Publications by authors named "Zhouqing Huang"

35 Publications

Berberine Regulated miR150-5p to Inhibit P2X7 Receptor, EMMPRIN and MMP-9 Expression in oxLDL Induced Macrophages.

Front Pharmacol 2021 20;12:639558. Epub 2021 Apr 20.

Department of Pathology, The First Affiliated Hospital of WenZhou Medical University, Wenzhou, China.

Elevated extracellular matrix metalloproteinase inducer (EMMPRIN) and matrix metalloproteinase-9 (MMP-9) in oxidized low density lipoprotein (oxLDL)-induced macrophages leads to the progression of vulnerable plaques by degradation of the extracellular matrix. Our previous report showed that berberine regulates the expression of both EMMPRIN and MMP-9. In addition, P2X7 receptor (P2X7R) upregulation plays a crucial role in the development of atherosclerosis. However, it is unclear whether berberine regulated P2X7R level to inhibit both EMMPRIN and MMP-9 expession in macrophages. In the present study, we investigated the impact of berberine on P2X7R expression and the regulation of P2X7R in the expression of EMMPRIN and MMP-9 in oxLDL-induced macrophages. We found that P2X7R expression was increased, miR150-5p was reduced in oxLDL-induced macrophages, relatively. And A-438079 (a P2X7R inhibitor) or miR150-5p mimic treatment greatly reversed the upregulation of EMMPRIN and MMP-9 expression. Moreover, A-438079 significantly reduced oxLDL-induced AMP-activated protein kinase-α (AMPK-α) phosphorylation and reversed the activation of mitogen-activated protein kinase (MAPK), which in turn decreased the expression of EMMPRIN and MMP-9. These findings illustrate that P2X7R suppresses EMMPRIN and MMP-9 expression by inhibiting the AMPK-α/MAPK pathway in oxLDL-induced macrophages. Accordingly, exposure to berberine markedly upregulated miR150-5p, decreased P2X7R expression and downregulated MMP-9 and EMMPRIN levels in oxLDL-induced macrophages, resulting in AMPK-α/MAPK (JNK, p38, and ERK) inactivation. Overall, these results indicate that berberine increased miR150-5p level, subsequently inhibits P2X7R-mediated EMMPRIN and MMP-9 expression by suppressing AMPK-α and MAPK signaling in oxLDL-induced macrophages.
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http://dx.doi.org/10.3389/fphar.2021.639558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093865PMC
April 2021

Evaluation of the Criteria to Distinguish Left Bundle Branch Pacing From Left Ventricular Septal Pacing.

JACC Clin Electrophysiol 2021 Apr 22. Epub 2021 Apr 22.

Department of Cardiology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; The Key Lab of Cardiovascular Disease, Science and Technology of Wenzhou, Wenzhou, China. Electronic address:

Objectives: This study sought to assess the predictive value of the proposed electrocardiogram and intracardiac electrogram characteristics for confirmation of left bundle branch (LBB) capture.

Background: Previously proposed criteria to distinguish left bundle branch pacing (LBBP) and left ventricular septum (LVS) pacing (LVSP) have not been fully validated.

Methods: A His bundle pacing lead, an LBBP lead, and a multielectrode catheter at the LVS were placed. Direct LBB capture was defined as demonstration of retrograde His potential on the His bundle pacing lead and/or anterograde left conduction system potentials on the multielectrode catheter during LBBP. The routinely used parameters-His, LBB potential, time from stimulus to left ventricular activation (Stim-LVAT), and paced QRS morphology during LVSP and LBBP at various depths and outputs were analyzed.

Results: Thirty patients (21 non-left bundle branch block [LBBB], 9 LBBB) who demonstrated direct LBB capture using the defined criteria were included. The proportion of paced right bundle branch block was 100% during LBB capture in all patients compared to 23.4% in non-LBBB and 44.4% in LBBB during LVSP. LBB potential was recorded in all patients during intrinsic rhythm (non-LBBB group) or His corrective pacing in LBBB. Paced QRS duration was longer during selective LBBP compared to nonselective LBBP or LVSP only. All patients with characteristics of selective LBBP or abrupt decrease in Stim-LVAT of ≥10 ms demonstrated LBB capture.

Conclusions: Direct LBB capture can be confirmed by recording retrograde His potential and anterograde left conduction system potentials. Abrupt decrease in Stim-LVAT of ≥10 ms and demonstration of selective LBBP could be used as simple criteria to confirm LBB capture.
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http://dx.doi.org/10.1016/j.jacep.2021.02.018DOI Listing
April 2021

Long-Term Safety and Feasibility of Left Bundle Branch Pacing in a Large Single-Center Study.

Circ Arrhythm Electrophysiol 2021 Feb 9;14(2):e009261. Epub 2021 Jan 9.

Department of Cardiology, the First Affiliated Hospital of Wenzhou Medical University, China (L.S., S. Wang, S. Wu, L.X., Z.H., X.C., R.Z., L.J., W.H.).

Background: Left bundle branch pacing (LBBP) is a novel pacing method and has been observed to have low and stable pacing thresholds in prior small short-term studies. The objective of this study was to evaluate the feasibility and safety of LBBP in a large consecutive diverse group of patients with long-term follow-up.

Methods: This study prospectively enrolled 632 consecutive pacemaker patients with attempted LBBP from April 2017 to July 2019. Pacing parameters, complications, ECG, and echocardiographic measurements were assessed at implant and during follow-up of 1, 6, 12, and 24 months.

Results: LBBP was successful in 618/632 (97.8%) patients according to strict criteria for LBB capture. Mean follow-up time was 18.6±6.7 months. Two hundred thirty-one patients had follow-up over 2 years. LBB capture threshold at implant was 0.65±0.27 mV at 0.5 ms and 0.69±0.24 mV at 0.5 ms at 2-year follow-up. A significant decrease in QRS duration was observed in patients with left bundle branch block (167.22±18.99 versus 124.02±24.15 ms, <0.001). Postimplantation left ventricular ejection fraction improved in patients with QRS≥120 ms (48.82±17.78% versus 58.12±13.04%, <0.001). The number of patients with moderate and severe tricuspid regurgitation decreased at 1 year. Permanent right bundle branch injury occurred in 55 (8.9%) patients. LBB capture threshold increased to >3 V or loss of bundle capture in 6 patients (1%), 2 patients of them had a loss of conduction system capture. Two patients required lead revision due to dislodgement.

Conclusions: This large observational study suggests that LBBP is feasible with high success rates and low complication rates during long-term follow-up. Therefore, LBBP appears to be a reliable method for physiological pacing for patients with either a bradycardia or heart failure pacing indication.
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http://dx.doi.org/10.1161/CIRCEP.120.009261DOI Listing
February 2021

Suppression of Netrin-1 attenuates angiotension II-induced cardiac remodeling through the PKC/MAPK signaling pathway.

Biomed Pharmacother 2020 Oct 17;130:110495. Epub 2020 Jul 17.

The Key Laboratory of Cardiovascular Disease of Wenzhou, Department of Cardiology, The First Affiliated Hospital of WenZhou Medical University, WenZhou, ZheJiang, China. Electronic address:

Background: Myocardial remodeling caused by angiotensin II (Ang II) is essential for the pathological process of heart failure. Netrin-1, which is an axonal guidance cue, has been shown to be involved in the inflammatory response, tumorigenesis, and angiogenesis in non-neuronal tissues. However, the role of Netrin-1 in cardiac remodeling has not been fully elucidated.

