Publications by authors named "Rui-Wei Guo"

26 Publications

  • Page 1 of 1

TRPC6 and TRPC4 Heteromultimerization Mediates Store Depletion-Activated NCX1 Reversal in Proliferative Vascular Smooth Muscle Cells.

Channels (Austin) 2018 01;12(1):119-125

d Department of Cardiology , Kunming General Hospital of Chengdu Military Command , Kunming , Yunnan , China.

Store depletion has been shown to induce Ca entry by Na+/Ca+ exchange (NCX) 1 reversal in proliferative vascular smooth muscle cells (VSMCs). The study objective was to investigate the role of transient receptor potential canonical (TRPC) channels in store depletion and NCX1 reversal in proliferative VSMCs. In cultured VSMCs, expressing TRPC1, TRPC4, and TRPC6, the removal of extracellular Na was followed by a significant increase of cytosolic Ca concentration that was inhibited by KBR, a selective NCX1 inhibitor. TRPC1 knockdown significantly suppressed store-operated, channel-mediated Ca entry, but TRPC4 knockdown and TRPC6 knockdown had no effect. Separate knockdown of TRPC1, TRPC4, or TRPC6 did not have a significant effect on thapsigargin-initiated Na increase in the peripheral regions with KBR treatment, but knockdown of both TRPC4 and TRPC6 did. Stromal interaction molecule (STIM)1 knockdown significantly reduced TRPC4 and TRPC6 binding. The results demonstrated that TRPC4-TRPC6 heteromultimerization linked Ca store depletion and STIM1 accumulation with NCX reversal in proliferative VSMCs.
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http://dx.doi.org/10.1080/19336950.2018.1451696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5972809PMC
January 2018

Impaired decision-making and functional neuronal network activity in systemic lupus erythematosus.

J Magn Reson Imaging 2018 12 14;48(6):1508-1517. Epub 2018 Mar 14.

First Affiliated Hospital of Shantou University Medical College, Shantou, China.

Background: Systemic lupus erythematosus (SLE) is associated with cognitive deficit but the exact neural mechanisms remain unclear.

Purpose: To explore sequential brain activities using functional magnetic resonance imaging (fMRI) during the performance of a decision-making task, and to determine whether serum or clinical markers can reflect the involvement of the brain in SLE.

Subjects: Sixteen female SLE patients without overt clinical neuropsychiatric symptoms and 16 healthy controls were included.

Field Strength/sequence: 1.5T, T -weighted anatomic images, gradient-echo echo-planar imaging sequence, and 3D images.

Assessment: The computer-based Iowa Gambling Task (IGT) for assessing decision-making was performed by SLE patients and 16 matched controls; brain activity was recorded via blood oxygen level-dependent (BOLD) fMRI. The amplitudes of the average BOLD responses were calculated for each individual subject, and activation data from fMRI experiments were compared between the two groups.

Statistical Tests: Two-sample t-test; repeated-measures analysis of variance (ANOVA); linear regression analyses.

Results: Imaging revealed activity in a distributed network of brain regions in both groups, including the ventromedial prefrontal cortex (vmPFC), the orbitofrontal cortex (OFC), the dorsolateral prefrontal cortex (dlPFC), the anterior cingulate cortex (ACC), the posterior cingulate cortex (PCC), and the striatum, as well as the insular, parietal, and occipital cortices. Compared to controls, SLE patients showed lower activation in a convergence zone and the limbic system, namely, the OFC, vmPFC, ACC, and PCC, but greater activation in memory, emotion, and behavior systems involving the dlPFC, the insular cortex and the striatum. Furthermore, brain activation in the vmPFC was positively correlated with IGT scores (r = 0.63, P < 0.001), but inversely related to disease activity (r = -0.57, P < 0.01).

Data Conclusion: The dynamics among the aforementioned neural systems (some hyperfunctioning, others hypofunctioning) may shed some light on the pathologic mechanisms underlying SLE without overt clinical neuropsychiatric symptoms. In addition, disease activity may potentially be used as an effective biomarker reflecting cerebral involvement in SLE.

Level Of Evidence: 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;48:1508-1517.
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http://dx.doi.org/10.1002/jmri.26006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6282848PMC
December 2018

Decision-making in primary onset middle-age type 2 diabetes mellitus: a BOLD-fMRI study.

Sci Rep 2017 08 31;7(1):10246. Epub 2017 Aug 31.

The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong Province, 515041, China.

Although type 2 diabetes mellitus (T2DM) is a well-recognized risk factor for dementia, the neural mechanisms that underlying cognitive impairment in T2DM remain unclear. We used functional magnetic resonance imaging (fMRI) during a computerized version of the Iowa Gambling Task to investigate the neural basis of decision making at the initial onset stage of T2DM. Eighteen newly diagnosed middle-aged T2DM patients, with no previous diabetic treatment history, and 18 matched controls were recruited. Results indicated that T2DM patients made more disadvantageous decisions than controls. Compared to healthy subjects, T2DM patients showed decreased activation in the ventral medial prefrontal cortex (VMPFC), orbitofrontal cortex (OFC) and anterior cingulate cortex, and increased activity in the dorsolateral prefrontal cortex, posterior cingulate cortex, insula and occipital lobes. IGT performance positively correlated with changes in brain activation in the VMPFC and OFC in both groups. Moreover, poor glycemic control was associated with decision-making function both in behavioral and brain activity in the VMPFC and OFC in patients. Conclusively, T2DM patients may suffer from weaknesses in their prefrontal cortex functions that lead to poorer decision-making under ambiguity, at least as assessed by the IGT.
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http://dx.doi.org/10.1038/s41598-017-10228-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5579021PMC
August 2017

MicroRNA-99a inhibits insulin-induced proliferation, migration, dedifferentiation, and rapamycin resistance of vascular smooth muscle cells by inhibiting insulin-like growth factor-1 receptor and mammalian target of rapamycin.

