Publications by authors named "Zhi-Min Du"

55 Publications

MicroRNA-98 ameliorates doxorubicin-induced cardiotoxicity via regulating caspase-8 dependent Fas/RIP3 pathway.

Environ Toxicol Pharmacol 2021 Jul 19;85:103624. Epub 2021 Feb 19.

Institute of Clinical Pharmacology, The Second Affiliated Hospital of Harbin Medical University (University Key Laboratory of Drug Research), Heilongjiang Province, Harbin, 150086, China; Department of Clinical Pharmacology, College of Pharmacy, Harbin Medical University, Harbin, 150081, China; State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, 999078, China. Electronic address:

Cardiotoxicity is one of the primary limitations in the clinical use of the anticancer drug doxorubicin (DOX). However, the role of microRNAs (miRNAs) in DOX-induced cardiomyocyte death has not yet been covered. To investigate this, we observed a significant increase in miR-98 expression in neonatal rat ventricular myocytes after DOX treatment, and MTT, LIVE/Dead and Viability/Cytotoxicity staining showed that miR-98 mimic inhibited DOX-induced cell death. This was also confirmed by Flow cytometry and Annexin V-FITC/PI staining. Interestingly, the protein expression of caspase-8 was upregulated by miR-98 mimics during this process, whereas Fas and RIP3 were downregulated. In addition, the effect of miR-98 against the expression of Fas and RIP3 were restored by the specific caspase-8 inhibitor Z-IETD-FMK. Thus, we demonstrate that miR-98 protects cardiomyocytes from DOX-induced injury by regulating the caspase-8-dependent Fas/RIP3 pathway. Our findings enhance understanding of the therapeutic role of miRNAs in the treatment of DOX-induced cardiotoxicity.
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http://dx.doi.org/10.1016/j.etap.2021.103624DOI Listing
July 2021

The Emerging Role of BDNF/TrkB Signaling in Cardiovascular Diseases.

Life (Basel) 2021 Jan 19;11(1). Epub 2021 Jan 19.

Institute of Clinical Pharmacology, The Second Affiliated Hospital of Harbin Medical University (University Key Laboratory of Drug Research), Harbin 150086, China.

Brain-derived neurotrophic factor (BDNF) is one of the most abundantneurotrophins in the central nervous system. Numerous studies suggestthat BDNF has extensive roles by binding to its specific receptor, tropomyosin-related kinase receptor B (TrkB), and thereby triggering downstream signaling pathways. Recently, growing evidence highlightsthat the BDNF/TrkB pathway is expressed in the cardiovascular system andclosely associated with the development and outcome of cardiovascular diseases (CVD), including coronary artery disease, heart failure, cardiomyopathy, hypertension, and metabolic diseases. Furthermore, circulating BDNF has also been revealed as a new potential biomarker for both diagnosis and prognosis of CVD. In this review, we discuss the current evidence of the emerging role of BDNF/TrkBsignalingand address the challenges that remain in translating these discoveries to novel therapeutic strategies for CVD.
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http://dx.doi.org/10.3390/life11010070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833389PMC
January 2021

Comparison of intravascular ultrasound-guided with angiography-guided double kissing crush stenting for patients with complex coronary bifurcation lesions: Rationale and design of a prospective, randomized, and multicenter DKCRUSH VIII trial.

Am Heart J 2021 04 16;234:101-110. Epub 2021 Jan 16.

Division of Cardiology, The 7th People's Hospital of Zhengzhou, Zhengzhou, China.

Background: Double kissing (DK) crush approach for patients with coronary bifurcation lesions, particularly localized at distal left main or lesions with increased complexity, is associated with significant reduction in clinical events when compared with provisional stenting. Recently, randomized clinical trial has demonstrated the net clinical benefits by intravascular ultrasound (IVUS)-guided implantation of drug-eluting stent in all-comers. However, the improvement in clinical outcome after DK crush treatment guided by IVUS over angiography guidance for patients with complex bifurcation lesions have never been studied in a randomized fashion.

Trial Design: DKCRUSH VIII study is a prospective, multicenter, randomized controlled trial designed to assess superiority of IVUS-guided vs angiography-guided DK crush stenting in patients with complex bifurcation lesions according to DEFINITION criteria. A total of 556 patients with complex bifurcation lesions will be randomly (1:1 of ratio) assigned to IVUS-guided or angiography-guided DK crush stenting group. The primary end point is the rate of 12-month target vessel failure, including cardiac death, target vessel myocardial infarction, or clinically driven target vessel revascularization. The secondary end points consist of the individual component of primary end point, all-cause death, myocardial infarction, and in-stent restenosis. The safety end point is the incidence of definite or probable stent thrombosis. An angiographic follow-up will be performed for all patients at 13 months and clinical follow-up will be continued annually until 3 years after the index procedure.

Conclusions: DKCRUSH VIII trial is the first study designed to evaluate the differences in efficacy and safety between IVUS-guided and angiography-guided DK crush stenting in patients with complex true bifurcation lesions. This study will also provide IVUS-derived criteria to define optimal DK crush stenting for bifurcation lesions at higher complexity.
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http://dx.doi.org/10.1016/j.ahj.2021.01.011DOI Listing
April 2021

Meta-Analysis of Atrial Fibrillation and Outcomes in Patients With Heart Failure and Preserved Ejection Fraction.

Heart Lung Circ 2021 May 13;30(5):698-706. Epub 2020 Nov 13.

Department of Cardiology, The First Affiliated Hospital, Sun Yat-Sen University, and Key Laboratory on Assisted Circulation, Ministry of Health, Guangzhou, China. Electronic address:

Background: Atrial fibrillation (AF) is common in heart failure with preserved ejection fraction (HFpEF); However, the prognostic impact of AF on HFpEF patients has not been fully elucidated.

Methods: A literature search of the PubMed and EMBASE databases on literature published through April 2019 was undertaken. Combined hazard ratio (HR) estimates and 95% confidence intervals (CIs) were calculated using fixed-effects or random-effects models, depending on the heterogeneity. Subgroup analyses, sensitivity analysis and meta-regression analyses were also performed.

Results: Fourteen (14) eligible studies with 1,948,923 patients with HFpEF were included in the analysis. Atrial fibrillation was associated with an 11% increased risk of all-cause mortality in patients with HFpEF (HR 1.11, 95% CI 1.09-1.12). Sensitivity analysis confirmed the stability of the results. The stratification of studies by controlled or uncontrolled confounding factors affected the final estimate (confounder-controlled HR 1.21, 95% CI 1.12-1.30; confounder-uncontrolled HR 1.13, 95% CI 0.96-1.31). In addition, AF was an independent predictor of hospitalisation for heart failure (HR 1.32, 95% CI 1.15-1.52), cardiovascular death (HR 1.38, 95% CI 1.01-1.89) and stroke (HR 1.87, 95% CI 1.54-2.27).