Methods: The rat cardiomyocyte cell line H9c2 and primary neonatal rat cardiomyocytes were treated with Ang II. Cells were transfected with siRNA to silence Netrin-1 expression. Real-time polymerase chain reaction and Western blot analysis were used to detect the markers for fibrosis, apoptosis, and hypertrophy in cardiomyocytes. An Annexin V-EGFP/PI cell apoptosis detection kit was used to measure the level of apoptosis caused by angiotensin II.

Results: We found that Netrin-1 expression was upregulated in the H9c2 cells and the neonatal rat cardiomyocytes stimulated by Ang II. The increased Netrin-1 expression was decreased by valsartan to block AT1R. Importantly, the application of Netrin-1 siRNA significantly alleviated the degrees of myocardial hypertrophy, fibrosis (reflected by Myhc, collagen I, and TGF-β) and apoptosis (reflected by the level of Caspase 3, Bax, and Bcl-2) induced by Ang II. In addition, the silencing of Netrin-1 substantially decreased the phosphorylation of PKCα, JNK, and P38. We treated H9c2 cells with LY317615, SP600125, and SB203580, inhibitors of PKCα, JNK, and P38, respectively, thereby resulting in a substantial decrease in hypertrophy, fibrosis, and apoptosis.

Conclusions: Ang II produces cardiac hypertrophy, fibrosis, and apoptosis through the upregulation of Netrin-1 and the activation of the AT1R/PKCα/MAPK (JNK, P38) pathway. Suppression of Netrin-1 can relieve Ang II-induced cardiac remodeling via inhibition of the PKCα/MAPK (JNK and P38) signaling pathway. Thus, Netrin-1 may be a novel therapeutic target for Ang II-mediated cardiac remodeling.
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http://dx.doi.org/10.1016/j.biopha.2020.110495DOI Listing
October 2020

Left Bundle Branch Pacing for Cardiac Resynchronization Therapy: Nonrandomized On-Treatment Comparison With His Bundle Pacing and Biventricular Pacing.

Can J Cardiol 2021 02 7;37(2):319-328. Epub 2020 May 7.

Department of Cardiology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; The Key Lab of Cardiovascular Disease of Wenzhou, Wenzhou, China. Electronic address:

Background: Left bundle branch pacing (LBBP) is a novel method for delivering cardiac resynchronization therapy (CRT). We compared on-treatment outcomes with His bundle pacing (HBP) and biventricular pacing (BVP) in this nonrandomized observational study.

Methods: Consecutive patients with left-ventricular ejection fraction (LVEF) ≤ 40% and typical left bundle branch block (LBBB) referred for CRT received BVP, HBP, or LBBP. QRS duration, pacing threshold, LVEF, and New York Heart Association (NYHA) class were assessed.

Results: One hundred thirty-seven patients were recruited: 49 HBP, 32 LBBP, and 54 BVP; 2 did not receive CRT. The majority of patients had nonischemic cardiomyopathy. Mean paced QRS duration was 100.7 ± 15.3 ms, 110.8 ± 11.1 ms, and 135.4 ± 20.2 ms during HBP, LBBP, and BVP, respectively. HBP and LBBP demonstrated a similar absolute increase (Δ) in LVEF (+23.9% vs +24%, P = 0.977) and rate of normalized final LVEF (74.4% vs 70.0%, P = 0.881) at 1-year follow-up. This was significantly higher than in the BVP group (Δ LVEF +16.7% and 44.9% rate of normalized final LVEF, P < 0.005). HBP and LBBP also demonstrated greater improvements in NYHA class compared with BVP. LBBP was associated with higher R-wave amplitude (11.2 ± 5.1 mV vs 3.8 ± 1.9 mV, P < 0.001) and lower pacing threshold (0.49 ± 0.13 V/0.5 ms vs 1.35 ± 0.73 V/0.5 ms, P < 0.001) compared with HBP.

Conclusion: LBBP appears to be a promising method for delivering CRT. We observed similar improvements in symptoms and LV function with LBBP and HBP. These improvements were significantly greater than those seen in patients treated with BVP in this nonrandomized study. These promising findings justify further investigation with randomized trials.
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http://dx.doi.org/10.1016/j.cjca.2020.04.037DOI Listing
February 2021

1,25(OH)D Strengthens the Vasculogenesis of Multipotent Mesenchymal Stromal Cells from Rat Bone Marrow by Regulating the PI3K/AKT Pathway.

Drug Des Devel Ther 2020 16;14:1157-1167. Epub 2020 Mar 16.

Department of Cardiology, The Key Lab of Cardiovascular Disease of Wenzhou, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, People's Republic of China.

Background: Multipotent mesenchymal stromal cells (MSCs) have recently been reported to promote vasculogenesis by differentiating into endothelial cells and releasing numerous cytokines and paracrine factors. However, due to low cell activity, their potential for clinical application is not very satisfactory. This study aimed to explore the effects and mechanisms of 1,25-dihydroxyvitamin D (1,25(OH)D) on the vasculogenesis of MSCs.

Methods: MSCs were isolated from the femurs and tibias of rats and characterized by flow cytometry. After treatment with different concentrations of 1,25(OH)D (0 µM, 0.1 µM and 1 µM), the proliferation of MSCs was analyzed by Cell Counting Kit-8 (CCK-8), and the migratory capability was measured by Transwell assays and cell scratch tests. Capillary-like structure formation was observed by using Matrigel. Western blotting was used to detect the expression of FLK-1 and vWF to investigate the differentiation of MSCs into endothelial cells. Western blotting and gelatin zymography were used to detect the expression and activities of VEGF, MMP-2 and MMP-9 secreted by MSCs under the influence of 1,25(OH)D Finally, the VDR antagonist pyridoxal-5-phosphate (P5P) and the PI3K/AKT pathway inhibitor LY294002 were utilized to test the phosphorylation levels of key kinases in the PI3K/AKT pathway by Western blotting and the formation of capillary-like structures in Matrigel.

Results: The proliferation and migratory capability of MSCs and the ability of MSCs to form a tube-like structure in Matrigel were enhanced after treatment with 1,25(OH)D. Moreover, MSCs treated with 1,25(OH)D showed high expression of vWF and Flk-1. There was a significant increase in the expression of VEGF, MMP-2 and MMP-9 secreted by MSCs treated with 1,25(OH)D as well as in the activity of MMP-2 and MMP-9. The phosphorylation level of AKT increased with time after 1,25(OH)D treatment, while LY294002 weakened AKT phosphorylation. In addition, the ability to form capillary-like structures was reduced when the VDR and PI3K/AKT pathways were blocked.

Conclusion: This study confirmed that 1,25(OH)D treatment can strengthen the ability of MSCs to promote vasculogenesis in vitro, and the mechanism may be related to the activation of the PI3K/AKT pathway.
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http://dx.doi.org/10.2147/DDDT.S222244DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7083642PMC
February 2021

ODYSSEY EAST: Alirocumab efficacy and safety vs ezetimibe in high cardiovascular risk patients with hypercholesterolemia and on maximally tolerated statin in China, India, and Thailand.

J Clin Lipidol 2020 Jan - Feb;14(1):98-108.e8. Epub 2019 Nov 18.

R&D, Sanofi, China.

Background: The proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab significantly reduces low-density lipoprotein cholesterol (LDL-C).

Objective: This study (ODYSSEY EAST) assessed the efficacy and safety of alirocumab vs ezetimibe in high cardiovascular risk patients from Asia.

Methods: Patients (n = 615) from China, India, and Thailand with hypercholesterolemia at high cardiovascular risk on maximally tolerated statin were randomized (2:1) to alirocumab (75 mg every 2 weeks [Q2W]; with dose increase to 150 mg Q2W at week 12 if week 8 LDL-C was >1.81 mmol/L [>70 mg/dL]) or ezetimibe (10 mg daily) for 24 weeks. The primary efficacy endpoint was percentage change in calculated LDL-C from baseline to week 24. Safety was assessed throughout.