Biochem Biophys Res Commun 2017 04 15;486(2):414-422. Epub 2017 Mar 15.

Department of Cardiology, Kunming General Hospital of Chengdu Military Area, China. Electronic address:

Patients with type 2 diabetes mellitus (T2DM) are characterized by insulin resistance and are subsequently at high risk for atherosclerosis. Hyperinsulinemia has been associated with proliferation, migration, and dedifferentiation of vascular smooth muscle cells (VSMCs) during the pathogenesis of atherosclerosis. Moreover, insulin-like growth factor-1 receptor (IGF-1R) and mammalian target of rapamycin (mTOR) have been demonstrated to be the underlying signaling pathways. Recently, microRNA-99a (miR-99a) has been suggested to regulate the phenotypic changes of VSMCs in cancer cells. However, whether it is involved in insulin-induced changes of VSCMs has not been determined. In this study, we found that insulin induced proliferation, migration, and dedifferentiation of mouse VSMCs in a dose-dependent manner. Furthermore, the stimulating effects of high-dose insulin on proliferation, migration, and dedifferentiation of mouse VSMCs were found to be associated with the attenuation of the inhibitory effects of miR-99a on IGF-1R and mTOR signaling activities. Finally, we found that the inducing effect of high-dose insulin on proliferation, migration, and dedifferentiation of VSMCs was partially inhibited by an active mimic of miR-99a. Taken together, these results suggest that miR-99a plays a key regulatory role in the pathogenesis of insulin-induced proliferation, migration, and phenotype conversion of VSMCs at least partly via inhibition of IGF-1R and mTOR signaling. Our results provide evidence that miR-99a may be a novel target for the treatment of hyperinsulinemia-induced atherosclerosis.
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http://dx.doi.org/10.1016/j.bbrc.2017.03.056DOI Listing
April 2017

Changes in levels of angiotensin II and its receptors in a model of inverted stress-induced cardiomyopathy.

Eur J Med Res 2014 Oct 9;19:54. Epub 2014 Oct 9.

Department of Cardiology, Kunming General Hospital of Chengdu Military Command, Daguan Road, No212, Yunnan, 650032, China.

Background: Stress-induced cardiomyopathy (SIC) has gained increasing attention worldwide and is characterized by extensive ventricular akinesis, Beta-blockers and angiotensin-converting enzyme inhibitors (ACEIs) are the main treatments for SIC patients. The pharmacological mechanism of action of beta-blockers results in the inhibition of the biological effects of catecholamines. However, the mechanism of action of ACEIs in the treatment of cardiomyopathy is not known. Our aim is to assess changes in levels of angiotensin II, angiotensin-II receptors and ACE responses to SIC.

Methods: A model of inverted SIC was established in rabbits by vagal electrical stimulation. The serum concentration of angiotensin II and angiotensin (1-7) was detected by enzyme-linked immunosorbent assay. Expression of angiotensin-II receptors was measured by Western blotting and real-time reverse transcription-polymerase chain reaction (RT-PCR), with localization detected by immunofluorescent staining. ACE-II expression in the myocardium was measured by Western blotting.

Results: From one day after vagal stimulation, concentrations of angiotensin II were significantly higher in the experimental group than those in the control group (P <0.05). Stress induced a time-dependent decrease in angiotensin subtype-1 (AT1) expression and a time-dependent increase in AT2 expression only in the apical portion of the myocardium. From three days after vagal stimulation, angiotensin (1-7) levels were significantly lower in the experimental group compared with the control group (P <0.05). Expression of the ACE-II protein was significantly downregulated in the experimental group compared with the control group from three days after vagal stimulation (P <0.05).

Conclusions: Expression of angiotensin II, its receptors, ACE-II and angiotensin (1-7) was altered in response to SIC. The renin-angiotensin system could represent a therapeutic target in the prevention of SIC.
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http://dx.doi.org/10.1186/s40001-014-0054-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4240840PMC
October 2014

MicroRNA-155 inhibits angiotensin II-induced vascular smooth muscle cell proliferation.

J Renin Angiotensin Aldosterone Syst 2014 Jun 15;15(2):109-16. Epub 2014 Apr 15.

Department of Cardiology, Kunming General Hospital of Chengdu Military Area, China.

Background: MicroRNA-155 (miR-155) is a multifunctional signal microRNA that participates in a variety of cardiovascular diseases and is involved in physiological and pathological processes in different cell types.

Objective: The objective of this article is to examine the effect of miR-155 on angiotensin II (Ang II)-induced primary mice vascular smooth muscle cell (VSMC) proliferation.

Methods: Primary cultured VSMCs from the aorta of C57/BL6 mice were incubated with Ang II and miR-155. Cells were counted using CCK-8 and EdU, and flow cytometric analysis of cell cycle progression was performed. Angiotensin II 1 type receptor (AT1R) gene and protein expression were measured by real-time polymerase chain reaction and Western blotting.

Results: 1) Ang II increased the viability of VSMCs in a dose- and time-dependent manner. 2) miR-155 opposed the Ang II-induced increase in VSMC viability. 3) miR-155 inhibited Ang II-induced proliferation of VSMCs. 4) miR-155 increased the number of VSMCs in the G1 phase compared to G2 and M cell cycle phases. 5) miR-155 decreased ATR1 gene and protein expression.

