Abstract:The mechanical force caused by elevated blood pressure plays a decisive role in vascular differentiation and development, the maintenance of normal vascular structure and function, and the process of vascular lesions. Abnormal elevation of blood lipid and/or blood glucose synergistically accelerate mechanical force-initiated vascular remodeling and the occurrence and development of diseases. Mechanical forces can nonspecifically activate all transmembrane protein molecules in vascular cells, leading to simultaneous activation of intracellular multi-signal channel molecules (secondary effector molecules). The upstream multi-pathway molecular signals converge on the node molecules of signal network and then diverge to the downstream pathway molecules, and finally start more signaling pathway activation, and amplify the signal cascades. Then, a series of pathophysiological changes such as cell differentiation, migration, inflammation, phenotypic changes, calcification, proliferation, and apoptosis occur. Finally, the structural and functional changes of blood vessels, such as atherosclerosis, become the main cause of death and disability caused by cardiovascular and cerebrovascular diseases. This paper reviews the research progress from this research group and international peers, that is, vascular remodeling is closely related to the effect of mechanical force generated by elevated blood pressure on vascular smooth muscle cells.

Abstract:Myocardial fibrosis is the excessive deposition of extracellular matrix(ECM) in the cardiac interstitium caused by a variety of injury factors, which can lead to the decline of ventricular compliance, myocardial diastolic and systolic dysfunction and arrhythmia. It is closely related to the severity of cardiac insufficiency and poor prognosis. Fibroblasts, endothelial cells, pericytes and immune cells in cardiac interstitium can be divided into a variety of subgroups due to different genomic expression, and regulate myocardial fibrosis through phenotypic transformation, fine regulation of ECM components and secretion of pro-fibrosis or anti-fibrosis factors. This article reviews the role of cardiac interstitial cells in cardiac fibrosis and reveals the molecular mechanisms including signal transduction networks and epigenetic modifications, which will provide new therapeutic strategies and targets for preventing and alleviating cardiac fibrosis.

Abstract:Aim To investigate the effect of low shear stress (LSS) on the expression of Bmi-1 in human umbilical vein endothelial cells (HUVEC) and its possible mechanism. Methods Human umbilical vein endothelial cells were cultured in vitro. Immunofluorescence was used to detect the localization of Bmi-1 in the cells. 0.5 h, 1 h, 2 h and 4 h were loaded into human umbilical vein endothelial cells by parallel plate flow chamber system. The expression of Bmi-1 mRNA was detected by real-time quantitative RT-PCR. The expression of Bmi-1 protein was detected by Western blot.Specific signal inhibitor SB2219 was used to investigate the signal transduction pathway. Results Immunofluorescence observation showed that Bmi-1 was mainly distributed in the nucleus of human umbilical vein endothelial cells. The expression of Bmi-1 was significantly increased after 0.5 h of LSS, the expression of Bmi-1 mRNA and protein decreased gradually with the prolongation of the time (1 h, 2 h and 4 h); the shear stress could significantly activate phosphorylated p38 expression; SB2219 could significantly inhibit the expression of Bmi-1. Conclusion LSS can induce the expression of Bmi-1 in human umbilical vein endothelial cells, the expression of Bmi-1 is closely related to the length of stimulation, this effect may be regulated by p38 signal.

Abstract:Aim To observe the effects of alprostadil （prostaglandin E1, PGE1） on cardiac function in diabetic rats and to explore the protective effects and its mechanism. Methods 10 SD rats were selected to be normal control group from the 50 rats, and the others were given high-sugar high-fat diet for four weeks and received intraperitoneal injection of 0.1% streptozotocin to establishe diabetic rats model. Successful model rats were randomly divided into model group, PGE1 low-dose group, PGE1 middle-dose group and PGE1 high-dose group, then PGE1 low, middle, and high-dose group were respectively given 0.5, 1.0, 2.0 μg/kg alprostadil per-day intraperitoneal injection. Normal control group and model group were given an equal volume of normal saline. After treatment for 8 weeks, the following indexes of each group was measured: To detect the concentrations of serum transforming growth factor-β1 （TGF-β1）, plasma amino-terminal pro-B-type natriuretic peptide （NT-proBNP） and glycosylated hemoglobin A1 （HbA1c） To measure the collagen volume fraction （CVF） of myocardial tissue by Masson staining To detect the expressions of TGF-β1, Smad3, Smad7 proteins in myocardial tissue by Western blot. Results Compared with the control group, the concentrations of TGF-β1, NT-proBNP, HbA1c and myocardial fibrosis index CVF of model group were significantly increased, the expressions of TGF-β1 and Smad3 proteins in myocardial tissue were significantly increased, and the expression of Smad7 protein was significantly decreased （all P<0.01）. Compared with the model group, the concentrations of TGF-β1, NT-proBNP and myocardial CVF in the PGE1 middle and high-dose group were significantly reduced, the expressions of TGF-β1 and Smad3 proteins in myocardial tissue were significantly decreased, and the expression of Smad7 protein was significantly increased （all P<0.01） The changes were the most obvious in PGE1 high-dose group. There was no significant difference in each index between the PGE1 low-dose group and model group. Conclusion Alprostadil can inhibit myocardial fibrosis and improve cardiac function in diabetic rats, and the mechanism of which is related to the regulation of TGF-β1/Smad signal transduction pathway.