Results: Baseline data were similar in both groups. LDL-C levels were reduced from baseline to week 24 by 56.0% and 20.3% in the alirocumab and ezetimibe groups, respectively (P < .0001 vs ezetimibe). Overall, 18.8% of alirocumab-treated patients received a dose increase to 150 mg Q2W. At week 24, 85.1% of alirocumab-treated and 40.5% of ezetimibe-treated patients reached LDL-C <1.81 mmol/L (<70 mg/dL, P < .0001 vs ezetimibe). Treatment-emergent adverse events occurred in 68.5% of alirocumab-treated and 63.1% of ezetimibe-treated patients, with upper respiratory tract infection the most common (alirocumab: 13.3%; ezetimibe: 14.1%). Injection-site reactions occurred more frequently in alirocumab-treated patients (2.7%) than in ezetimibe-treated patients (1.0%).

Conclusions: Alirocumab significantly reduced LDL-C vs ezetimibe in high cardiovascular risk patients from Asia and was generally well tolerated. These findings are consistent with previous ODYSSEY studies.
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http://dx.doi.org/10.1016/j.jacl.2019.10.015DOI Listing
June 2021

Relationship between plasma cancer antigen (CA)-125 level and one-year recurrence of atrial fibrillation after catheter ablation.

Clin Chim Acta 2020 Mar 20;502:201-206. Epub 2019 Nov 20.

The Key Laboratory of Cardiovascular Disease of Wenzhou, Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical University, Fuxue 2 Rd, Wenzhou, Zhejiang Province 325000, China. Electronic address:

Background: Previous studies have shown that plasma cancer antigen-125 (CA-125) is closely related to heart failure and new-onset atrial fibrillation (AF), but no study reported the relationship between CA-125 concentrations and advanced recurrence of AF ablation. This research is the first to describe CA-125 as a biomarker for the recurrence of AF after ablation.

Methods: A total of 422 AF patients undergoing catheter ablation were included in this study.

Results: During the 1-y follow-up, 326 patients (77.25%) maintained a sinus rhythm, whereas 83 patients (20.44%) presented AF recurrence. The patients with AF recurrence showed higher CA-125 concentrations at baseline than those with maintained sinus rhythm (P = 0.0001). Multivariate Cox proportional hazards regression analyses revealed that persistent AF (HR 2.212; 95% CI: 1.396-3.504, P = 0.001) and CA-125 concentration (HR, 1.003; 95% (CI): 1.000-1.005, P = 0.019) were independent predictors of AF recurrence. According to the receiver operating characteristic (ROC) analysis, CA-125 yielded an optimal cut-off value of 11.05 U/ml, and its sensitivity and specificity reached 65.6% and 85.0%, respectively. In addition, the area under the curve (AUC) value spanned 80.3% (95% CI: 0.750-0.857, P < 0.0001). Moreover, the results of the subgroup analysis indicated that patients with persistent atrial fibrillation have higher concentrations of CA-125 and have an increased risk of the recurrence of AF.

Conclusions: High CA-125 concentration is an independent predictor of AF recurrence after 1 y of AF ablation, especially in patients with persistent AF.
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http://dx.doi.org/10.1016/j.cca.2019.11.001DOI Listing
March 2020

Aerobic Exercise Ameliorates Myocardial Inflammation, Fibrosis and Apoptosis in High-Fat-Diet Rats by Inhibiting P2X7 Purinergic Receptors.

Front Physiol 2019 11;10:1286. Epub 2019 Oct 11.

Department of Physical Education, Wenzhou Medical University, Wenzhou, China.

Background: High-fat-diet (HFD) is associated with chronic low-grade inflammation. P2X7 purinergic receptors (P2X7R) are key regulators of inflammasome activation. The benefits of exercise are partly attributed to its anti-inflammatory effect, but whether it regulates P2X7R expression to improve remodeling in cardiac myocytes treated by HFD is not completely clarified.

Methods: Three groups of Sprague-Dawley (SD) rats were studied: (1) control group (fed a normal chow diet), (2) HFD group, and (3) HFD+ exercise group. H9c2 myocytes were pretreated with or without A438079 (a P2X7R inhibitor) and then exposed to 200 μM palmitic acid (PA) for 24 h. The levels of mRNA and protein were measured by real-time PCR and Western blot, respectively. Masson staining and hematoxylin-eosin (HE) staining were used to identify remodeling of the heart. The concentration of IL-1β in serum or supernatants were measured by ELISA.

Results: , collagen deposition and the number of disordered cells significantly increased in the hearts of the HFD group compared to the control group. However, exercise markedly reversed these changes in the myocardium, and the same trends were observed in the expression of MMP9, collagen I and TGF-β. Notably, the expression of P2X7R, NLRP3, caspase-1 in the hearts, and serum IL-1β level were also greatly upregulated in the heart of the HFD diet rats, and all these changes were ameliorated in the HFD + EX group. As expected, exercise also reduced the number of TUNEL-positive cells, which was consistent with the caspase-3, Bax, and Bcl-2 results. Moreover, exercise reduced body weight and blood lipid concentrations in the HFD diet rats. , we observed that the hallmark of fibrosis, inflammation and apoptosis in H9c2 myocytes enhanced by PA, and the P2X7R inhibitor treatment significantly reduced the expression of the NLRP3, caspase-1, suppressed the secretion of IL-1β of H9c2 cells, inhibited collagen I, TGF-β, MMP9, Bax, caspase-3 levels and increased the expression of Bcl-2, compared with the PA group. In addition, a decrease of the number of TUNEL-positive cells used by A438079 further support that cardiomyocytes apoptosis could be inhibited.

Conclusion: Aerobic exercise reversed the cardiac remodeling via the reduction of inflammation, fibrosis and apoptosis in HFD rats, at least in part through inhibiting P2X7R expression in cardiomyocytes.
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http://dx.doi.org/10.3389/fphys.2019.01286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6798156PMC
October 2019

Emodin alleviates myocardial ischemia/reperfusion injury by inhibiting gasdermin D-mediated pyroptosis in cardiomyocytes.

Drug Des Devel Ther 2019 25;13:975-990. Epub 2019 Mar 25.

Department of Cardiology, The Key Lab of Cardiovascular Disease of Wenzhou, The First Affiliated Hospital of WenZhou Medical University, WenZhou, ZheJiang, People's Republic of China,

Background: Emodin has recently been reported to have a powerful antiinflammatory effect, protecting the myocardium against ischemia/reperfusion (I/R) injury. Pyroptosis is a proinflammatory programmed cell death that is related to many diseases. The present study investigated the effect of emodin on pyroptosis in cardiomyocytes.

Materials And Methods: Sprague Dawley rats were randomly divided into sham, I/R, and I/R+Emodin groups. I/R model was subjected to 30 minutes' ligation of left anterior descending coronary artery, followed by 2 hours of reperfusion. Cardiomyocytes were exposed to hypoxic conditions for 1 hour and normoxic conditions for 2 hours. The level of the pyroptosis was detected by Western blot, real-time PCR analysis, and ELISA.

Results: The level of gasdermin D-N domains was upregulated in cardiomyocytes during I/R or hypoxia/reoxygenation (H/R) treatment. Moreover, emodin increased the rate of cell survival in vitro and decreased the myocardial infarct size in vivo via suppressing the levels of I/R-induced pyroptosis. Additionally, the expression of TLR4, MyD88, phospho-IκBα, phospho-NF-κB, and the NLRP3 inflammasome was significantly upregulated in cardiomyocytes subjected to H/R treatment, while emodin suppressed the expression of these proteins.