Conclusion: miR-155 downregulation of Ang II-induced VSMC viability identifies it as an important regulator of cell proliferation.
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http://dx.doi.org/10.1177/1470320313503693DOI Listing
June 2014

microRNA-155 is inversely associated with severity of coronary stenotic lesions calculated by the Gensini score.

Coron Artery Dis 2014 Jun;25(4):304-10

Department of Cardiology, Kunming General Hospital of Chengdu Military Area, Yunnan, China.

Objectives: This study aimed to investigate the association between microRNA-155 (miR-155) and the severity and extent of coronary stenotic lesions.

Patients And Methods: We measured the miR-155 expression by real-time PCR in 110 consecutive patients undergoing coronary angiography for suspected coronary artery disease. The severity and extent of coronary stenotic lesions were evaluated on the basis of coronary angiography findings by the Gensini score.

Results: The miR-155 expression was significantly lower in 56 patients with coronary heart disease than those in 54 controls (P<0.01). The level of miR-155 in peripheral blood mononuclear cells or plasma was lower in patients with unstable angina pectoris and acute myocardial infarction than in patients with chest pain syndrome, whereas no statistically significant differences were observed between patients with stable angina pectoris and chest pain syndrome. Spearman's correlation analysis showed that the expression of miR-155 in plasma correlated positively with the expression in peripheral blood mononuclear cells. The levels of miR-155 in the patients with diseased vessels of two and three or more were significantly lower than in those with diseased vessel of zero and one. The levels of miR-155 were not significantly different among groups with diseased vessels of zero and one. miR-155 were associated negatively with Gensini scores (r = -0.663, P<0.001). The miR-155 expression was correlated significantly to age (r = -0.227), hypertension (r = -0.440), total cholesterol (r = 0.239), high-density lipoprotein cholesterol (r = 0.280), low-density lipoprotein cholesterol (r = -0.315), tobacco use (r = -0.363), angiotensin-converting enzyme inhibitor (r = -0.250), statins (r = -0.368), and high-sensitivity C-reactive protein (r = -0.515).

Conclusion: miR-155 expression is associated inversely with complicated proatherogenic metabolic risk factors, and the severity of coronary stenotic lesions calculated by Gensini scores.
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http://dx.doi.org/10.1097/MCA.0000000000000088DOI Listing
June 2014

Effect of sex on recovery of ejection fraction in patients with anterior ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention.

Coron Artery Dis 2014 Mar;25(2):133-7

Departments of aCardiology bObstetrics and Gynecology, Kunming General Hospital of Chengdu Military Command, Yunnan, China.

Objectives: Myocardial necrosis after ST-segment elevation myocardial infarction (STEMI) can cause left ventricular systolic dysfunction, which has been associated with poor outcomes. Some authors have reported that women have higher mortality rates after primary percutaneous coronary intervention (PCI), but differences between the sexes with regard to recovery of ejection fraction (EF) in patients with STEMI receiving primary PCI have not been evaluated. We aimed to assess the effect of sex on EF recovery in patients with anterior wall STEMI after primary PCI.

Patients And Methods: A total of 202 consecutive patients (134 men) admitted due to anterior wall STEMI to our hospital over 44 months were evaluated. All patients were taken directly to the Cardiac Catheterization Laboratory for primary PCI. Baseline clinical variables were collected, and left ventricular ejection fraction (LVEF) was measured by echocardiography using the biplane Simpson model on the day after PCI and 6 months later.

Results: Women were significantly older than men (66.9±8.5 vs. 59.5±9.8, P<0.001). They also had a higher prevalence of hypertension and were less likely to be smokers compared with men. The time from symptom onset to hospital admission was longer in women than in men (8.9±3.0 vs. 7.8±2.4 h, P=0.048). At 1 day and 6 months after PCI, the EF was lower in women compared with men. The difference in values between 1 day and 6 months after PCI was also significantly lower in women compared with men (3.0±2.3 vs. 5.8±3.7, P<0.001). Multivariable linear regression analyses showed that being female was a significant predictor of LVEF recovery, even after adjustment for important clinical covariates.

Conclusion: These data suggest that being female is an independent determinant of LVEF recovery in patients with anterior myocardial infarction after primary PCI.
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http://dx.doi.org/10.1097/MCA.0000000000000060DOI Listing
March 2014

miR-155 inhibits oxidized low-density lipoprotein-induced apoptosis of RAW264.7 cells.

Mol Cell Biochem 2013 Oct;382(1-2):253-61

Macrophage apoptosis is a prominent feature of advanced atherosclerotic plaques. Here, we examined the hypothesis that the apoptotic machinery is regulated by microRNA-155 (miR-155). Constitutive expression of miR-155 was detected in RAW264.7 cells, which was increased following stimulation with oxidized low-density lipoprotein (OxLDL) in a dose- and time-dependent manner. OxLDL-treated RAW264.7 cells showed a marked time- and dose-dependent increase in apoptosis, which was suppressed in the presence of mimics and increased with antagonists of miR-155. Bioinformatics analysis revealed Fas-associated death domain-containing protein (FADD) as a putative target of miR-155. Luciferase reporter assay and Western blot further disclosed that miR-155 inhibits FADD expression by directly targeting the 3'-UTR region. We propose that miR-155 attenuates the macrophage apoptosis, at least in part, through FADD regulation, since forced expression of FADD blocked the ability of miR-155 to inhibit apoptosis. Our results collectively suggest that miR-155 attenuates apoptosis of OxLDL-mediated RAW264.7 cells by targeting FADD, supporting a possible therapeutic role in atherosclerosis.
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http://dx.doi.org/10.1007/s11010-013-1741-4DOI Listing
October 2013

Functional blockage of EMMPRIN ameliorates atherosclerosis in apolipoprotein E-deficient mice.