Conclusions: Atrial fibrillation was associated with worse clinical outcomes in patients with HFpEF. Further investigation is required to see whether AF is the primary offender in these patients or merely a bystander to worse diastolic function.
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http://dx.doi.org/10.1016/j.hlc.2020.10.010DOI Listing
May 2021

Serum Albumin and Incident Heart Failure: Insights From Epidemiological and Mendelian Randomization Studies.

Circ Genom Precis Med 2020 12 15;13(6):e002989. Epub 2020 Nov 15.

Department of Cardiology, The First Affiliated Hospital of Sun Yat-Sen University (X.-d.Z., S.-z.Z., H.-m.Z., X.-b.Z., X.-t.S., Z.-m.D., X.-x.L.).

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http://dx.doi.org/10.1161/CIRCGEN.120.002989DOI Listing
December 2020

Exploring the causal pathway from body mass index to coronary heart disease: a network Mendelian randomization study.

Ther Adv Chronic Dis 2020 27;11:2040622320909040. Epub 2020 May 27.

Cardiology Department, The First Affiliated Hospital of Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, 510080, PR China.

Background: We applied a network Mendelian randomization (MR) framework to determine the causal association between body mass index (BMI) and coronary heart disease (CHD) and explored whether glycated hemoglobin (HbA1c) and lipid parameters (total cholesterol, TC; low-density lipoprotein cholesterol, LDL; high-density lipoprotein cholesterol, HDL; triglycerides, TG) serve as causal mediators from BMI to CHD by integrating summary-level genome-wide association study data.

Methods: Network MR analysis, an approach using genetic variants as the instrumental variables for both the exposure and mediator to infer causality was performed. Summary statistics from the GIANT consortium were used ( = 152,893) for BMI, CARDIoGRAMplusC4D consortium data were used ( = 184,305) for CHD, Global Lipids Genetics Consortium data were used ( = 108,363) for TC, LDL, HDL and TG, and MAGIC consortia data were used ( = 108,363) for HbA1c.

Results: The inverse-variance-weighted-method estimate indicated that the odds ratio (95% confidence interval) for CHD was 1.562 (1.391-1.753) per 1 standard deviation (kg/m) increase in BMI. Results were consistent in MR Egger method and weighted-median methods. MR estimate indicated that BMI was positively associated with HbA1c and TG, and negatively associated with HDL, but was not associated with TC or LDL. Moreover, HbA1c, TC, LDL, and TG were positively associated with CHD, yet there was no causal association between HDL and CHD. HbA1c was positively associated with TC, LDL, and HDL, but was not associated with TG.

Conclusions: Higher BMI conferred an increased risk of CHD, which was partially mediated by HbA1c and lipid parameters. HbA1c and TG might be the main mediators in the link from BMI to CHD.
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http://dx.doi.org/10.1177/2040622320909040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7257848PMC
May 2020

Aloe-emodin exerts cholesterol-lowering effects by inhibiting proprotein convertase subtilisin/kexin type 9 in hyperlipidemic rats.

Acta Pharmacol Sin 2020 Aug 18;41(8):1085-1092. Epub 2020 Mar 18.

Institute of Clinical Pharmacology, The Second Affiliated Hospital of Harbin Medical University (University Key Laboratory of Drug Research, Heilongjiang Province), Harbin, 150086, China.

Hyperlipidemia (HPL) characterized by metabolic disorder of lipids and cholesterol is one of the important risk factors for cardiovascular diseases. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a potent circulating regulator of LDL through its ability to induce degradation of the low-density lipoprotein cholesterol receptor (LDLR) in the lysosome of hepatocytes. Aloe-emodin (AE) is one of potentially bioactive components of Chinese traditional medicine Daming capsule. In this study we evaluated the HPL-lowering efficacy of AE in both in vivo and in vitro HPL models. High-fat diet-induced rats were treated with AE (100 mg/kg per day, ig) for 6 weeks. We found that AE administration significantly decreased the levels of total cholesterol (TC) and LDL in the serum and liver tissues. Moreover, AE administration ameliorated HPL-induced hepatic lipid aggregation. But AE administration did not significantly inhibit HMG-CoA reductase activity in the liver of HPL rats. A cellular model of HPL was established in human hepatoma (HepG2) cells treated with cholesterol (20 μg/mL) and 25-hydroxycholesterol (2 μg/mL), which exhibited markedly elevated cholesterol levels. The increased cholesterol levels could be reversed by subsequent treatment with AE (30 μM). In both the in vivo and in vitro HPL models, we revealed that AE selectively suppressed the sterol-regulatory element-binding protein-2 (SREBP-2) and hepatocyte nuclear factor (HNF)1α-mediated PCSK9 signaling, which in turn upregulated LDL receptor (LDLR) and promoted LDL uptake. This study demonstrates that AE reduces cholesterol content in HPL rats by inhibiting the hepatic PCSK9/LDLR pathway.
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http://dx.doi.org/10.1038/s41401-020-0392-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470781PMC
August 2020

Meta-Analysis of the Impact of Pre-Procedural Serum Albumin on Mortality in Patients Undergoing Transcatheter Aortic Valve Replacement.

Int Heart J 2020 Jan 17;61(1):67-76. Epub 2020 Jan 17.

Department of Cardiology, The First Affiliated Hospital, Sun Yat-Sen University, and Key Laboratory on Assisted Circulation, Ministry of Health.

Pre-procedural serum albumin's impact on prognosis after transcatheter aortic valve replacement (TAVR) has been studied. Literature on the prognostic role of serum albumin in the survival of patients undergoing TAVR shows conflicting results. This meta-analysis was conducted to evaluate the impact of pre-procedural serum albumin on outcomes after TAVR. A comprehensive literature search of EMBASE, MEDLINE, and the Cochrane Library was undertaken through July 2019. The primary end points were 30-day and one-year all-cause mortality after TAVR. Risk ratios (HRs) and 95% confidence intervals (CIs) were calculated using the random-effect model. Ten eligible studies with 8,236 patients were analyzed. Of the 8,236 patients undergoing TAVR, with a mean age of 83 years, 48.8% were men and were categorized into two groups according to low and normal serum albumin (cut-off value: 3.5 or 4 g/dL). Overall, low albumin was significantly associated with an approximately two-fold increase in 30-day all-cause mortality (HR, 2.09; 95% CI, 1.53-2.86) and a 61% increase risk for one-year mortality (HR, 1.61; 95% CI, 1.31-1.98) in patients after TAVR. Sensitivity analyses showed the results to be robust. The association of low albumin level with an increase in one-year mortality risk was not modified by study design, albumin cut-off value, Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM), and study quality. In conclusion, low albumin levels were associated with poor prognosis in patients after TAVR. Pre-procedural albumin can be used as a simple tool related to prognosis after TAVR.
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http://dx.doi.org/10.1536/ihj.19-395DOI Listing
January 2020

The long non-coding RNA TUG1-miR-9a-5p axis contributes to ischemic injuries by promoting cardiomyocyte apoptosis via targeting KLF5.