Conclusion: This study confirms that emodin treatment was able to alleviate myocardial I/R injury and inhibit pyroptosis in vivo and in vitro. The inhibitory effect of emodin on pyroptosis was mediated by suppressing the TLR4/MyD88/NF-κB/NLRP3 inflammasome pathway. Therefore, emodin may provide an alternative treatment for myocardial I/R injury.
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http://dx.doi.org/10.2147/DDDT.S195412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6438141PMC
September 2019

Pacing parameters and success rates of permanent His-bundle pacing in patients with narrow QRS: a single-centre experience.

Europace 2019 May;21(5):763-770

Department of Cardiology, The Heart Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.

Aims: High and unstable capture thresholds affect the success rate of permanent His-bundle pacing (HBP). We aimed to introduce the modified techniques during different periods and the corresponding success rate of HBP implantation.

Methods And Results: Patients from a single centre who had intrinsic QRS < 120 ms and HBP attempts were included in the study. The success rate and pacing parameters were described for three periods based on procedural modifications, i.e. Stage 1 using the conventional HBP procedure (August 2012 to May 2013), Stage 2 with addition of the dual-lead method (June 2013 to October 2014), and Stage 3 with the further addition of stability assessment during fixation (November 2014 to October 2016). The patients with successful permanent HBP were followed. A total of 310 patients were included with the average age of 70.3 ± 10.7 years. The success rate of acute HBP was 84.85%, 98.3%, and 99.20% during Stages 1-3, respectively (P < 0.001). The permanent HBP implantation rates increased from 77.3% during Stage 1 to 85.7% during Stage 2 and 89.6% during Stage 3 (P = 0.07). The acute His-bundle capture threshold reduced from 1.30 ± 0.7 V/0.5 ms during Stage 1 to 1.11 ± 0.6 V/0.5 ms during Stage 2 and further to 0.85 ± 0.51 V/0.5 ms during Stage 3 (P < 0.001). At the 12-month follow-up, the mean change in the HBP threshold decreased from 0.60 ± 0.59 V/0.5 ms during Stage 1 to 0.33 ± 0.39 V/0.5 ms during Stage 3 (P = 0.002).

Conclusion: The HBP implantation success rate, pacing threshold, and its stability during follow-up were improved by using the dual-lead method and stability assessment techniques.
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http://dx.doi.org/10.1093/europace/euy281DOI Listing
May 2019

P2X7 receptor regulates EMMPRIN and MMP‑9 expression through AMPK/MAPK signaling in PMA‑induced macrophages.

Mol Med Rep 2018 Sep 16;18(3):3027-3033. Epub 2018 Jul 16.

The Key Laboratory of Cardiovascular Disease of Wenzhou, Department of Cardiology, Cardiac Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China.

The rupture of atherosclerotic plaques may result in the formation of thrombi, which may induce subsequent cardiac events such as acute myocardial infarction. Overproduction of matrix metalloproteinases (MMPs) and extracellular matrix metalloproteinase inducers (EMMPRINs) by monocytes and macrophages may lead to rupture of atherosclerotic plaques as a result of the degradation of the extracellular matrix. The purinergic 2X7 receptor (P2X7R) is expressed in macrophages that are assembled in atherosclerotic lesions of human carotid arteries. P2X7R may serve a crucial role in the development of atherosclerosis; therefore, the present study aimed to determine whether P2X7R regulated the expression of EMMPRIN and MMP‑9 in phorbol 12‑myristate 13‑acetate (PMA)‑induced macrophages. In addition, the potential molecular mechanisms involved in this process were investigated. THP‑1 human monocytic cells were pretreated with A‑438079 (a specific inhibitor of P2X7R) for 1 h and subsequently incubated with or without PMA for 48 h. Exposure to A‑438079 significantly decreased the expression of MMP‑9 and EMMPRIN in the PMA‑induced macrophages and attenuated the activation (phosphorylation) of mitogen‑activated protein kinase (MAPK) signaling, including c‑Jun N‑terminal kinase, p38 and extracellular signal‑regulated kinase. The present study also demonstrated that 5'‑AMP‑activated protein kinase (AMPK) was activated by PMA exposure during differentiation from monocytes to macrophages. This activation was reversed by A‑438079 treatment through the inhibition of P2X7R expression. These results suggested that the inhibition of P2X7R may be able to suppress the AMPK/MAPK signaling pathway and consequently downregulate both EMMPRIN and MMP‑9 expression in PMA‑induced macrophages.
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http://dx.doi.org/10.3892/mmr.2018.9282DOI Listing
September 2018

Inhibition of LncRNA-HRIM Increases Cell Viability by Regulating Autophagy Levels During Hypoxia/Reoxygenation in Myocytes.

Cell Physiol Biochem 2018 18;46(4):1341-1351. Epub 2018 Apr 18.

Backgrund/Aims: Ischemia reperfusion (I/R) promotes the severity of cardiomyocyte injury. Long noncoding RNAs (LncRNAs) are key regulators in cardiovascular diseases. However, the association between LncRNAs and myocardial I/R injury has not been thoroughly characterized to date. We attempted to clarify the potential biological role of a LncRNA (E230034O05Rik), which we named hypoxia/reoxygenation (H/R) injury-related factor in myocytes (HRIM), by investigating the differential expression of LncRNAs between groups of myocytes exposed to either a normal level of oxygen or to H/R.

Methods: Microarray analysis was used to determine analyze the global differential expression of LncRNAs in H9c2 myocytes exposed either to a normal level of oxygen or to H/R. Target LncRNA levels were further verified in vitro and ex vivo by real-time polymerase chain reaction (qPCR). Cell viability was analyzed using the Cell Counting Kit-8 assay. Autophagy levels were confirmed by Western blotting, transmission electron microscopy, and autophagic double-labeled (mRFP-GFP-LC3) adenovirus analyses.

Results: Gene expression profiling revealed that 797 LncRNAs and 1898 mRNAs were differentially expressed in the H/R group compared with the normal oxygen group. Among these LncRNAs and mRNAs, 6 upregulated LncRNAs and 2 downregulated LncRNAs in the H/R group were selected and further validated by qPCR in vitro and ex vivo. Additionally, LncRNA-HRIM was inhibited by specific siRNAs in H9c2 myocytes exposed to H/R. The inhibition of LncRNA-HRIM by siRNA prevented cell death by suppressing excessive autophagic activity in myocytes, This finding suggests a detrimental role of LncRNA-HRIM in the regulation of I/R injury.

Conclusions: LncRNAs are involved in H/R injury of H9c2 myocytes. Inhibition of LncRNA-HRIM increased cell viability by reducing autophagy in myocytes during H/R.
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http://dx.doi.org/10.1159/000489149DOI Listing
July 2018

Inhibition of hsa-miR-6086 protects human umbilical vein endothelial cells against TNFα-induced proliferation inhibition and apoptosis via CDH5.

Gene 2018 Jun 29;661:202-208. Epub 2018 Mar 29.