Int J Cardiol 2013 Oct 1;168(4):3248-53. Epub 2013 May 1.

Department of Postgraduate, Third Military Medical University, Chongqing 400038, China.

Background: Extracellular matrix metalloproteinase inducer (EMMPRIN), a 58-kDa cell surface glycoprotein, has been identified as a key receptor for transmitting cellular signals mediating metalloproteinase activities, as well as inflammation and oxidative stress. Clinical evidence has revealed that EMMPRIN is expressed in human atherosclerotic plaque; however, the relationship between EMMPRIN and atherosclerosis is unclear. To evaluate the functional role of EMMPRIN in atherosclerosis, we treated apolipoprotein E-deficient (ApoE(-/-)) mice with an EMMPRIN function-blocking antibody.

Methods And Results: EMMPRIN was found to be up-regulated in ApoE(-/-) mice fed a 12-week high-fat diet in contrast to 12 weeks of normal diet. Administration of a function-blocking EMMPRIN antibody (100 μg, twice per week for 4 weeks) to ApoE(-/-) mice, starting after 12 weeks of high-fat diet feeding caused attenuated and more stable atherosclerotic lesions, less reactive oxygen stress generation on plaque, as well as down-regulation of circulating interleukin-6 and monocyte chemotactic protein-1 in ApoE(-/-) mice. The benefit of EMMPRIN functional blockage was associated with reduced metalloproteinases proteolytic activity, which delayed the circulating monocyte transmigrating into atherosclerotic lesions.

Conclusion: EMMPRIN antibody intervention ameliorated atherosclerosis in ApoE(-/-) mice by the down-regulation of metalloproteinase activity, suggesting that EMMPRIN may be a viable therapeutic target in atherosclerosis.
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http://dx.doi.org/10.1016/j.ijcard.2013.04.141DOI Listing
October 2013

Atorvastatin inhibits the 5-lipoxygenase pathway and expression of CCL3 to alleviate atherosclerotic lesions in atherosclerotic ApoE knockout mice.

J Cardiovasc Pharmacol 2013 Aug;62(2):205-11

Department of Cardiology, Kunming General Hospital of Chengdu Military Command, Kunming, China.

Background: The 5-lipoxygenase (5-LO) pathway and the chemokine CCL3 are involved in the inflammatory processes of atherosclerosis. Statins have shown cholesterol-independent pleiotropic effects on antiimmune and antiinflammatory responses in atherosclerosis. We postulated that this effect may be associated with the 5-LO pathway and CCL3.

Methods And Results: ApoE knockout mice were randomized into control group (normal diet), atherosclerosis group (high-cholesterol diet), and atorvastatin group (high-cholesterol diet and atorvastatin). Sixteen weeks later, aortic roots were stained with hematoxylin and eosin. Total cholesterol and low-density lipoprotein cholesterol were measured by the enzymatic methods. The gene and protein expressions of 5-LO and CCL3 were detected separately through real-time reverse transcription polymerase chain reaction and western blotting analyses. The serum levels of leukotriene B4 and leukotriene D4 were measured by enzyme-linked immunosorbent assay. All mice have atherosclerotic plaques, mice in the control group have only tiny atherosclerotic plaques, but mice in the atherosclerosis group and atorvastatin group have typical atherosclerotic plaques. The corrected plaque areas (plaque area/luminal area) of the aortas of mice in the atorvastatin group were significantly decreased compared with those of the atherosclerosis group. The serum cholesterol levels of the atorvastatin group were not of significant difference compared with those of the atherosclerosis group. The gene and protein expressions of 5-LO and CCL3 in the aortas, as well as the serum levels of leukotriene B4 and leukotriene D4 in atorvastatin group, were markedly reduced compared with those of the atherosclerosis group.

Conclusion: These data suggested that atorvastatin significantly alleviated atherosclerotic lesions by inhibiting the 5-LO pathway and down regulating the expression of CCL3 in ApoE-/- mice.
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http://dx.doi.org/10.1097/FJC.0b013e3182967fc0DOI Listing
August 2013

Stim1- and Orai1-mediated store-operated calcium entry is critical for angiotensin II-induced vascular smooth muscle cell proliferation.

Cardiovasc Res 2012 Feb 22;93(2):360-70. Epub 2011 Nov 22.

Department of Cardiology, Kunming General Hospital of Chengdu Military Area, Yunnan 650032, China.

Aim: Despite the fact that angiotensin (Ang) II is a critical regulator of the proliferation and migration of vascular smooth muscle cells (VSMCs), the effect of Ang II on VSMC proliferation has remained unclear. In this study, we determined whether Stim1- and Orai1-mediated store-operated calcium (Ca(2+)) entry (SOCE) plays a critical role in Ang II-induced VSMC proliferation and Ang II-accelerated neointimal growth after balloon injury of rat carotid arteries.

Methods And Results: Knockdown of Stim1 and Orai1, putative calcium sensors/modulators, suppressed Ang II-mediated Ca(2+) entry and cell proliferation in synthetic VSMCs. Stim1 and Orai1 short interfering RNAs (siRNAs) decreased neointimal growth induced by Ang II in balloon-injured rat carotid arteries. Ang II significantly increased the expression of Stim1 and Orai1 in neointima. In addition, our results showed that receptor subtype-1 (AT1) significantly contributed to Ang II-induced Ca(2+) entry and proliferation of synthetic VSMCs. However, we found that transient receptor potential canonical 1 (Trpc1) had no effect on Ang II-induced SOCE or cell proliferation of synthetic VSMCs.