Cell Death Dis 2019 12 2;10(12):908. Epub 2019 Dec 2.

Institute of Clinical Pharmacy, the Second Affiliated Hospital of Harbin Medical University (The University Key Laboratory of Drug Research, Heilongjiang Province), Harbin, 150086, China.

Non-coding RNAs participate in many cardiac pathophysiological processes, including myocardial infarction (MI). Here we showed the interplay between long non-coding RNA taurine-upregulated gene 1 (lncR-TUG1), miR-9a-5p (miR-9) and Krüppel-like factor 5 (KLF5). LncR-TUG1 was upregulated in ischemic heart and in cultured cardiomyocytes exposed to HO. Knockdown of lncR-TUG1 markedly ameliorated impaired cardiac function of MI mice. Further study showed that lncR-TUG1 acted as a competitive endogenous RNA of miR-9, and silencing of lncR-TUG1 inhibited cardiomyocyte apoptosis by upregulating miR-9 expression. Furthermore, the miR-9 overexpression obviously prevented ischemia injury and significantly inhibited HO-induced cardiomyocyte apoptosis via inhibition of mitochondrial apoptotic pathway. KLF5, as a target gene of miR-9 by dual-luciferase reporter assay, was involved in the process of miR-9 in regulating cardiomyocyte apoptosis. Our data identified the KLF5 was downregulated by miR-9 overexpression and knockdown of KLF5 inhibited cardiomyocyte apoptosis induced by HO. MiR-9 exerts anti-cardiomyocyte apoptotic affects by targeting KLF5. Collectively, our data identify a novel function of lncR-TUG1/miR-9/KLF5 axis in regulating cardiomyocyte apoptosis that affects myocardial infarction progression.
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http://dx.doi.org/10.1038/s41419-019-2138-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6885510PMC
December 2019

Brain-derived neurotrophic factor mimetic, 7,8-dihydroxyflavone, protects against myocardial ischemia by rebalancing optic atrophy 1 processing.

Free Radic Biol Med 2019 12 28;145:187-197. Epub 2019 Sep 28.

Institute of Clinical Pharmacology, The Second Affiliated Hospital (The University Key Laboratory of Drug Research, Heilongjiang Province), Department of Clinical Pharmacology, College of Pharmacy, Harbin Medical University, Harbin, 150086, China; State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, Macau, China. Electronic address:

Brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) pathway is associated with ischemic heart diseases (IHD). 7,8-dihydroxyflavone (7,8-DHF), BDNF mimetic, is a potent agonist of TrkB. We aimed to investigate the effects and the underlying mechanisms of 7,8-DHF on cardiac ischemia. Myocardial ischemic mouse model was induced by ligation of left anterior descending coronary artery. 7,8-DHF (5 mg/kg) was administered intraperitoneally two days after ischemia for four weeks. Echocardiography, HE staining and transmission electron microscope were used to examine the function, histology and ultrastructure of the heart. H9c2 cells were treated with hydrogen peroxide (HO), 7,8-DHF or TrkB inhibitor ANA-12. The effects of 7,8-DHF on cell viability, mitochondrial membrane potential (MMP) and mitochondrial superoxide generation were examined. Furthermore, mitochondrial fission and protein expression of mitochondrial dynamics (Mfn2 [mitofusin 2], OPA1 [optic atrophy 1], Drp1 [dynamin-related protein 1] and Fis-1 [fission 1]) was detected by mitotracker green staining and western blot, respectively. 7,8-DHF attenuated cardiac dysfunction and cardiomyocyte abnormality of myocardial ischemic mice. Moreover, 7,8-DHF increased cell viability and reduced cell death accompanied by improving MMP, inhibiting mitochondrial superoxide and preventing excessive mitochondrial fission of HO-treated H9c2 cells. The cytoprotective effects of 7,8-DHF were antagonized by ANA-12. Mechanistically, 7,8-DHF repressed OMA1-dependent conversion of L-OPA1 into S-OPA1, which was abolished by Akt inhibitor. In conclusion, 7,8-DHF protects against cardiac ischemic injury by inhibiting the proteolytic cleavage of OPA1. These findings provide a novel pharmacological effect of 7,8-DHF on mitochondrial dynamics and a new potential target for IHD.
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http://dx.doi.org/10.1016/j.freeradbiomed.2019.09.033DOI Listing
December 2019

Phenomapping of subgroups in hypertensive patients using unsupervised data-driven cluster analysis: An exploratory study of the SPRINT trial.

Eur J Prev Cardiol 2019 11 18;26(16):1693-1706. Epub 2019 Jun 18.

Department of Cardiology, First Affiliated Hospital of Sun Yat-Sen University, China.

Background: Hypertensive patients are highly heterogeneous in cardiovascular prognosis and treatment responses. A better classification system with phenomapping of clinical features would be of greater value to identify patients at higher risk of developing cardiovascular outcomes and direct individual decision-making for antihypertensive treatment.

Methods: An unsupervised, data-driven cluster analysis was performed for all baseline variables related to cardiovascular outcomes and treatment responses in subjects from the Systolic Blood Pressure Intervention Trial (SPRINT), in order to identify distinct subgroups with maximal within-group similarities and between-group differences. Cox regression was used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) for cardiovascular outcomes and compare the effect of intensive antihypertensive treatment in different clusters.

Results: Four replicable clusters of patients were identified: cluster 1 (index hypertensives); cluster 2 (chronic kidney disease hypertensives); cluster 3 (obese hypertensives) and cluster 4 (extra risky hypertensives). In terms of prognosis, individuals in cluster 4 had the highest risk of developing primary outcomes. In terms of treatment responses, intensive antihypertensive treatment was shown to be beneficial only in cluster 4 (HR 0.73, 95% CI 0.55-0.98) and cluster 1 (HR 0.54, 95% CI 0.37-0.79) and was associated with an increased risk of severe adverse effects in cluster 2 (HR 1.18, 95% CI 1.05-1.32).

Conclusion: Using a data-driven approach, SPRINT subjects can be stratified into four phenotypically distinct subgroups with different profiles on cardiovascular prognoses and responses to intensive antihypertensive treatment. Of note, these results should be taken as hypothesis generating that warrant further validation in future prospective studies.
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http://dx.doi.org/10.1177/2047487319856733DOI Listing
November 2019

MicroRNA-155 Promotes Myocardial Infarction-Induced Apoptosis by Targeting RNA-Binding Protein QKI.