Department of Cardiology, the Key Lab of Cardiovascular Disease of Wenzhou, the First Affiliated Hospital of WenZhou Medical University, Wenzhou 325000, China. Electronic address:

MiRNAs are considered as a novel class of biomarkers or treatment targets for cardiovascular diseases. Hsa-miR-6086, a novel mi-RNA, was reported to be downregulated during the differentiation of human embryonic stem cells into endothelial cells (ECs). Interestingly, CDH5 (cadherin 5), encoding a classical cadherin of the cadherin superfamily, is a cellular marker of ECs and has been reported to be a target of hsa-miR-6086. However, the role of hsa-miR-6086 in ECs is virtually unknown. Herein, we report that hsa-miR-6086 was markedly induced by TNFα stimulation in human umbilical vein endothelial cells (HUVECs), whereas CDH5 expression was greatly reduced. Importantly, TNFα-induced suppression of CDH5 expression was largely prevented by inhibiting hsa-miR-6086, and hsa-miR-6086 mimic greatly decrease CDH5 expression in HUVECs, suggesting that the induction of hsa-miR-6086 is responsible for CDH5 downregulation by TNFα. In addition, restoration of CDH5 expression level by either inhibiting hsa-miR-6086 or exogenously expressing CDH5 cDNA that is not affected by hsa-miR-6086 protected HUVECs against TNFα-induced apoptosis and cell growth inhibition. Taken together, our study reveals that hsa-miR-6086 is induced by TNFα and mediates TNFα-induced HUVEC growth inhibition through downregulating CDH5 expression. Hence, hsa-miR-6086 might be a new target for treating TNFα-induced endothelial dysfunction.
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http://dx.doi.org/10.1016/j.gene.2018.03.091DOI Listing
June 2018

NACHT, LRR and PYD domains-containing protein 3 inflammasome is activated and inhibited by berberine via toll-like receptor 4/myeloid differentiation primary response gene 88/nuclear factor-κB pathway, in phorbol 12-myristate 13-acetate-induced macrophages.

Mol Med Rep 2018 Feb 29;17(2):2673-2680. Epub 2017 Nov 29.

Department of Cardiology, The Key Laboratory of Cardiovascular Disease of Wenzhou, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China.

The nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP-3) inflammasome has recently emerged as a pivotal regulator of chronic inflammation. The present study investigated the expression of NLRP3 inflammasome in phorbol 12-myristate 13-acetate (PMA)-induced macrophages, and aimed to identify the effects of berberine on the inflammasome. Human monocytic THP-1 cells were pretreated with berberine for 1 h and then induced with PMA for 48 h. Total RNA and protein were collected for reverse transcription-quantitative polymerase chain reaction and western blot analysis, respectively. Supernatants were collected to determine IL-1β levels by using ELISA. The present study demonstrated that NLRP3 inflammasome and IL-1β were activated in PMA-induced macrophages in a time-dependent manner, whereas berberine significantly inhibited their expression in a dose-dependent manner in PMA-induced macrophages. Furthermore, berberine also suppressed the toll-like receptor 4 (TLR4)/myeloid differentiation primary response gene 88 (Myd88)/nuclear factor (NF)-κB signaling pathway which was activated during the conversion of THP-1 cells to macrophages by PMA. In conclusion, berberine reduced NLRP3 inflammasone expression by suppressing the activation of the TLR4/Myd88/NF-κB signaling pathway in PMA-induced macrophages. This inhibitory effect may imply an important role of berberine on chronic inflammation and atherogenic progression in coronary artery disease.
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http://dx.doi.org/10.3892/mmr.2017.8189DOI Listing
February 2018

Inhibition of autophagy by berberine enhances the survival of H9C2 myocytes following hypoxia.

Mol Med Rep 2017 Aug 14;16(2):1677-1684. Epub 2017 Jun 14.

Cardiac Center, Department of Cardiology, The Key Laboratory of Cardiovascular Disease of Wenzhou, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China.

Hypoxia may induce apoptosis and autophagy to promote cardiomyocyte injury. The present study investigated the effect of berberine, a natural extract of Rhizoma Coptidis, on hypoxia‑induced autophagy and apoptosis in the H9c2 rat myocardial cell line. Expression levels of apoptosis and autophagy markers were upregulated in H9c2 myocytes during hypoxia and cell viability was reduced. However, berberine significantly reduced hypoxia‑induced autophagy in H9c2 myocytes, as demonstrated by the ratio of microtubule‑associated proteins 1A/1B light chain 3 I/II and the expression levels of B‑cell lymphoma 2 (Bcl‑2)/adenovirus E1B 19 kDa protein‑interacting protein 3, and promoted cell viability. In addition, expression levels of the Bcl‑2 anti‑apoptotic protein were significantly downregulated, and expression levels of pro‑apoptotic proteins Bcl‑2‑associated X protein and cleaved caspase‑3 were upregulated during hypoxia injury in cardiac myocytes. This was reversed by treatment with berberine or the autophagy inhibitor 3‑methyladenine, whereas the autophagy agonist rapamycin had the opposite effects, suggesting that berberine reduces myocyte cell death via inhibition of autophagy and apoptosis during hypoxia. In addition, Compound C, a 5' adenosine monophosphate‑activated protein kinase (AMPK) inhibitor, reduced apoptosis and autophagy in hypoxic myocytes, suggesting that the activation of the AMPK signaling pathway may be involved in this process. These findings suggested that berberine protects cells from hypoxia‑induced apoptosis via inhibition of autophagy and suppression of AMPK activation. Therefore, berberine may be a potential therapeutic agent for the treatment of patients with cardiac myocyte injury and ischemia.
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http://dx.doi.org/10.3892/mmr.2017.6770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5562068PMC
August 2017

Inhibition of epidermal growth factor receptor attenuates atherosclerosis via decreasing inflammation and oxidative stress.

Sci Rep 2017 04 4;8:45917. Epub 2017 Apr 4.

Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.

Atherosclerosis is a progressive disease leading to loss of vascular homeostasis and entails fibrosis, macrophage foam cell formation, and smooth muscle cell proliferation. Recent studies have reported that epidermal growth factor receptor (EGFR) is involved vascular pathophysiology and in the regulation of oxidative stress in macrophages. Although, oxidative stress and inflammation play a critical role in the development of atherosclerosis, the underlying mechanisms are complex and not completely understood. In the present study, we have elucidated the role of EGFR in high-fat diet-induced atherosclerosis in apolipoprotein E null mice. We show increased EGFR phosphorylation and activity in atherosclerotic lesion development. EGFR inhibition prevented oxidative stress, macrophage infiltration, induction of pro-inflammatory cytokines, and SMC proliferation within the lesions. We further show that EGFR is activated through toll-like receptor 4. Disruption of toll-like receptor 4 or the EGFR pathway led to reduced inflammatory activity and foam cell formation. These studies provide evidence that EGFR plays a key role on the pathogenesis of atherosclerosis, and suggests that EGFR may be a potential therapeutic target in the prevention of atherosclerosis development.
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http://dx.doi.org/10.1038/srep45917DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5379239PMC
April 2017

Curcumin Alleviates oxLDL Induced MMP-9 and EMMPRIN Expression through the Inhibition of NF-κB and MAPK Pathways in Macrophages.

Front Pharmacol 2017 14;8:62. Epub 2017 Feb 14.

Division of Cardiology, The Key Lab of Cardiovascular Disease of Wenzhou, The First Affiliated Hospital of WenZhou Medical University WenZhou, China.