Conclusions: We show for the first time that Stim1- and Orai1-mediated SOCE may be critical for Ang II-induced VSMC proliferation. This provides important information with respect to targeting cardiovascular diseases under the enhanced renin-Ang system.
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http://dx.doi.org/10.1093/cvr/cvr307DOI Listing
February 2012

Angiotensin II induces extracellular matrix metalloproteinase inducer expression via an AT1R dependent pathway in aortic atherosclerotic plaque in apolipoprotein E knockout mice.

J Renin Angiotensin Aldosterone Syst 2012 Mar 21;13(1):67-75. Epub 2011 Oct 21.

Department of Cardiology, Kunming General Hospital of Chengdu Military Area, Yunnan, China.

Unlabelled: The pathogenesis of acute coronary syndrome is rupture of vulnerable plaque. Extracellular matrix metalloproteinase inducer (EMMPRIN) is reported to have a important role in the destabilization of atheroma.

Objectives: this investigation examined the effect of angiotensin II (Ang II) on EMMPRIN expression in atherosclerotic plaques in ApoE knockout mice.

Methods: ApoE knockout mice were fed a high fat diet to establish an atherosclerosis model then intervention was made with Ang II and valsartan. EMMPRIN gene and its protein expression were measured by real-time PCR immunohistochemistry, and Western blot.

Results: EMMPRIN gene and protein expression intervened with Ang II were significantly increased; valsartan could inhibit the effect of Ang II.

Conclusion: Ang II up-regulated EMMPRIN expression in atherosclerotic plaque via AT1R, and valsartan could inhibit the effect of Ang II.
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http://dx.doi.org/10.1177/1470320311423780DOI Listing
March 2012

Silencing stromal interaction molecule 1 by RNA interference inhibits the proliferation and migration of endothelial progenitor cells.

Biochem Biophys Res Commun 2010 Jul 25;398(2):315-20. Epub 2010 Jun 25.

Institute of Cardiovascular Diseases of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, People's Republic of China.

Knockdown of stromal interaction molecule 1 (STIM1) significantly suppresses neointima hyperplasia after vascular injury. Endothelial progenitor cells (EPCs) are the major source of cells that respond to endothelium repair and contribute to re-endothelialization by reducing neointima formation after vascular injury. We hypothesized that the effect of STIM1 on neointima hyperplasia inhibition is mediated through its effect on the biological properties of EPCs. In this study, we investigated the effects of STIM1 on the proliferation and migration of EPCs and examined the effect of STIM1 knockdown using cultured rat bone marrow-derived EPCs. STIM1 was expressed in EPCs, and knockdown of STIM1 by adenoviral delivery of small interfering RNA (siRNA) significantly suppressed the proliferation and migration of EPCs. Furthermore, STIM1 knockdown decreased store-operated channel entry 48h after transfection. Replenishment with recombinant human STIM1 reversed the effects of STIM1 knockdown. Our data suggest that the store-operated transient receptor potential canonical 1 channel is involved in regulating the biological properties of EPCs through STIM1. STIM1 is a potent regulator of cell proliferation and migration in rat EPCs and may play an important role in the biological properties of EPCs.
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http://dx.doi.org/10.1016/j.bbrc.2010.06.088DOI Listing
July 2010

The effect of the expression of angiotensin II on extracellular matrix metalloproteinase inducer (EMMPRIN) in macrophages is mediated via the AT1/COX-2/PGE2 pathway.

Inflamm Res 2010 Dec 20;59(12):1033-40. Epub 2010 Jun 20.

Department of Cardiology, Kunming General Hospital of Chengdu Military Area, Yunnan, 650032, China.

Aim: To explore the expression of extracellular matrix metalloproteinase inducer (EMMPRIN) in THP-1 macrophages induced by angiotensin II (Ang II) and the mechanism of EMMPRIN expression.

Methods: THP-1 cells were cultured and induced into macrophages, then stimulated with 10(-6) mol/L Ang II. Levels of EMMPRIN gene and its protein were measured by real-time polymerase chain reaction and western blotting. Prostaglandin E(2) (PGE(2)) expression was assayed by enzyme-linked immunosorbent assay. Antagonists of the angiotensin type-1 receptor (AT(1)R) and angiotensin type-2 receptor (AT(2)R) were used to inhibit the effect of Ang II, and PGE(2) added to detail the mechanism of Ang II-induced EMMPRIN expression.

Results: Ang II clearly induced the expression of EMMPRIN mRNA and protein in macrophages; this expression peaked at 12 h and declined after 24 h. The tendency of enhancement of the levels of cyclooxygenase-2 (COX-2) and PGE(2) was coincident with EMMPRIN expression. AT(1)-receptor antagonists and COX-2 inhibitors inhibited the effect of Ang II, but AT(2)-receptor antagonists did not.

Conclusion: Ang II can up-regulate EMMPRIN expression in THP-1 macrophages via the AT(1)/COX-2/PGE(2) signal transduction pathway, and the effect can be inhibited by losartan and NS-398.
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http://dx.doi.org/10.1007/s00011-010-0223-3DOI Listing
December 2010

Angiotensin II induces EMMPRIN expression in THP-1 macrophages via the NF-kappaB pathway.

Regul Pept 2010 Aug 6;163(1-3):88-95. Epub 2010 May 6.

Department of Cardiology, Kunming General Hospital of Chengdu Military Area, Yunnan 650032, China.

Background: Recent studies on atherosclerosis showed that an inducer of MMPs, EMMPRIN, is highly expressed in human atheromas. This suggested the important role of EMMPRIN in the stability of atherosclerotic plaques. Angiotensin II, one of the main functional peptides in the renin-angiotensin system, is involved in the advancement of atherosclerosis. We evaluated the effect of angiotensin II on EMMPRIN expression in THP-1 macrophages, and postulated the potential mechanisms underlying its effects.