Oxid Med Cell Longev 2019 5;2019:4579806. Epub 2019 May 5.

Institute of Clinical Pharmacy, The Second Affiliated Hospital of Harbin Medical University (The University Key Laboratory of Drug Research, Heilongjiang Province), Harbin 150086, China.

Acute myocardial infarction (AMI) is the leading cause of sudden death worldwide. MicroRNA-155 (miR-155) has been reported to target antiapoptotic genes in various diseases models, but the functional role of miR-155 in response to MI injury needs further investigations. This study investigated the role of miR-155 in myocardial ischemia injury. TUNEL and flow cytometry were performed to measure cell apoptosis. Western blot analysis was employed to detect protein expressions of Bcl-2, XIAP, Bax, and caspase-3. qRT-PCR was used to quantify miRNA levels. We showed that miR-155 was dynamically elevated in murine hearts subjected to MI and in neonatal rat ventricular cardiomyocyte (NRVM) injury induced by hydrogen peroxide (HO). In response to HO, the silencing of miR-155 using AMO-155 (antisense inhibitor oligodeoxyribonucleotides) significantly increased cell viability and reduced cell apoptosis. Moreover, AMO-155 reversed the HO-induced downregulation of Bcl-2 and XIAP and upregulation of Bax and cleaved-caspase-3. Further study revealed that AMO-155 resulted in a decrease of HO-induced JC-1-labelled monomeric cell number. In addition, AMO-155 markedly decreased infarct size, ameliorated impaired cardiac function, and significantly reduced apoptotic cell percentages in MI mice heart. The RNA-binding protein Quaking (QKI) was predicted as a target gene of miR-155 through bioinformatic analysis, and AMO-155 attenuated the downregulation of QKI in HO-treated cardiomyocytes and MI mice heart. Knockdown of QKI by siRNA abolished the antiapoptotic effects of AMO-155. Taken together, miR-155 is upregulated in the MI heart and NRVMs in response to HO stress, and downregulating of miR-155 protects cardiomyocytes against apoptosis. Mechanistically, it is probably due to the repression of QKI signaling pathway.
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http://dx.doi.org/10.1155/2019/4579806DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6525929PMC
December 2019

Comparative outcomes of heart failure among existent classes of anti-diabetic agents: a network meta-analysis of 171,253 participants from 91 randomized controlled trials.

Cardiovasc Diabetol 2019 04 8;18(1):47. Epub 2019 Apr 8.

Department of Cardiology, First Affiliated Hospital of Sun Yat-Sen University, No. 58 Zhong Shan 2nd Road, Guangzhou, 510080, China.

Background: The cardiovascular (CV) safety in terms of heart failure among different classes of treatment remains largely unknown. We sought to assess the comparative effect of these agents on heart failure outcomes.

Methods: This study was registered in the International Prospective Register of Systematic Reviews (CRD 42016042063). MEDLINE, EMBASE, and the Cochrane Library Central Register of Controlled Trials were searched. For the primary outcomes reported previously, studies between Jan 1, 1980 and June 30, 2016 were screened, and subsequently updated till Jan 24, 2019. We performed network meta-analysis to obtain estimates for the outcomes of heart failure, in particular by rankograms for ranking of heart failure risk as well as by pairwise comparisons among all classes of anti-diabetic medications.

Results: A total of 91 trials were included, among which were 171,253 participants and 4163 reported cases of heart failure events. As for rankograms, the surface under the cumulative ranking curves (SUCRA) of sodium-glucose co-transporters 2 and thiazolidinediones were 93.4% and 4.3%, respectively, signifying the lowest and highest risk of heart failure, respectively. As for pairwise comparisons in the network, sodium-glucose co-transporters 2 were significantly superior to insulin (OR: 0.75, 95% CI 0.62-0.91), dipeptidyl peptidase 4 inhibitors (OR: 0.68, 95% CI 0.59-0.78), glucagon-like peptide-1 receptor agonists (OR: 0.65, 95% CI 0.54-0.78), and thiazolidinediones (OR: 0.46, 95% CI 0.27-0.77) in terms of heart failure risk. Furthermore, in an exploratory analysis among subjects with underlying heart failure or at risk of heart failure, the superiority of sodium-glucose co-transporters 2 was still significant.

Conclusions: In terms of heart failure risk, sodium-glucose co-transporters 2 were the most favorable option among all classes of anti-diabetic medications.
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http://dx.doi.org/10.1186/s12933-019-0853-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454617PMC
April 2019

Ablation of interleukin-17 alleviated cardiac interstitial fibrosis and improved cardiac function via inhibiting long non-coding RNA-AK081284 in diabetic mice.

J Mol Cell Cardiol 2018 02 3;115:64-72. Epub 2018 Jan 3.

Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang 150081, PR China. Electronic address:

Interleukin 17 (IL-17) plays an important role in the pathogenesis of cardiac interstitial fibrosis. In this study, we explored the role of interleukin-17 in the development of diabetic cardiomyopathy and the underlying mechanisms. The level of IL-17 increased in both the serum and cardiac tissue of diabetic mice. Knockout of IL-17 improved cardiac function of diabetic mice induced by streptozotocin (STZ), and significantly alleviated interstitial fibrosis as manifested by reduced collagen mRNA expression and collagen deposition evaluated by Masson's staining. High glucose treatment induced collagen production were abolished in cultured IL-17 knockout cardiac fibroblasts (CFs). The levels of long noncoding RNA-AK081284 were increased in the CFs treated with high glucose or IL-17. Knockout of IL-17 abrogated high glucose induced upregulation of AK081284. Overexpression of AK081284 in cultured CFs promoted the production of collagen and TGFβ1. Both high glucose and IL-17 induced collagen and TGFβ1 production were mitigated by the application of the siRNA for AK081284. In summary, deletion of IL-17 is able to mitigate myocardial fibrosis and improve cardiac function of diabetic mice. The IL-17/AK081284/TGFβ1 signaling pathway mediates high glucose induced collagen production. This study indicates the therapeutic potential of IL-17 inhibition on diabetic cardiomyopathy disease associated with fibrosis.
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http://dx.doi.org/10.1016/j.yjmcc.2018.01.001DOI Listing
February 2018

A Nomogram to Predict Contrast Induced Nephropathy in Patients Undergoing Percutaneous Coronary Intervention.

Int Heart J 2017 Apr 21;58(2):191-196. Epub 2017 Mar 21.

Department of Cardiology, The First Affiliated Hospital, Sun Yat-sen University.