Rupture of vulnerable atherosclerotic plaques is the leading cause of acute myocardial infarction (AMI) and unstable angina pectoris (UA). However, it still lacks an effective therapy to stabilize the vulnerable atherosclerotic plaques. Numerous reports have shown that upregulation of MMP-9 (matrix metalloproteinase-9) and EMMPRIN (extracellular matrix metalloproteinase inducer) in macrophages is involved in the progression and development of vulnerable plaques. Here we evaluated the impact of curcumin on the expression of MMP-9 and EMMPRIN in macrophages. Macrophages were pretreated with curcumin or specific inhibitors (p38 MAPK inhibitor, NF-κB p65 inhibitor) for 1 h, then cells were cultured with oxLDL for indicated time. Real-time PCR and Western blot analysis were used to evaluate the expression of mRNA and proteins. Translocation of NF-κB p65 was detected by using laser confocal microscopy. Here we showed that curcumin attenuated the MMP-9 and EMMPRIN expression in oxLDL stimulated macrophages. Further studies revealed that curcumin inhibited oxLDL induced NF-κB activation and p38 MAPK phosphorylation. These findings illustrated that curcumin can inhibit the expression of EMMPRIN and MMP-9 in oxLDL stimulated macrophages through down regulation of NF-κB and p38 MAPK signaling pathways, which might be the molecular mechanism for the anti-atherosclerotic effect of curcumin.
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http://dx.doi.org/10.3389/fphar.2017.00062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5306337PMC
February 2017

Curcumin Represses NLRP3 Inflammasome Activation via TLR4/MyD88/NF-κB and P2X7R Signaling in PMA-Induced Macrophages.

Front Pharmacol 2016 10;7:369. Epub 2016 Oct 10.

The Key Lab of Cardiovascular Disease of Wenzhou, Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical University Wenzhou, China.

In the NOD-like receptor (NLR) family, the pyrin domain containing 3 (NLRP3) inflammasome is closely related to the progression of atherosclerosis. This study aimed to assess the effects of curcumin on NLRP3 inflammasome in phorbol 12-myristate 13-acetate (PMA)-induced macrophages and explore its underlying mechanism. Human monocytic THP-1 cells were pretreated with curcumin for 1 h and subsequently induced with PMA for 48 h. Total protein was collected for Western blot analysis. Cytokine interleukin (IL)-1β release and nuclear factor kappa B (NF-κB) p65 translocation were detected by ELISA assay and cellular NF-κB translocation kit, respectively. Curcumin significantly reduced the expression of NLRP3 and cleavage of caspase-1 and IL-1β secretion in PMA-induced macrophages. Moreover, Bay (a NF-κB inhibitor) treatment considerably suppressed the expression of NLRP3 inflammasome in PMA-induced THP-1 cells. Curcumin also markedly inhibited the upregulation of toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), phosphorylation level of IκB-α, and activation of NF-κB in PMA-induced macrophages. In addition, purinergic 2X7 receptor (P2X7R) siRNA was administered, and it significantly decreased NLRP3 inflammasome expression in PMA-induced macrophages. Furthermore, curcumin reversed PMA-stimulated P2X7R activation, which further reduced the expression of NLRP3 and cleavage of caspase-1 and IL-1β secretion. Silencing of P2X7R using siRNA also suppressed the activation of NF-κB pathway in PMA-induced macrophages, but P2X7R-silenced cells did not significantly decrease the expression of TLR4 and MyD88. Curcumin inhibited NLRP3 inflammasome through suppressing TLR4/MyD88/NF-κB and P2X7R pathways in PMA-induced macrophages.
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http://dx.doi.org/10.3389/fphar.2016.00369DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5056188PMC
October 2016

MicroRNA-21 protects against cardiac hypoxia/reoxygenation injury by inhibiting excessive autophagy in H9c2 cells via the Akt/mTOR pathway.

J Cell Mol Med 2017 03 29;21(3):467-474. Epub 2016 Sep 29.

Department of Cardiology, The Key Lab of Cardiovascular Disease of Wenzhou, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.

MicroRNAs and autophagy play critical roles in cardiac hypoxia/reoxygenation (H/R)-induced injury. Here, we investigated the function of miR-21 in regulating autophagy and identified the potential molecular mechanisms involved. To determine the role of miR-21 in regulating autophagy, H9c2 cells were divided into the following six groups: control group, H/R group, (miR-21+ H/R) group, (miR-21-negative control + H/R) group, (BEZ235+ H/R) group and (miR-21+ BEZ235+ H/R) group. The cells underwent hypoxia for 1 hr and reoxygenation for 3 hrs. Cell count kit-8 was used to evaluate cell function and apoptosis was analysed by Western blotting. Western blotting and transmission electron microscopy were used to investigate autophagy. We found that miR-21 expression was down-regulated, and autophagy was remarkably increased in H9c2 cells during H/R injury. Overexpression of miR-21 with a miR-21 precursor significantly inhibited autophagic activity and decreased apoptosis, accompanied by the activation of the AKT/mTOR pathway. In addition, treatment with BEZ235, a novel dual Akt/mTOR inhibitor, resulted in a significant increase in autophagy and apoptosis. However, we found that miR-21-mediated inhibition of apoptosis and autophagy was partly independent of Akt/mTOR activation, as demonstrated in cells treated with both miR-21 and BEZ235. We showed that miR-21 could inhibit H/R-induced autophagy and apoptosis, which may be at least partially mediated by the Akt/mTOR signalling pathway.
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http://dx.doi.org/10.1111/jcmm.12990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5323864PMC
March 2017

Combined Treatment with Amlodipine and Atorvastatin Calcium Reduces Circulating Levels of Intercellular Adhesion Molecule-1 and Tumor Necrosis Factor-α in Hypertensive Patients with Prediabetes.

Front Aging Neurosci 2016 25;8:206. Epub 2016 Aug 25.

The Key Laboratory of Cardiovascular Disease of Wenzhou, Department of Cardiology, The First Affiliated Hospital of WenZhou Medical University WenZhou, ZheJiang, China.

Objective: To assess the effect of amlodipine and atorvastatin on intercellular adhesion molecule (ICAM)-1 and tumor necrosis factor (TNF)-α expression, as endothelial function and inflammation indicators, respectively, in hypertensive patients with and without prediabetes.

Methods: Forty-five consecutive patients with hypertension, diagnosed according to JNC7, were divided into two groups based on the presence (HD group, n = 23) or absence (H group, n = 22) of prediabetes, diagnosed according to 2010 ADA criteria, including impaired glucose tolerance (IGT) and fasting glucose tests. All patients simultaneously underwent 12-week treatment with daily single-pill amlodipine besylate/atorvastatin calcium combination (5/10 mg; Hisun-Pfizer Pharmaceuticals Co. Ltd). Serum isolated before and after treatment from overnight fasting blood samples was analyzed by ELISA.

Results: In the HD and H groups after vs. before 12-week amlodipine/atorvastatin treatment, there were significantly (all P < 0.01) lower levels of ICAM-1 (3.06 ± 0.34 vs. 4.07 ± 0.70 pg/ml; 3.26 ± 0.32 vs. 3.81 ± 0.60 pg/ml, respectively) and TNF-α (78.71 ± 9.19 vs. 110.94 ± 10.71 pg/ml; 80.95 ± 9.33 vs. 101.79 ± 11.72 pg/ml, respectively), with more pronounced reductions in HD vs. H group (ICAM-1Δ: 1.01 ± 0.80 vs. 0.55 ± 0.64 pg/ml, respectively, P = 0.037; TNF-αΔ: 32.23 ± 14.33 vs. 20.84 ± 14.89 pg/ml, respectively, P = 0.011), independent of the blood pressure (BP) and cholesterol level reduction.

Conclusions: Amlodipine/atorvastatin improved endothelial function and inflammation, as reflected by lower circulating levels of ICAM-1 and TNF-α, more prominently in hypertensives with than without prediabetes. Starting statin treatment before overt diabetes in hypertensives might thus improve cardiovascular outcomes.
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http://dx.doi.org/10.3389/fnagi.2016.00206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4996984PMC
September 2016

Atorvastatin suppresses NLRP3 inflammasome activation via TLR4/MyD88/NF-κB signaling in PMA-stimulated THP-1 monocytes.

Biomed Pharmacother 2016 Aug 9;82:167-72. Epub 2016 May 9.