Methods And Results: We established THP-1 macrophages using PMA. The effect of angII on EMMPRIN expression in THP-1 macrophages was then investigated. Results from analyses of RT-PCR and western blotting showed that angII could upregulate EMMPRIN expression. This was mediated via the AT1R, but not the AT2R. The NF-kappaB inhibitor PDTC and P65 RNAi treatment could suppress the effect of angII on EMMPRIN, suggesting the involvement of the NF-kappaB pathway. A gelatin zymography assay showed that MMP-9 activity was related to EMMPRIN expression.

Conclusion: AngII upregulates the expression of EMMPRIN. NF-kappaB is the critical factor involved in the upregulation of EMMPRIN induced by angII.
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http://dx.doi.org/10.1016/j.regpep.2010.04.012DOI Listing
August 2010

Inhibitor of DNA binding-1 promotes the migration and proliferation of endothelial progenitor cells in vitro.

Mol Cell Biochem 2010 Feb 22;335(1-2):19-27. Epub 2009 Aug 22.

Department of Cardiology, Institute of Cardiovascular Science of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, People's Republic of China.

Migration and proliferation of endothelial progenitor cells (EPCs) are the key mechanisms in re-endothelialization after vascular injury. Inhibitor of DNA binding-1 (Id1) function has been linked to the proliferation, migration, and senescence of cells, and studies have shed light on the relationship between Id1 and the biological functions of EPCs. On the basis of the available data concerning Id1 and the behavior of EPCs, we hypothesized that Id1 was an important regulator in modulating the migration and proliferation of EPCs. Culture of spleen-derived EPCs was done as previously described. Id1 was presented at low levels in EPCs. Id1 was localized predominantly in the cytoplasm, and was rapidly upregulated by stimulation with serum and vascular endothelial growth factor. The migration and proliferation of EPCs were extensively improved by overexpression of adenovirus-mediated exogenous Id1 and inhibited by silencing of endogenous Id1 in EPCs. These results suggest that Id1 has a direct role in regulation of the migration and proliferation in EPCs.
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http://dx.doi.org/10.1007/s11010-009-0236-9DOI Listing
February 2010

A meprin inhibitor suppresses atherosclerotic plaque formation in ApoE-/- mice.

Atherosclerosis 2009 Nov 4;207(1):84-92. Epub 2009 May 4.

Department of Cardiology, No 2 Hospital Affiliated to Third Military Medical University, Xinqiao Hospital, Chongqing 400037, China.

Meprin is a member of the astacin family of zinc metalloendopeptidases. It is widely distributed in the body, and hydrolyzes and inactivates several endogenous vasoactive peptides, some of which could alter various functions of cells in the arterial wall. We assessed the influence of chronic meprin inhibition by daily administration of actinonin (5mg/kg body weight per day; i.p.) on the development of atherosclerotic changes in ApoE(-/-) mice. Mice were fed a high-fat (21% fat), cholesterol-rich (1% cholesterol) Western-type diet for 16 weeks starting at 10 weeks of age. At 20 weeks of age, randomly selected ApoE(-/-) mice were treated with Western-type diet chow pellets supplemented with commercially available actinonin (meprin-I group) for 6 weeks; the diet of control ApoE(-/-) mice was supplemented with saline (placebo group). There was no difference in body weight, hemodynamic data and serum lipids between the two groups at the end of the dietary period. Meprin-I treatment was found to elevate levels of natriuretic peptides (NPs) in plasma and the vascular wall by radioimmunoassay. Meprin-I treatment also decreased plaque volume and suppressed lipid deposition in carotid arteries. Meprin-I treatment reduced production of reactive oxygen species (ROS) and apoptosis (which are associated with atherosclerosis) in the vascular wall. In in vitro experiments, meprin-I treatment increased NP function on cell apoptosis, proliferation, and intracellular ROS generation in the THP-1 cell line and primary vascular smooth muscle cells (VSMC). These results suggest that the meprin inhibitor actinonin may have a protective role in atherosclerosis, and that meprin inhibition may be therapeutically useful in atherosclerosis prevention. Suppression of degradation in the arteries of endogenously released NPs (particularly atrial natriuretic peptide and brain natriuretic peptide), or other kinins known to have anti-atherosclerotic actions, may at least partially contribute to the inhibitory effects of meprin-I on atherosclerotic changes.
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http://dx.doi.org/10.1016/j.atherosclerosis.2009.04.036DOI Listing
November 2009

Role of TRPC1 and NF-kappaB in mediating angiotensin II-induced Ca2+ entry and endothelial hyperpermeability.

Peptides 2009 Jul 23;30(7):1368-73. Epub 2009 Apr 23.

Department of Cardiology, Kunming General Hospital of Chengdu Military Area, Yunnan 650032, China.

Endothelial dysfunction is associated with cardiovascular diseases. The Ca(2+) influx occurring via activation of plasmalemma Ca(2+) channels was shown to be critical in signaling the increase in endothelial permeability in response to a variety of permeability-increasing mediators. It has been reported that angiotensin II (AngII) could induce Ca(2+) signaling in some cells, and transient receptor potential canonical 1 (TRPC1) had an important role in this process. The objective of this study was to examine the mechanism of AngII-induced Ca(2+) entry and vascular endothelial hyperpermeability. Human umbilical vein endothelial cells (HUVECs) exposed to AngII exhibited dose-dependent increase in [Ca(2+)]i and endothelial permeability. Quantitative real-time RT-PCR and Western blotting showed that the level of TRPC1 expression had increased significantly at 12h and at 24h after treatment of HUEVCs with AngII. The expression of p65 was suppressed using an RNAi strategy. The results showed that the NF-kappaB signaling pathway and type-1 receptor of AngII was involved in AngII-induced TRPC1 upregulation. Moreover, knockdown of TRPC1 and NF-kappaB expression attenuates AngII-induced [Ca(2+)]i and endothelial permeability. NF-kappaB and TRPC1 have critical roles in AngII-induced Ca(2+) entry and endothelial permeability.
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http://dx.doi.org/10.1016/j.peptides.2009.04.007DOI Listing
July 2009

[Association between plasma macrophage migration inhibitory factor concentration and coronary artery lesion severity.].