Contrast-induced nephropathy (CIN) is the third leading cause of hospital-acquired acute kidney injury (AKI). Emerging evidence has revealed that soluble klotho (sklotho) could be a novel biomarker for early AKI diagnosis. The aims of this study were to assess the predictive role of sklotho for CIN and to develop a prediction nomogram in patients undergoing percutaneous coronary intervention (PCI). This study is registered on Clinicaltrials.gov (NCT 02650336).Patients aged 18 years or older undergoing planned PCI were prospectively recruited between May 2014 and July 2015. CIN was defined as an increase in serum creatinine of 0.5 mg/dL within 48-72 hours after the procedure. Plasma sklotho was measured by enzyme linked immunosorbent assay (ELISA). Stratified analysis, interaction test, covariate screening, and curve fitting were performed to explore the association between sklotho and CIN. A nomogram was then developed and validated using the bootstrapped technique.A total of 192 patients aged 54.75 ± 12.19 years were selected, 32 (16.7%) of whom were diagnosed with CIN. A logistic regression model indicated significant associations between CIN and sklotho, age > 75 years, diabetes, and the Mehran risk score. Saturation effects analysis detected a two-stage change between sklotho and CIN, with the inflection point was 477.4 pg/mL. The area under the ROC curve was 0.758 and the sensitivity and specificity of this point were 90.6% and 53.9%, respectively. A nomogram was developed for the prediction of CIN and showed a bootstrapped-corrected area under the curve value of 0.913. In addition, sklotho significantly increased the predictive value of the nomogram.A strong association between sklotho and CIN was identified in patients undergoing elective PCI. A lower level of sklotho would be well correlated with CIN. The nomogram with sklotho is a useful tool to predict CIN in patients who will undergo PCI.
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http://dx.doi.org/10.1536/ihj.16-213DOI Listing
April 2017

Renin-angiotensin system inhibitors in patients with coronary artery disease who have undergone percutaneous coronary intervention.

Ther Adv Cardiovasc Dis 2016 Jun 15;10(3):172-7. Epub 2016 May 15.

Department of Cardiology, the First Affiliated Hospital of Sun Yat-sen University, No. 58, ZhongShan Er Road, Guangzhou 510080, P. R. China

The percutaneous coronary intervention (PCI) procedure has become one of the pivotal options in the treatment of coronary artery disease (CAD). Although the PCI procedure has rapidly developed in China, some concerns including in-stent restenosis and dissatisfactory long-term prognosis remain unsolved. Large-scale randomized controlled clinical trials indicate that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) can reduce all-cause mortality and recurrent cardiac events in patients with CAD. ACEIs/ARBs are recommended as a fundamental treatment in the secondary prevention of CAD and reduce in-stent restenosis after PCI. This review focuses on the role of ACEIs/ARBs in improving long-term prognosis and reducing in-stent restenosis.
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http://dx.doi.org/10.1177/1753944716648851DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5933676PMC
June 2016

Combination of microRNA-21 and microRNA-146a Attenuates Cardiac Dysfunction and Apoptosis During Acute Myocardial Infarction in Mice.

Mol Ther Nucleic Acids 2016 Mar 15;5:e296. Epub 2016 Mar 15.

Institute of Clinical Pharmacology of the Second Affiliated Hospital, Harbin Medical University, Harbin, China.

Recent studies have revealed the cytoprotective roles of microRNAs (miRNAs) miR-21 and miR-146a against ischemic cardiac injuries. While these studies investigated each of these miRNAs as an independent individual factor, our previous study has suggested the possible interaction between these two miRNAs. The present study was designed to investigate this possibility by evaluating the effects of miR-21 and miR-146a combination on cardiac ischemic injuries and the underlying mechanisms. MiR-21 and miR-146a synergistically decreased apoptosis under ischemia/hypoxic conditions in cardiomyocytes compared with either miR-21 or miR-146a alone. Mice coinjected with agomiR-21 and agomiR-146a had decreased infarct size, increased ejection fraction (EF), and fractional shortening (FS). These effects were greater than those induced by either of the two agomiRs. Furthermore, greater decreases in p38 mitogen-associated protein kinase phosphorylation (p-p38 MAPK) were observed with miR-21: miR-146a combination as compared to application of either of the miRNAs. These data suggest that combination of miR-21 and miR-146a has a greater protective effect against cardiac ischemia/hypoxia-induced apoptosis as compared to these miRNAs applied individually. This synergistic action is mediated by enhanced potency of inhibition of cardiomyocyte apoptosis by the miR-21-PTEN/AKT-p-p38-caspase-3 and miR-146a-TRAF6-p-p38-caspase-3 signal pathways.
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http://dx.doi.org/10.1038/mtna.2016.12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5014454PMC
March 2016

Deletion of interleukin-6 alleviated interstitial fibrosis in streptozotocin-induced diabetic cardiomyopathy of mice through affecting TGFβ1 and miR-29 pathways.

Sci Rep 2016 Mar 14;6:23010. Epub 2016 Mar 14.

Department of Pharmacology (Key Laboratory of Cardiovascular Medicine Research, Ministry of Education; State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), Harbin Medical University, Harbin, Heilongjiang 150081, P. R. China.

Interleukin 6 (IL-6) has been shown to be an important regulator of cardiac interstitial fibrosis. In this study, we explored the role of interleukin-6 in the development of diabetic cardiomyopathy and the underlying mechanisms. Cardiac function of IL-6 knockout mice was significantly improved and interstitial fibrosis was apparently alleviated in comparison with wildtype (WT) diabetic mice induced by streptozotocin (STZ). Treatment with IL-6 significantly promoted the proliferation and collagen production of cultured cardiac fibroblasts (CFs). High glucose treatment increased collagen production, which were mitigated in CFs from IL-6 KO mice. Moreover, IL-6 knockout alleviated the up-regulation of TGFβ1 in diabetic hearts of mice and cultured CFs treated with high glucose or IL-6. Furthermore, the expression of miR-29 reduced upon IL-6 treatment, while increased in IL-6 KO hearts. Overexpression of miR-29 blocked the pro-fibrotic effects of IL-6 on cultured CFs. In summary, deletion of IL-6 is able to mitigate myocardial fibrosis and improve cardiac function of diabetic mice. The mechanism involves the regulation of IL-6 on TGFβ1 and miR-29 pathway. This study indicates the therapeutic potential of IL-6 suppression on diabetic cardiomyopathy disease associated with fibrosis.
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http://dx.doi.org/10.1038/srep23010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4789642PMC
March 2016

Design, synthesis, and antihypertensive activity of curcumin-inspired compounds via ACE inhibition and vasodilation, along with a bioavailability study for possible benefit in cardiovascular diseases.

Drug Des Devel Ther 2016 5;10:129-39. Epub 2016 Jan 5.

Department of Cardiology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.