Department of Cardiology, The Key Lab of Cardiovascular disease of Wenzhou, The First Affiliated Hospital of Wenzhou Medical University, 2 Fuxue Road, Wenzhou, Zhejiang 325000, PR China. Electronic address:

Aims: Increasing evidence shows that NLRP3 inflammasome is closely associated with the progression of atherosclerosis. The purpose of the present study was to evaluate the effects of atorvastatin on NLRP3 inflammasome in PMA-stimulated THP-1 cells and explore its underlying mechanism.

Methods: Human monocytic THP-1 cells were pretreated with atorvastatin for 1h and then induced by PMA for 48h. Total protein was collected for real-time PCR and Western blot analysis. Cytokine IL-1β release was detected by ELISA assay. And the NF-κB p65 translocation was detected by cellular NF-κB translocation kit.

Results: It was shown that atorvastatin significantly reduced the expression of NLRP3, the cleavage of caspase-1 and IL-1β in PMA-induced THP-1 cells. Moreover, Bay (a NF-κB inhibitor) treatment greatly suppressed the expression of NLRP3, the cleavage of caspase-1 and IL-1β in PMA-induced THP-1 cells, suggesting that the activation of NF-κB pathway takes part in regulating the expression of NLRP3 inflammasome. In addition, atorvastatin markedly inhibited the up-regulation of toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88) and the activation of nuclear factor kappa b (NF-κB) in PMA-stimulated THP-1 cells.

Conclusions: Atorvastatin exerts an anti-inflammatory effect by inhibiting NLRP3 inflammasome through suppressing TLR4/MyD88/NF-κB pathway in PMA-induced THP-1 monocytes.
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http://dx.doi.org/10.1016/j.biopha.2016.04.043DOI Listing
August 2016

Relaxin Level in Patients With Atrial Fibrillation and Association with Heart Failure Occurrence: A STROBE Compliant Article.

Medicine (Baltimore) 2016 May;95(21):e3664

From the Department of Cardiovascular Medicine, the First Affiliated Hospital of Wenzhou Medical University; The Key Lab of Cardiovascular Disease of Wenzhou, Wenzhou, China.

Atrial fibrillation (AF) is the most common arrhythmia requiring medical treatment and has been associated with enhanced atrial fibrosis and heart failure (HF). Relaxin (RLX), an antifibrosis and antiinflammatory peptide hormone, may be used to evaluate atrial fibrosis and is associated with HF occurrence in AF. We aimed to clarify the clinical significance of RLX level in patients with AF.We measured circulating levels of RLX and other fibrosis-related factors in 311 patients with sinus rhythm (SR; n = 116) or AF (n = 195). All discharged AF patients were followed up for the occurrence of HF for a mean of 6 months.Circulating levels of RLX were significantly different in patients with AF as compared with SR (P < 0.001), and in the subgroup analysis of AF. RLX level was correlated with left atrial diameter (LAD; R = 0.358, P < 0.001). Among followed up AF patients, on Kaplan-Meier curve analysis, patients with the third RLX tertile (T3) had a significantly higher HF rate than those with the 1st tertile (T1) (P = 0.002) and the cut-off value was 294.8 ng/L (area under the ROC curve [AUC] = 0.723). On multivariable analysis, HF occurrence with AF was associated with increased tertile of serum RLX level (odds ratio [OR] 2.659; confidence interval [95% CI] 1.434-4.930; P = 0.002).RLX is associated with fibrosis-related biomarkers and significantly elevated in AF. RLX was related to the HF occurrence in patients with AF.
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http://dx.doi.org/10.1097/MD.0000000000003664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4902350PMC
May 2016

Serum Markers of Endothelial Dysfunction and Inflammation Increase in Hypertension with Prediabetes Mellitus.

Genet Test Mol Biomarkers 2016 Jun 11;20(6):322-7. Epub 2016 May 11.

Department of Cardiology, The Key Lab of Cardiovascular Disease of Wenzhou, The First Affiliated Hospital of Wenzhou Medical University , Wenzhou, P.R. China .

Aims: The aim of this study was to examine endothelial dysfunction and inflammation in hypertension and prediabetes by studying adhesion molecules and inflammatory factors.

Methods And Results: This study included 133 outpatients. Participants were categorized into three groups based on the presence or absence of hypertension and prediabetes: control subjects without prediabetes and hypertension (N group, n = 39); patients with hypertension only (H group, n = 34); and patients with hypertension and prediabetes (HD group, n = 60). Hypertension was diagnosed according to JNC7 criteria. Prediabetes was defined according to 2010 American Diabetes Association criteria. Plasma was isolated from overnight fasting blood samples for enzyme-linked immunosorbent assay (ELISA) analysis of concentrations of intercellular adhesion molecule-1 (ICAM-1), tumor necrosis factor-α (TNF-α), P-selectin, and interleukin-6 (IL-6) as indicators of endothelial function and inflammation. We found that the H and HD groups showed significantly higher levels of all four biomarkers compared with the N group (all p < 0.01). The HD group also showed significantly higher levels of ICAM-1 (p = 0.042) and TNF-α (p < 0.01) compared with the H group; no significant differences in P-selectin (p = 0.59) and IL-6 (p = 0.70) levels were observed among these groups.

Conclusions: Prediabetes and hypertension induce endothelial dysfunction and inflammation by elevating levels of soluble adhesion molecules and inflammatory cytokines. The comorbidity of these diseases may exacerbate inflammation and endothelial dysfunction by enhancing the expression of ICAM-1 and TNF-α.
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http://dx.doi.org/10.1089/gtmb.2015.0255DOI Listing
June 2016

Berberine alleviates cardiac ischemia/reperfusion injury by inhibiting excessive autophagy in cardiomyocytes.

Eur J Pharmacol 2015 Sep 21;762:1-10. Epub 2015 May 21.

Department of Cardiology, The key lab of cardiovascular disease of Wenzhou, The First Affiliated Hospital of WenZhou Medical University, 2 Fuxue Road, WenZhou, ZheJiang 325000, PR China. Electronic address:

Ischemia/reperfusion (I/R)-induced autophagy increases the severity of cardiomyocyte injury. The aim of this study was to investigate the effects of berberine, a natural extract from Rhizoma coptidis, on the I/R-induced excessive autophagy in in vitro and in vivo models. Autophagy was increased both in H9c2 myocytes during hypoxia/reoxygenation (H/R) injury and in mouse hearts exposed to I/R. And the expression level of p-AMPK and p-mTORC2 (Ser2481) were increased during H/R period. In addition, the increased autophagy level was correlated with reduced cell survival in H9c2 myocytes and increased infarct size in mouse hearts. However, berberine treatment significantly enhanced the H/R-induced cell viability and reduced I/R-induced myocardial infarct size, which was accompanied by improved cardiac function. The beneficial effect of berberine is associated with inhibiting the cellular autophagy level, due to decreasing the expression level of autophagy-related proteins such as SIRT1, BNIP3, and Beclin-1. Furthermore, both the level of p-AMPK and p-mTORC2 (Ser2481) in H9c2 myocytes exposed to H/R were decreased by berberine. In summary, berberine protects myocytes during I/R injury through suppressing autophagy activation. Therefore, berberine may be a promising agent for treating I/R-induced cardiac myocyte injury.
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http://dx.doi.org/10.1016/j.ejphar.2015.05.028DOI Listing
September 2015

Curcumin inhibits autophagy and apoptosis in hypoxia/reoxygenation-induced myocytes.

Mol Med Rep 2015 Jun 9;11(6):4678-84. Epub 2015 Feb 9.

Department of Cardiology, The Key Laboratory of Cardiovascular Disease of Wenzhou, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China.