Zhonghua Xin Xue Guan Bing Za Zhi 2008 Oct;36(10):912-5

Department of Cardiology, Kunming General Hospital of Chengdu Military Area, Kunming 650032, China.

Objective: To investigate the relationship between the plasma macrophage migration inhibitory factor (MIF), activator protein-1 (AP-1) and MMP-9 concentrations and the severity of coronary artery lesions in coronary heart disease (CHD) patients.

Methods: Patients were divided into normal controls (n = 35), stable angina pectoris (SAP, n = 32) and acute coronary syndrome (ACS, n = 75) according to the coronary angiography (CAG), clinical and laboratory examinations. The CAG severity and extent of coronary lesions were analyzed by means of Gensini coronary score system. Enzyme linked immunosorent assay was used to measure the plasma MIF, AP-1 and MMP-9 concentrations.

Results: Plasma MIF, AP-1 and MMP-9 concentrations were significant increased in CHD patients [MIF: (14.97 +/- 2.11) microg/L, AP-1: 1.43 +/- 0.33, MMP-9: (1.48 +/- 0.14) microg/L] compared to those in control group [MIF: (9.07 +/- 1.28) microg/L, AP-1: 0.71 +/- 0.13, MMP-9: (1.01 +/- 0.07) microg/L, all P < 0.05]. The MIF, AP-1 and MMP-9 concentrations in ACS group [MIF: (16.66 +/- 2.56) microg/L, AP-1: 1.56 +/- 0.22, MMP-9: (1.58 +/- 0.14) microg/L] were also significant higher than those in SAP group [MIF: (11.01 +/- 2.12) microg/L, AP-1: 1.04 +/- 0.25, MMP-9: (1.25 +/- 0.07) microg/L, all P < 0.05] and there was significant positive correlation between MIF, AP-1 and MMP-9 concentrations and the Gensini score of coronary artery lesions (all P < 0.05). AP-1 was positively correlated with MMP-9 in CHD patients (P < 0.05).

Conclusions: Plasma MIF, AP-1 and MMP-9 concentrations were positively correlated to the severity of coronary lesions in CHD patients. Higher MIF, AP-1 and MMP-9 concentrations in ACS patients than in SAP patients might suggest higher plaque instability in ACS patients.
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October 2008

An essential role for stromal interaction molecule 1 in neointima formation following arterial injury.

Cardiovasc Res 2009 Mar 3;81(4):660-8. Epub 2008 Dec 3.

Department of Cardiology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, China.

Aims: There is evidence to suggest that stromal interaction molecule 1 (STIM1) functions as a Ca2+ sensor on the endoplasmic reticulum, leading to transduction of signals to the plasma membrane and opening of store-operated Ca2+ channels (SOC). SOC have been detected in vascular smooth muscle cells (VSMCs) and are thought to have an essential role in the regulation of contraction and cell proliferation. We hypothesized that knockdown of STIM1 inhibits VSMC proliferation and suppresses neointimal hyperplasia.

Methods And Results: We examined the effect of the knockdown of STIM1 using a rat balloon injury model and cultured rat aortic VSMCs. Interestingly, knockdown of rat STIM1 by adenovirus delivery of small interfering RNA (siRNA) significantly suppressed neointimal hyperplasia in a rat carotid artery balloon injury model at 14 days after injury. The re-expression of human STIM1 to smooth muscle reversed the effect of STIM1 knockdown on neointimal formation. Rat aortic VSMCs were used for the in vitro assays. Knockdown of endogenous STIM1 significantly inhibited proliferation and migration of VSMCs. Moreover, STIM1 knockdown induced cell-cycle arrest in G0/G1 and resulted in a marked decrease in SOC. Replenishment with recombinant human STIM1 reversed the effect of siRNA knockdown. These results suggest STIM1 has a critical role in neointimal formation in a rat model of vascular injury.

Conclusion: STIM1 may represent a novel therapeutic target in the prevention of restenosis after vascular interventions.
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http://dx.doi.org/10.1093/cvr/cvn338DOI Listing
March 2009

New insights into the activation mechanism of store-operated calcium channels: roles of STIM and Orai.

J Zhejiang Univ Sci B 2008 Aug;9(8):591-601

Department of Cardiovascular, Xinqiao Hospital, University of the Third Military Medical, Chongqing 400037, China.

The activation of Ca2+ entry through store-operated channels by agonists that deplete Ca2+ from the endoplasmic reticulum (ER) is a ubiquitous signaling mechanism, the molecular basis of which has remained elusive for the past two decades. Store-operated Ca2+-release-activated Ca2+ (CRAC) channels constitute the sole pathway for Ca2+ entry following antigen-receptor engagement. In a set of breakthrough studies over the past two years, stromal interaction molecule 1 (STIM1, the ER Ca2+ sensor) and Orai1 (a pore-forming subunit of the CRAC channel) have been identified. Here we review these recent studies and the insights they provide into the mechanism of store-operated Ca2+ channels (SOCCs).
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http://dx.doi.org/10.1631/jzus.B0820042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2491688PMC
August 2008

Angiotensin II induces matrix metalloproteinase-9 expression via a nuclear factor-kappaB-dependent pathway in vascular smooth muscle cells.