Abstract:Signal transducer and activator of transcription 4 （STAT4） is one of the signal transducer and activator of transcription （STAT） protein family which share common structural features. As an intracellular signal transducer,STAT4 involves in cellular differentiation,inflammation and other physiological or pathological process. Some recent studies suggest that STAT4 influence innate and adaptive immunity as well as the distribution of arterial smooth muscle cells in the process of atherogenesis. Therefore,extensive researches are necessary in revealing underlying mechanisms of STAT4’s role in the process of atherogenesis.

Abstract:Aim To induce myocardial fibrosis by establishing type 2 diabetes mellitus rat model,and explore prevention and treatment mechanism about Apelin-13 which is one subtype of endogenous ligand of proteins related to the angiotensin Ⅱ type 1 receptor for myocardial fibrosis of diabetes mellitus rats. Methods High fat and sugar diet combined with intravenous injection of a small dose of streptozotocin （STZ） was used to build type 2 diabetes mellitus rat model.48 Wistar rats were randomly divided into four groups: control group,model group,Apelin-13 group,blocker group （SB431542 group）.Rats in different groups were given homologous intervention for 12 weeks,specimens were collected for Masson staining to observe morphological changes and interstitial collagen deposition of myocardial,and collagen volume fraction （CVF） was measured.Contents of collagen Ⅰ and Ⅲ in myocardial tissue were detected by ELISA.Expressions of transforming growth factor-β1 （TGF-β1）,TGF-β1 receptorⅠ（TβRⅠ） were measured with immunohistochemical staining.Expressions of pathway protein smad2,p-smad2,smad3 and p-smad3 were measured by Western blot. Results Compared with control group,CVF and contents of collagenⅠand Ⅲ of myocardial tissue in model group increased obviously,accompanied with the increasing of signal transduction pathway protein TGF-β1,TβRⅠ,smad2,p-smad2,smad3 and p-smad3 （P<0.01）.Compared with model group,myocardial fibrosis dicators （CVF,collagenⅠand Ⅲ） in rats who received Apelin-13 or SB431542 significantly reduced,expressions of all pathways protein in Apelin-13 group were adjusted downward significantly （P<0.01）,differences of TGF-β1,TβRⅠhad no statistically significance between SB431542 and model group （P＞0.05）,expressions of other signal protein were obviously decreased （P<0.01）. Conclusions Exogenous Apelin-13 can restrain myocardial fibrosis in diabetes mellitus rats by weakening excessive activation of TGF-β1/TβR/smads signal transduction pathway.

Abstract:Biomechanical stress existing in the human body plays a pivotal role in the progression of human development, growth or diseases.But how the mechanical stress acts on the organism leading to a series of changed pathophysiology is an attractive issue.Significantly advanced progresses concerning mechanical stress-related tissue or cell remodeling have been made in the recent years, especially in cardiovascular area.For instance, we already realized that mechanical stress resulted from increased blood pressure (e.g. hypertension) or abnormal hemodynamics due to altered angioarchitecture (e.g. atherosclerosis) may not only be an initiator but also be a terminator in the development, maintenance or promotion of the cardiovascular diseases.Thus, mechanical stress as an independent risk factor has more obviously deleterious effects on changed structure and function of blood vessels compared with most of other growth factors and active polypeptides.This review will focus on the current advances from our and other investigators regarding the effects of mechanical stress on normal structure, function, and diseases of blood vessels.