Primary percutaneous coronary intervention, or thombolytic therapy, provides effective myocardial blood reconstruction in patients with acute myocardial infarction to reduce acute myocardial ischemic injury. However, reperfusion can itself induce cardiomyocyte death, termed myocardial reperfusion injury (I/R). Hypoxia/reoxygenation (H/R) induces apoptosis and excessive autophagy among cardiomyocytes, leading to cell death. The present study investigated the effect of curcumin, a natural extract from Curcuma longa, on these two cellular processes in H9c2 myocytes. The levels of cellular apoptosis and autophagy were found to be upregulated in the H9c2 myocytes during H/R and were correlated with a reduced rate of cell survival. However, curcumin significantly suppressed the levels of H/R‑induced apoptosis (expression of annexin V) and autophagy (LC3B‑II/LC3B‑I ratio) in the H9c2 myocytes and promoted cell survival. Additionally, the expression of B‑cell lymphoma 2 (Bcl‑2) was significantly downregulated and the expression levels of Bcl‑2‑associated X protein, beclin‑1, Bcl‑2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3) and silent information regulation 1 (SIRT1) were significantly upregulated in myocytes following H/R injury. These effects on the expression of these proteins were reversed by curcumin treatment. These findings suggested that the protective effect of curcumin against H/R injury in the H9c2 myocytes was through the inhibition of apoptosis and autophagy by inducing the expression of Bcl‑2 and inhibiting the expression levels of Bax, beclin‑1, BNIP3 and SIRT1. Therefore, curcumin may offer a promising therapeutic approach for the treatment of cardiomyocyte injury resulting from I/R.
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http://dx.doi.org/10.3892/mmr.2015.3322DOI Listing
June 2015

Curcumin inhibits EMMPRIN and MMP-9 expression through AMPK-MAPK and PKC signaling in PMA induced macrophages.

J Transl Med 2014 Sep 21;12:266. Epub 2014 Sep 21.

In coronary arteries, plaque disruption, the major acute clinical manifestations of atherosclerosis, leads to a subsequent cardiac event, such as acute myocardial infarction (AMI) and unstable angina pectoris (UA). Numerous reports have shown that high expression of MMP-9 (matrix metalloproteinase-9), MMP-13 (matrix metalloproteinase-13) and EMMPRIN (extracellular matrix metalloproteinase induce) in monocyte/macrophage results in the plaque progression and destabilization. Curcumin exerts well-known anti-inflammatory and antioxidant effects and probably has a protective role in the atherosclerosis. The purpose of our study was to investigate the molecular mechanisms by which curcumin affects MMP-9, MMP13 and EMMPRIN in PMA (phorbol 12-myristate 13-acetate) induced macrophages. Human monocytic cells (THP-1 cells) were pretreated with curcumin or compound C for 1 h, and then induced by PMA for 48 h. Total RNA and proteins were collected for real-time PCR and Western blot analysis, respectively. In the present study, the exposure to curcumin resulted in attenuated JNK, p38, and ERK activation and decreased expression of MMP-9, MMP-13 and EMMPRIN in PMA induced macrophages. Moreover, we demonstrated that AMPK (AMP-activated protein kinase) and PKC (Protein Kinase C) was activated by PMA during monocyte/macrophage differentiation. Furthermore, curcumin reversed PMA stimulated PKC activation and suppressed the chronic activation of AMPK, which in turn reduced the expression of MMP-9, MMP-13 and EMMPRIN. Therefore, it is suggested that curcumin by inhibiting AMPK-MAPK (mitogen activated protein kinase) and PKC pathway may led to down-regulated EMMPRIN, MMP-9 and MMP-13 expression in PMA-induced THP-1 cells.
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http://dx.doi.org/10.1186/s12967-014-0266-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4205290PMC
September 2014

Berberine‑attenuated monocyte adhesion to endothelial cells induced by oxidized low‑density lipoprotein via inhibition of adhesion molecule expression.

Mol Med Rep 2013 Feb 14;7(2):461-5. Epub 2012 Dec 14.

Cardiac Center, The First Affiliated Hospital of Wenzhou Medical College, Zhejiang 325000, P.R. China.

Recruitment of monocytes to endothelial cells is important during early stages of atherosclerosis development. This process is predominantly mediated by cellular adhesion molecules, including vascular cell adhesion molecule‑1 (VCAM‑1) and intercellular adhesion molecule‑1 (ICAM‑1), which are expressed by activated endothelial cells in response to a number of inflammatory stimuli, including oxidized low‑density lipoprotein (oxLDL). Previous studies have demonstrated that berberine, a natural extract from Rhizoma coptidis, prevents oxLDL‑induced endothelial cellular apoptosis. However, its effect on the adhesion of monocytes to endothelial cells and the mechanism associated with this process remains unclear. In the present study, berberine was revealed to markedly reduce oxLDL‑induced monocyte adhesion to human umbilical vein endothelial cells. In addition, the inhibitory mechanism of berberine was associated with suppression of adhesion molecule expression, including VCAM‑1 and ICAM‑1. Results indicate that berberine plays a protective role in the early stages of atherosclerosis.
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http://dx.doi.org/10.3892/mmr.2012.1236DOI Listing
February 2013

A case of simultaneous anterior and inferior ST-segment elevation myocardial infarction due to isolated occlusion of a wrapped right posterior descending artery.

J Electrocardiol 2013 Jan-Feb;46(1):13-5. Epub 2012 Nov 17.

Department of Cardiology, The First Affiliated Hospital of Wenzhou Medical College, Wenzhou, China.

We present a case of a 72-year-old man with acute coronary syndrome due to isolated acute occlusion of a wrapped right posterior descending artery. Electrocardiogram showed simultaneous anterior and inferior ST-segment elevations. We discuss the causes of this exceptional electrocardiographic pattern.
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http://dx.doi.org/10.1016/j.jelectrocard.2012.10.005DOI Listing
August 2013

Berberine-induced inhibition of adipocyte enhancer-binding protein 1 attenuates oxidized low-density lipoprotein accumulation and foam cell formation in phorbol 12-myristate 13-acetate-induced macrophages.

Eur J Pharmacol 2012 Sep 13;690(1-3):164-9. Epub 2012 Jul 13.

Department of Cardiology of Cardiac Center, The First Affiliated Hospital of Wenzhou Medical College, 2 Fuxue Road, WenZhou, ZheJiang 325000, PR China.

The phagocytosis of oxidized low-density lipoprotein (oxLDL) by monocyte-derived macrophages and the subsequent differentiation of macrophages into foam cells are the key steps in atherogenesis. Scavenger receptors, such as CD36 and lectin-like low-density lipoprotein receptor 1 (LOX-1), are responsible for the uptake of oxLDL. Adipocyte enhancer-binding protein 1 (AEBP1) regulates many key genes associated with intracellular cholesterol efflux. The present study investigated the function of berberine, a compound isolated from Rhizoma coptidis, on foam cell formation, and explored the possible underlying mechanism. We found that berberine inhibited the oxLDL uptake of macrophages and reduced foam cell formation in a dose-dependent manner. Moreover, AEBP1 expression in macrophages increased and decreased after oxLDL and berberine treatments in a dose-dependent manner, respectively. Berberine reduced the expression of scavenger receptors CD36 and LOX-1, but did not affect the expression of CD68 in oxLDL-stimulated macrophages. Overall, berberine reduced foam cell formation by a dual mechanism, which decreased oxLDL internalization via the suppression of CD36 and LOX-1, and increased cholesterol efflux by inhibiting AEBP1 expression in macrophages.
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http://dx.doi.org/10.1016/j.ejphar.2012.07.009DOI Listing
September 2012