Regul Pept 2008 Apr 5;147(1-3):37-44. Epub 2008 Jan 5.

Department of Cardiology, Kunming General Hospital of Chengdu Military Area, Yunnan, 650032, China.

Angiotensin II (AngII) is widely recognized as a critical regulator of the development of atherosclerosis. Matrix metalloproteinases (MMPs) are thought to participate in plaque destabilization through degradation of the extracellular matrix. In the present study, we investigated the potential mechanism of AngII-induced MMP-9 expression in vascular smooth muscle cells (VSMC). AngII upregulated the expression of MMP-9 significantly in VSMC obtained from rat aorta. RNAi-mediated knockdown of p65 and losartan, an inhibitor of AngII receptors subtype-1 (AT1), could abolish AngII-induced MMP-9 expression. In addition, AngII induced the NF-kappaB binding activity via AT1 and AT2 receptors in VSMC, and AngII-induced activation of NF-kappaB is not associated with significant downregulation of IkappaB. In summary, this study demonstrates that AngII stimulates NF-kappaB nuclear translocation in VSMC via AT1 and AT2. AngII increases the expression of MMP-9 in VSMC, and AT1 and NF-kappaB pathways have an important role in this response.
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http://dx.doi.org/10.1016/j.regpep.2007.12.005DOI Listing
April 2008

[Association between murine double minute 2 expression and AngII and ceramide induced endothelial cells apoptosis].

Zhonghua Xin Xue Guan Bing Za Zhi 2007 Oct;35(10):945-8

Department of Cardiology, Kunming General Hospital of Chengdu Army, Kunming 650032, China.

Objective: To observe the relationship between murine double minute 2 (mdm2) expression and AngII and ceramide induced human umbilical endothelial cells apoptosis.

Method: Human umbilical endothelial cells (ECs) were cultured in vitro and treated with angiotensin II alone or in combination with losartan (an inhibitor of AT1), PD123319 (an inhibitor of AT2) and FB1 (an inhibitor of ceramidase) respectively. ECs were also treated with different doses of C2-ceramide. The apoptosis of ECs was detected with Tunel, the mdm2 mRNA and protein expressions were measured with reverse transcription-polymerase chain reaction (RT-PCR) and Western blot.

Results: PD123319 and FB1 but not losartan inhibited AngII induced ECs apoptosis and down-regulated the AngII induced increased mdm2 expressions. C2-ceramide also induces ECs apoptosis and down-regulated mdm2 expressions at protein and mRNA levels in a dose-dependent manner.

Conclusions: AngII binding with AT2 induces ECs apoptosis via ceramide. AngII and ceramide induce EC apoptosis by inhibiting mdm2.
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October 2007

Angiotensin II induces NF-kappa B activation in HUVEC via the p38MAPK pathway.

Peptides 2006 Dec 9;27(12):3269-75. Epub 2006 Nov 9.

Department of Cardiology, Kunming General Hospital of Chengdu Military Area, Yunnan 650032, China.

Angiotensin II (Ang II) is the main active peptide of the renin-angiotensin system (RAS), producing a number of inflammatory mediators that lead to endothelial dysfunction and the progression of atherosclerosis. Ang II-induced NF-kappaB nuclear translocation plays a pivotal role in this response. This study examines the NF-kappaB activation mechanism elicited by Ang II in human umbilical vein endothelial cells (HUVEC). Electrophoretic mobility shift assays and Western blotting revealed that Ang II, signaling via AT(1), produces a time-dependent increase in NF-kappaB DNA binding and IkappaBalpha degradation. These results also demonstrate that Ang II leads to MAPK phosphorylation and p38MAPK pathway-induced NF-kappaB activation. Furthermore, AT(1) is required for p38MAPK phosphorylation induced by Ang II. This study provides evidence that Ang II elicits NF-kappaB activation via the p38MAPK pathway in HUVEC.
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http://dx.doi.org/10.1016/j.peptides.2006.08.014DOI Listing
December 2006

[Angiotensin II up-regulates expression of inducible nitric oxide synthase in human umbilical endothelial cells: roles of AT1 and AT2].

Zhonghua Xin Xue Guan Bing Za Zhi 2006 Jul;34(7):647-50

Department of Cardiology, Kunming General Hospital of Chengdu Army, Kunming 650032, China.

Objective: Angiotensin II is an important pro inflammation factor in the cardiovascular system. This experiment is aimed to study the effects of angiotensin II on inducible nitric oxide synthase expression in human umbilical endothelial cells.

Methods: Human umbilical endothelial cells were cultured in vitro and treated with angiotensin II alone or in combination with AT1, AT2 and NF-kappaB inhibitors respectively. The inducible nitric oxide synthase expressions at protein and mRNA levels were measured with Western blot and reverse transcription-polymerase chain reaction (RT-PCR), and the activity of NF-kappaB was analyzed with EMSA.

Results: Angiotensin II up-regulated inducible nitric oxide synthase expressions at the protein and mRNA levels at 5 h (P < 0.05), the activity of NF-kappaB was enhanced at 2 h (P < 0.05). These effects could be blocked by AT1 and NF-kappaB inhibitors but not by AT2 inhibitor.

Conclusion: Angiotensin II can upregulate the expression of inducible nitric oxide synthase through NF-kappaB pathway in human umbilical endothelial cells. AT1, other than AT2, play a key role in this process.
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July 2006
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