Abstract:Aim Previous study demonstrated that tetramethylpyrazine(TMP)had an inhibitory effect on the TF expression induced by thrombin in human umbilical vein endothelium derived cell line human umbilical vascular endothelial cells(HUVEC).However,its mechanisms were not fully understood.In this study,we observed the role of nitric oxide(NO)and transcription factor NF-κB in the regulation of TMP on tissue factor(TF)expression.Methods HUVEC were cultured in RPMI-1640.TF activity was determined with one-stage clotting assay measuring total cellular pro-coagulant activity(PCA).TF mRNA was examined by semi-quantitative reverse transcription polymerase chain reaction(RT-PCR).Immunohistochemical analysis was performed to evaluate the translocation of NF-κB.Results NG-nitro-L-arginine methylate(L-NAME)is an inhibitor of nitric oxide synthase(NOS),and it alone had no marked effects on PCA and TF mRNA in HUVEC,but L-NAME significantly decrease the inhibitory effects of TMP on PCA increment induced by thrombin(P<0.05).Immunohistochemical analysis demonstrated that NF-κB translocation from cytoplasm to the nucleus was found after treatment of endothelial cells with thrombin.TMP inhibited thrombin-induced NF-κB translocation from cytoplasm to the nucleus.Conclusion NO pathway participates in the inhibitory effect of TMP on the expression of TF induced by thrombin.TMP can inhibit TF expression induced by thrombin through suppressing NF-κB activation.

Abstract:Aim To study the effect of rhynchophylline and isorhynchophylline on the apoptosis of vascular smooth muscle cell (VSMC) induced by angiotensin Ⅱ (AngⅡ) its mechanism in rats. Methods The apoptosis model in VSMCs induced by angiotensin Ⅱ was established. The effect of rhynchophylline and isorhynchophylline on the cell morphology, apoptosis rate, [Ca2+]i concentration, Bcl-2 and Bax protein expression and mRNA expression were observed by invert phase contrast microscope, flow cytometry and RT-PCR. Results The rhynchophylline and isorhynchophylline could induce the apoptosis of VSMCs, increase cell apoptosis rate, decrease cell [Ca2+]i concentration and down regulate Bcl-2, Bax protein and mRNA expression. Conclusion The rhynchophylline and isorhynchophylline may induce the apoptosis of VSMC, whose mechanisms might be related to decreasing cell [Ca2+]i concentration and down regulating Bcl-2 and Bax protein expression and mRNA expression.

Abstract:Aim To investigate the effect and signal transduction pathway of UrotensinⅡ (UⅡ) on endothelin-1 (ET-1) production in cultured aortic tissues of rat. Methods Aortic slices were incubated with different concentration of UⅡ(10-10～10-7 mol/L) for 3 or 6 h. ET-1 both in medium and tissues were measured with radioimmunoassay. Different inhibitors were added to the medium to study the role of different signal transduction pathways in the stimulating effect of UⅡon production of ET-1. Results The study showed that UⅡ significantly stimulated ET-1 secretion (ET-1 in medium) and production (ET-1 both in medium and tissues) from rat aortic tissues, in a time and concentration dependent manner. After incubation for 3 h, ET-1 secretion and production were increased by 146% and 87.9% respectively in 10-8mol/L of UⅡ group than the control group. After incubation for 6h, ET-1 secretion was increased by 59.2%, 108%, 159.6% and 178.0% in UⅡ (10-10, 10-9, 10-8, 10-7 mol/L) group respectively. And ET-1 production was increased by 40.6%, 68.4%, 103.1% and 105.7% in 10-10～10-7 mol/L of UⅡ group respectively. Furthermore, the effect of UⅡ (10-8 mol/L) were inhibited by 34.1%, 24.5%, 32.2%, 32.1% and 27.6% (p<0.01) in secretion and by 33.5%, 31.5%, 25.8%, 28.0% and 36.8% (p<0.01) in production when incubated with nicardipine, H7, PD98059, actinomycin D and cyclophosphamide respectively, which are inhibitors of calcium channel, PKC, MAPK, mRNA production and protein synthesis respectively. Conclusion UⅡ could stimulate ET-1 synthesis and secretion in rat aortic tissues, and this effect might be mediated by Ca2+, PKC, and MAPK signal transduction pathway. It was also proposed that UⅡ might play vasoconstrictive actions partly through ET-1 production.