulation of profilin-1 expression with an shRNA significantly attenuated AGEs-induced proatherogenic mediator release(P<0.05)and aortic remodeling.In vitro,incubation of vascular smooth muscle cells(VSMCs)with AGEs significantly promoted cell proliferation and upregulated the expression of the profilin-1 mRNA and protein(P<0.05).AGEs(200μg/mL,24 h)significantly upregulated the expression of the STAT3 mRNA and protein and JAK2 protein,which was blocked by a JAK2 inhibitor(T3042-1)and/or STAT3 inhibitor(T6308-1)(P<0.05).In addition,pretreatment with T3042-1 or T6308-1 significantly inhibited AGEs-induced RASMC proliferation(P<0.05).CONCLUSION AGEs induce proatherogenic events such as VSMC proliferation,proatherogenic mediator release,and vascular remodeling,changes that can be attenuated by silencing profilin-1 expression.These results suggest a crucial role for profilin-1 in AGEs-induced vasculopathy.展开更多
Objective:Our aim was to investigate the correlation between free fatty acid(FFA) spectrum, blood stasis(BS) score, and macroangiopathy in type 2 diabetic patients with or without BS, as well as the possible relations...Objective:Our aim was to investigate the correlation between free fatty acid(FFA) spectrum, blood stasis(BS) score, and macroangiopathy in type 2 diabetic patients with or without BS, as well as the possible relationship between BS and lipotoxicity. Methods: A total of 50 type 2 diabetes(T2D) patients with or without BS were enrolled from June to December 2014 in Shenzhen Traditional Chinese Medicine(TCM) Hospital, with 25 patients allocated to each of two groups. Basic information, BS score, blood glucose, blood lipids, etc., were measured for each patient. In addition, we tested the levels of interleukin(IL)?6, tumor necrosis factor α(TNF?α), and IL?18 with enzyme?linked immunosorbent assay. The macroangiopathy status of patients in the two groups was examined by color ultrasound and all factors related to BS scores were analyzed. Gas chromatography?mass spectrometry was used to explore the difference in the serum FFA spectra between the two different groups. In addition, the relationship between FFA spectra, BS scores, and macroangiopathy was analyzed. Results: BS scores, total cholesterol(TC), total triglyceride(TG), low?density lipoprotein cholesterol, IL?6, TNF?α, IL?18, carotid and femoral artery plaque, carotid intima?media thickness, carotid plaque area, and femoral artery plaque area were all significantly increased in T2D patients with BS syndrome(P < 0.05). A positive correlation was observed between age, duration of diabetes, carotid intima?media thickness, carotid plaque area, femoral artery plaque area, and BS score(P < 0.05). A total of 21 fatty acids were found in the serum, and total FFA(TFFA), saturated fatty acid(SFA), lauric acid(C12:0), palmitic acid(16:0), stearic acid(C18:0), arachidonic acid(C20:4n6), behenic acid(C22:0), and lignoceric acid(C24:0) scores were all found to contribute to the difference between FFA spectrums of the two groups; of the fatty acids, C12:0, C16:0, C18:0, C22:0, TFFA, and SFA positively correlated with BS scores as evaluated by Pearson's or Spearman's correlation analysis(P < 0.05). Only SFA entered the regression equation in the multiple linear regression analysis. C12:0, C16:0, C18:0, C20:4n6, TFFA, and SFA were positively correlated with carotid plaque area, whereas linoleic acid(C18:3n3), Cis?5, 8, 11, 14, and 17?eicosapentaenoic acids(C20:5n3) were negatively correlated(P < 0.05). C16:0 was positively correlated with the femoral artery plaque area and C18:3n3, cis?4, 7, 10, 13, 16, and 19?docosahexaenoic acids(C22:6) and nervonic acid were negatively correlated(P < 0.05). Conclusion: Serum FFA spectra were significantly different between T2D patients with BS and those without, and long?chain SFA made the greatest contribution. Serum FFA spectra were correlated with BS scores and diabetic macroangiopathy, which means that lipotoxicity and BS are correlated in T2D.展开更多
基金the National Natural Science Foundation of China,No.81000140,No.81770358,and No.82000339Natural Science Foundation of Hunan Province,No.2017JJ3486and the Fund for Health Care in Hunan Province,No.B2017-01.