This study describes the synthesis of a novel series of curcumin-inspired compounds via a facile synthetic route. The structures of these derivatives were ascertained using various spectroscopic and analytic techniques. The pharmacological effects of the target analogs were assessed by assaying their inhibition of angiotensin-converting enzyme (ACE). All of the synthesized derivatives exhibited considerable inhibition of ACE, with half-maximal inhibitory concentrations ranging from 1.23 to 120.32 μM. In a docking analysis with testicular ACE (tACE), the most promising inhibitor (4j) was efficiently accommodated in the deep cleft of the protein cavity, making close interatomic contacts with Glu162, His353, and Ala356, comparable with lisinopril. Compounds 4i, 4j, 4k, and 4l were further selected for determination of their vasodilator activity (cardiac output and stroke volume) on isolated rat hearts using the Langendorff technique. The bioavailability of compound 4j was determined in experimental mice.
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http://dx.doi.org/10.2147/DDDT.S96315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4708961PMC
October 2016

Effectiveness and Safety of Warfarin in Dialysis Patients With Atrial Fibrillation: A Meta-Analysis of Observational Studies.

Medicine (Baltimore) 2015 Dec;94(50):e2233

From the Department of Cardiology, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.

In routine practice, warfarin is widely used in dialysis patients with atrial fibrillation (AF) for stroke prevention though the ratio of risks to benefits remains unclear. Recent cohort studies investigating the association between warfarin use and the risks of stroke and bleeding in dialysis patients with AF present conflicting results. The objective of this study was to assess the effectiveness and safety of warfarin use in patients with AF undergoing dialysis. Three databases PubMed, EMBASE, and OVID were searched from their inception to August 2015. Observational studies which assessed the ischemic stroke or bleeding risk of warfarin use in dialysis patients with AF were included. Two reviewers independently extracted data and assessed methodological quality based on the Newcastle-Ottawa Scale score. Combined hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using the random-effects model and heterogeneity was assessed based on the Cochrane Q-statistic test and the I statistic. Metaregression analyses were performed to explore the source of heterogeneity. A total of 11 eligible studies with 25,407 patients were included in the analysis. Warfarin use, in comparison with no-warfarin use, was not associated with a lower risk for ischemic stroke (HR 0.95, 95% CI 0.66-1.35). Sensitivity analyses found results to be robust. Metaregression analysis showed that demographic feature, clinical characteristics, or study-level variable had no impact of warfarin use on stroke risk. In addition, warfarin use was associated with a 27% higher risk for bleeding (95% CI 1.04-1.54). Overall, warfarin use did not have a significant association with reduced mortality (95% CI 0.96-1.11). It appears that warfarin use is not beneficial in reducing stroke risk, but with a high risk for bleeding in dialysis patients with AF. Randomized trials are needed to determine the risk-benefit ratio of warfarin in dialysis patients with AF.
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http://dx.doi.org/10.1097/MD.0000000000002233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5058909PMC
December 2015

The Role of Macrolide Antibiotics in Increasing Cardiovascular Risk.

J Am Coll Cardiol 2015 Nov;66(20):2173-2184

Department of Cardiology, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China. Electronic address:

Background: Large cohort studies provide conflicting evidence regarding the potential for oral macrolide antibiotics to increase the risk of serious cardiac events.

Objectives: This study performed a meta-analysis to examine the link between macrolides and risk of sudden cardiac death (SCD) or ventricular tachyarrhythmias (VTA), cardiovascular death, and death from any cause.

Methods: We performed a search of published reports by using MEDLINE (January 1, 1966, to April 30, 2015) and EMBASE (January 1, 1980, to April 30, 2015) with no restrictions. Studies that reported relative risk (RR) estimates with 95% confidence intervals (CIs) for the associations of interest were included.

Results: Thirty-three studies involving 20,779,963 participants were identified. Patients taking macrolides, compared with those who took no macrolides, experienced an increased risk of developing SCD or VTA (RR: 2.42; 95% CI: 1.61 to 3.63), SCD (RR: 2.52; 95% CI: 1.91 to 3.31), and cardiovascular death (RR: 1.31; 95% CI: 1.06 to 1.62). No association was found between macrolides use and all-cause death or any cardiovascular events. The RRs associated with SCD or VTA were 3.40 for azithromycin, 2.16 for clarithromycin, and 3.61 for erythromycin, respectively. RRs for cardiovascular death were 1.54 for azithromycin and 1.48 for clarithromycin. No association was noted between roxithromycin and adverse cardiac outcomes. Treatment with macrolides is associated with an absolute risk increase of 118.1 additional SCDs or VTA, and 38.2 additional cardiovascular deaths per 1 million treatment courses.

Conclusions: Administration of macrolide antibiotics is associated with increased risk for SCD or VTA and cardiovascular death but not increased all-cause mortality.
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http://dx.doi.org/10.1016/j.jacc.2015.09.029DOI Listing
November 2015

[Overview on method and strategy of therapeutic material basis in traditional Chinese medicine by multidisciplinary approach].

Zhongguo Zhong Yao Za Zhi 2015 May;40(9):1644-8

Traditional Chinese medicine (TCM) has a good reputation for preventing or healing diseases in clinic due to its higher efficacy, minor toxicity and abundant resources. Screening bioactive components in TCMs is not only crucial for clarifying their action mechanisms, but also the basis of their safety and quality control. TCM is characterized by multiple components, multiple targets and multiple mechanisms, however the complex composition of TCM makes it difficult to study the therapeutic material basis which has become the bottleneck in the process of its modernization and internationalization. Recently, with the rapid development of modern technologies and the unceasing progress of various disciplines, multidisciplinary approach, such as analytical chemistry, chemistry of TCM, pharmacology, cell biology, systems biology and bioinformatics has been successfully applied to the study of TCM. Multidisciplinary approach realizes the communication and interaction of multi-discipline, and accelerates the research and development of TCM. This review summarizes the application of multidisciplinary approach which may have certain potential of bringing new thoughts to TCM research and provide references for screening and identification of therapeutic material basis of TCMs.
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May 2015

Rationale and design of RETAIN study: Rosuvastatin Effect on Telomere-telomerase system in Acute coronary syndrome patients undergoing percutaneous coronary Intervention.

Int J Cardiol 2015 Apr 24;184:388-390. Epub 2015 Feb 24.

Department of cardiology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, PR China. Electronic address:

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http://dx.doi.org/10.1016/j.ijcard.2015.02.032DOI Listing
April 2015

PDE5 inhibitor sildenafil in the treatment of heart failure: a meta-analysis of randomized controlled trials.

Int J Cardiol 2014 Apr 24;172(3):581-7. Epub 2014 Jan 24.

Department of Cardiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510000, PR China. Electronic address:

Background: Clinical trials have evaluated the use of phosphodiesterase (PDE) 5 inhibitors sildenafil as a potential adjunct in the treatment of heart failure (HF) with mixed results. Thus, we undertook a meta-analysis to evaluate the clinical viability of sildenafil in HF.

Methods: Relevant studies were searched and identified in the MEDLINE and EMBASE databases. Randomized clinical trials (RCT) comparing sildenafil to placebo, in heart failure patients, reporting at least one outcome of interest were included. Data were extracted regarding the characteristics and clinical outcomes.

Results: We identified 9 RCTs enrolling 612 HF patients. There were no significant differences in adverse events between sildenafil group and placebo group (RR=1.10, 95% CI=0.74 to 1.65, P=0.41), whereas sildenafil therapy was associated with a marked improvement in hemodynamic parameter peak VO2 (MD=3.25, 95% CI=2.07 to 4.42, P<0.00001) in HF with reduced ejection fraction (HFrEF) patients but not in HF with preserved ejection fraction (HFpEF) patients. Also, sildenafil therapy improved VO2 at anaerobic threshold (AT) (MD=3.47, 95% CI=1.68 to 5.27, P=0.0002), VE/VCO2 slope (MD=-7.06, 95% CI=-8.93 to -5.19, P<0.00001) and LV ejection fraction (MD=5.43, 95% CI=3.66 to 7.20, P<0.00001) compared to placebo in HF patients, which had no impact on blood pressure and heart rate. For quality of life (emotional function, fatigue and breathlessness), there was no significant difference between the two groups.

Conclusions: Sildenafil improved hemodynamic parameters particularly in HFrEF patients when compared to placebo, with no increase in adverse events. Sildenafil treatment was well tolerated and had no impact on quality of life.
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http://dx.doi.org/10.1016/j.ijcard.2014.01.102DOI Listing
April 2014

Vitexin protects against cardiac hypertrophy via inhibiting calcineurin and CaMKII signaling pathways.

Naunyn Schmiedebergs Arch Pharmacol 2013 Aug 28;386(8):747-55. Epub 2013 Apr 28.

Institute of Clinical Pharmacology, The Second Affiliated Hospital, Harbin Medical University, Harbin, 150086, Heilongjiang, People's Republic of China.

Vitexin is a flavone glycoside isolated from the leaf of Crataeguspinnatifida Bunge, the utility of which has been demonstrated in several cardiovascular diseases. However, its role in cardiac hypertrophy remains unclear. In the present study, we aimed to determine whether vitexin prevents cardiac hypertrophy induced by isoproterenol (ISO) in cultured neonatal rat ventricular myocytes in vitro and pressure overload-induced cardiac hypertrophy in mice in vivo. The results revealed that vitexin (10, 30, and 100 μM) dose-dependently attenuated cardiac hypertrophy induced by ISO in vitro. Furthermore, vitexin (3, 10, and 30 mg kg(-1)) prevented cardiac hypertrophy induced by transverse aortic constriction as assessed by heart weight/body weight, left ventricular weight/body weight and lung weight/body weight ratios, cardiomyocyte cross-sectional area, echocardiographic parameters, and gene expression of hypertrophic markers. Further investigation demonstrated that vitexin inhibited the increment of the resting intracellular free calcium induced by ISO. Vitexin also inhibited the expression of calcium downstream effectors calcineurin-NFATc3 and phosphorylated calmodulin kinase II (CaMKII) both in vitro and in vivo. Taken together, our results indicate that vitexin has the potential to protect against cardiac hypertrophy through Ca2+-mediated calcineurin-NFATc3 and CaMKII signaling pathways.
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http://dx.doi.org/10.1007/s00210-013-0873-0DOI Listing
August 2013

Transplantation of human umbilical cord-derived endothelial progenitor cells promotes re-endothelialization of the injured carotid artery after balloon injury in New Zealand white rabbits.

Chin Med J (Engl) 2013 ;126(8):1480-5

Division of Cardiology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China.

Background: Cell transplantation has great potential for promoting endothelial repair and reducing the complications of percutaneous coronary intervention (PCI). The aim of this study was to investigate the effect of transplantation of human umbilical cord blood endothelial progenitor cells (EPCs) on injured arteries.

Methods: Umbilical cord blood mononuclear cells were obtained from post-partum lying-in women, and EPCs were isolated, cultured, expanded and identified by immunofluorescence. The carotid arterial endothelium of New Zealand white rabbits was injured by dilatation with a 3F balloon, and the EPCs were injected into the lumen of the injured artery in the transplanted group (n = 16), while an equal volume of phosphated buffered saline (PBS) was injected into the control group after balloon injury (n = 16). The animals were sacrificed after either 2 or 4 weeks, and the grafted cells were identified by double immunofluorescence staining with human nuclear antigen (HNA) and CD31 antibodies. Arterial cross sections were analyzed by pathology, immunohistochemistry and morphometry to evaluate the reparative effects of EPCs. Proliferating cell nuclear antigen (PCNA) and transforming growth factor (TGF)-β1 mRNA expression were detected by reverse transcription-polymerase chain reaction (RT-PCR).

Results: Fluorescence-labeled EPCs were found in the neointima. The neointimal area and the neointimal/medial area ratio were significantly lower in the transplanted group than in the control group (P < 0.05). von Willebrand factor (vWF) immunohistostaining showed more VWF-positive cells in the transplanted animals than in the controls (8.75 ± 2.92 vs. 4.50 ± 1.77, P < 0.05). Compared with the control group, the transplanted group had lower expression of PCNA mRNA (0.67 ± 0.11 vs. 1.25 ± 0.40, P < 0.01) and higher expression of TGF-β1 mRNA (1.10 ± 0.21 vs. 0.82 ± 0.07, P < 0.05).

Conclusions: EPCs derived from human umbilical cord blood were successfully transplanted into injured vessels. The transplanted EPCs inhibited neointimal hyperplasia and promoted vascular re-endothelialization.
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June 2014

Verapamil reverses cardiac iron overload in streptozocin-induced diabetic rats.

Naunyn Schmiedebergs Arch Pharmacol 2013 Jul 7;386(7):645-50. Epub 2013 Apr 7.

Key Laboratory of Drug Research, Heilongjiang Higher Education Institutions, Harbin Medical University, Harbin, People's Republic of China.