文摘BACKGROUND The accumulation of advanced glycation end products(AGEs)have been implicated in the development and progression of diabetic vasculopathy.However,the role of profilin-1 as a multifunctional actin-binding protein in AGEs-induced atherosclerosis(AS)is largely unknown.AIM To explore the potential role of profilin-1 in the pathogenesis of AS induced by AGEs,particularly in relation to the Janus kinase 2(JAK2)and signal transducer and activator of transcription 3(STAT3)signaling pathway.METHODS Eighty-nine individuals undergoing coronary angiography were enrolled in the study.Plasma cytokine levels were detected using ELISA kits.Rat aortic vascular smooth muscle cells(RASMCs)were incubated with different compounds for different times.Cell proliferation was determined by performing the MTT assay and EdU staining.An AGEs-induced vascular remodeling model was established in rats and histological and immunohistochemical analyses were performed.The mRNA and protein levels were detected using real-time PCR and Western blot analysis,respectively.In vivo,shRNA transfection was performed to verify the role of profilin-1 in AGEs-induced proatherogenic mediator release and aortic remodeling.Statistical analyses were performed using SPSS 22.0 software.RESULTS Compared with the control group,plasma levels of profilin-1 and receptor for AGEs(RAGE)were significantly increased in patients with coronary artery disease,especially in those complicated with diabetes mellitus(P<0.01).The levels of profilin-1 were positively correlated with the levels of RAGE(P<0.01);additionally,the levels of both molecules were positively associated with the degree of coronary artery stenosis(P<0.01).In vivo,tail vein injections of AGEs induced the release of proatherogenic mediators,such as asymmetric dimethylarginine,intercellular adhesion molecule-1,and the N-terminus of procollagen III peptide,concomitant with apparent aortic morphological changes and significantly upregulated expression of the profilin-1 mRNA and protein in the thoracic aorta(P<0.05 or P<0.01).Downregulation of profilin-1 expression with an shRNA significantly attenuated AGEs-induced proatherogenic mediator release(P<0.05)and aortic remodeling.In vitro,incubation of vascular smooth muscle cells(VSMCs)with AGEs significantly promoted cell proliferation and upregulated the expression of the profilin-1 mRNA and protein(P<0.05).AGEs(200μg/mL,24 h)significantly upregulated the expression of the STAT3 mRNA and protein and JAK2 protein,which was blocked by a JAK2 inhibitor(T3042-1)and/or STAT3 inhibitor(T6308-1)(P<0.05).In addition,pretreatment with T3042-1 or T6308-1 significantly inhibited AGEs-induced RASMC proliferation(P<0.05).CONCLUSION AGEs induce proatherogenic events such as VSMC proliferation,proatherogenic mediator release,and vascular remodeling,changes that can be attenuated by silencing profilin-1 expression.These results suggest a crucial role for profilin-1 in AGEs-induced vasculopathy.
基金Natural Science Foundation of China(No.81173253)Sanming Project of Medicine in Shenzhen(No.SZSM201512043)supported the study
文摘Objective:Our aim was to investigate the correlation between free fatty acid(FFA) spectrum, blood stasis(BS) score, and macroangiopathy in type 2 diabetic patients with or without BS, as well as the possible relationship between BS and lipotoxicity. Methods: A total of 50 type 2 diabetes(T2D) patients with or without BS were enrolled from June to December 2014 in Shenzhen Traditional Chinese Medicine(TCM) Hospital, with 25 patients allocated to each of two groups. Basic information, BS score, blood glucose, blood lipids, etc., were measured for each patient. In addition, we tested the levels of interleukin(IL)?6, tumor necrosis factor α(TNF?α), and IL?18 with enzyme?linked immunosorbent assay. The macroangiopathy status of patients in the two groups was examined by color ultrasound and all factors related to BS scores were analyzed. Gas chromatography?mass spectrometry was used to explore the difference in the serum FFA spectra between the two different groups. In addition, the relationship between FFA spectra, BS scores, and macroangiopathy was analyzed. Results: BS scores, total cholesterol(TC), total triglyceride(TG), low?density lipoprotein cholesterol, IL?6, TNF?α, IL?18, carotid and femoral artery plaque, carotid intima?media thickness, carotid plaque area, and femoral artery plaque area were all significantly increased in T2D patients with BS syndrome(P < 0.05). A positive correlation was observed between age, duration of diabetes, carotid intima?media thickness, carotid plaque area, femoral artery plaque area, and BS score(P < 0.05). A total of 21 fatty acids were found in the serum, and total FFA(TFFA), saturated fatty acid(SFA), lauric acid(C12:0), palmitic acid(16:0), stearic acid(C18:0), arachidonic acid(C20:4n6), behenic acid(C22:0), and lignoceric acid(C24:0) scores were all found to contribute to the difference between FFA spectrums of the two groups; of the fatty acids, C12:0, C16:0, C18:0, C22:0, TFFA, and SFA positively correlated with BS scores as evaluated by Pearson's or Spearman's correlation analysis(P < 0.05). Only SFA entered the regression equation in the multiple linear regression analysis. C12:0, C16:0, C18:0, C20:4n6, TFFA, and SFA were positively correlated with carotid plaque area, whereas linoleic acid(C18:3n3), Cis?5, 8, 11, 14, and 17?eicosapentaenoic acids(C20:5n3) were negatively correlated(P < 0.05). C16:0 was positively correlated with the femoral artery plaque area and C18:3n3, cis?4, 7, 10, 13, 16, and 19?docosahexaenoic acids(C22:6) and nervonic acid were negatively correlated(P < 0.05). Conclusion: Serum FFA spectra were significantly different between T2D patients with BS and those without, and long?chain SFA made the greatest contribution. Serum FFA spectra were correlated with BS scores and diabetic macroangiopathy, which means that lipotoxicity and BS are correlated in T2D.