Accumulating evidence shows that iron overload is a new risk factor for diabetes mellitus. L-type Ca(2+) channel (LTCC) has been identified as an important mediator for ferrous iron uptake into cardiomyocytes. In this study, we aimed to examine the effects of verapamil, the LTCC blocker, on myocardial iron metabolism in diabetic rats. Diabetes was induced by intraperitoneal injection of streptozocin after intragastric administration of fat emulsion, and then treated by verapamil (5 mg · kg(-1) · day(-1)) for 1 week. The results showed that verapamil did not alter the blood glucose level of diabetic rats. However, elevated levels of superoxide dismutase, malonaldehyde, and serum ferritin in diabetic rats were decreased significantly by verapamil treatment. Moreover, serum, myocardial, and urine iron were elevated remarkably along with a decrease of hepatic iron in diabetic rats. After verapamil administration, serum and myocardial iron in diabetic rats were reduced significantly but urine and hepatic iron were increased. Furthermore, confocal microscopy demonstrated that intracellular-free iron concentration was elevated dramatically in cardiomyocytes of diabetic rats, which was markedly attenuated after verapamil treatment. In summary, our data demonstrated that verapamil prevented myocardial iron overload by inhibiting intracellular iron accumulation in diabetic cardiomyocytes.
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http://dx.doi.org/10.1007/s00210-013-0863-2DOI Listing
July 2013

Choline inhibits angiotensin II-induced cardiac hypertrophy by intracellular calcium signal and p38 MAPK pathway.

Naunyn Schmiedebergs Arch Pharmacol 2012 Aug 9;385(8):823-31. Epub 2012 May 9.

Department of Pharmacology (State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, Heilongjiang 150081, People's Republic of China.

Choline, an agonist of M(3) muscarinic acetylcholine receptors, is a precursor and metabolite of acetylcholine and is also a functional modulator of cellular membrane. However, the effect of choline on cardiac hypertrophy is not fully understood. The present study was therefore designed to explore whether choline could prevent cardiac hypertrophy induced by angiotensin II (Ang II) and clarify its potential mechanisms. Cardiac hypertrophy was induced by 0.6 mg kg(-1) day(-1) Ang II for 2 weeks in the presence or absence of choline pretreatment, while cardiomyocyte hypertrophy was induced by Ang II 0.1 μM for 48 h. We found that choline pretreatment attenuated the increment cell size of cardiomyocytes induced by Ang II both in vivo and in vitro. The high ANP and β-MHC levels induced by Ang II were also reversed by choline in cardiomyocytes. Meanwhile, choline pretreatment prevented the augment of reactive oxygen species (ROS) and intracellular calcium concentration in Ang II-treated cardiomyocytes. Furthermore, the upregulated phospho-p38 mitogen-activated protein kinase (MAPK) and calcineurin levels by Ang II in ventricular myocytes were attenuated by choline. In conclusion, choline prevents Ang II-induced cardiac hypertrophy through inhibition of ROS-mediated p38 MAPK activation as well as regulation of Ca(2+)-mediated calcineurin signal transduction pathway. Our results provide new insights into the pharmacological role of choline in cardiovascular diseases.
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http://dx.doi.org/10.1007/s00210-012-0740-4DOI Listing
August 2012

Activation of cardiac M3 muscarinic acetylcholine receptors has cardioprotective effects against ischaemia-induced arrhythmias.

Clin Exp Pharmacol Physiol 2012 Apr;39(4):343-9

Department of Pharmacology, State-Province Key Laboratories of Biomedicine and Pharmaceutics, Harbin Medical University, Baojian Road 157, Harbin 150081, China.

Increasing evidence indicates the important roles of M(3) muscarinic acetylcholine receptors (M(3) mAChR) in the regulation and maintenance of cardiac function and heart disease. In the present study, we investigated whether the M(3) mAChR mediates the cardioprotection against ischaemia-induced arrhythmias and the mechanisms involved. Myocardial ischaemia was established in Wistar rats by occlusion of the left anterior descending coronary artery. Rats were treated with choline chloride (an M(3) mAChR agonist; 10 mg/kg, i.v.) 10 min before occlusion. In addition, 4-diphenylacetoxy-N-methylpiperidine-methiodide (4-DAMP; 0.12 μg/kg, i.v.) was administered 5 min before choline in the 4-DAMP-treated group. Ischaemia-induced arrhythmias were evaluated in each group for a period of 1 h after occlusion. After 24 h occlusion, protein and mRNA levels of L-type Ca(2+) channels and the Na(+) /Ca(2+) exchanger (NCX) were determined. Ischaemia-induced arrhythmias following coronary artery occlusion were diminished by choline and this effect was reversed in the 4-DAMP-treated group. In vitro, the effects of myocardial ischaemia were simulated by incubating isolated ventricular cardiomyocytes with Tyrode's solution (pH 6.8). Intracellular Ca(2+) overload was confirmed and this was decreased by choline. Furthermore, choline reduced the L-type Ca(2+) current (I(C) (a,) (L) ) compared with cardiomyocytes incubated in Tyrode's solution (pH 6.8) alone. Choline reduced the 'ischaemia'-induced upregulated expression of L-type Ca(2+) channels and NCX at both the protein and mRNA level. Based on these results, choline has an obvious protective effect against ischaemia-induced arrhythmias that is mediated via activation of cardiac M(3) mAChR, which reduces Ca(2+) overload mediated by L-type Ca(2+) channels and the NCX.
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http://dx.doi.org/10.1111/j.1440-1681.2012.05672.xDOI Listing
April 2012

Protective effect of lipid microspheres 1 on myocardial injury following elective percutaneous coronary intervention in patients with angina pectoris: a pilot study.

J Cardiovasc Med (Hagerstown) 2011 Nov;12(11):790-4

Department of Cardiology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.

Background: Prostaglandin E1 incorporated into lipid microspheres (lipo-PGE1) is effective in the treatment of peripheral vascular disorders and diabetic neuropathy. It is unknown whether it has protective effects in patients with angina pectoris undergoing percutaneous coronary intervention (PCI).

Objectives: The goal of this pilot study was to investigate whether lipo-PGE1 has protective effects in patients with angina pectoris undergoing PCI.

Methods: A single-blinded, randomized controlled trial was conducted in 79 patients with stable or unstable angina pectoris. The control group received standard medical therapy, and the Lipo-PGE1 group (n = 40) received 20 μg/day of lipo-PGE1 intravenously, starting at least 48 h before PCI and continuing for 5 days. Cardiac troponin T (cTnT) and creatine kinase myocardial isoenzyme (CK-MB) were measured before lipo-PGE1 infusion and at 6, 12 and 24 h after PCI.

Results: The cTnT and CK-MB concentrations were lower in the lipo-PGE1 group than in the control group at 6 h (0.15 ± 0.33 vs. 0.43 ± 0.77; 2.87 ± 3.99 vs. 5.64 ± 6.27, respectively; P < 0.05), 12 h (0.20 ± 0.48 vs. 0.54 ± 0.85; 3.58 ± 5.22 vs. 7.45 ± 9.48; P <  0.05) and 24 h (0.18 ± 0.50 vs. 0.50 ± 0.75; 3.15 ± 4.50 vs. 6.16 ± 6.83; P < 0.05). The incidence of postprocedural myocardial injury, defined as an elevation of cTnT more than 0.1 ng/ml or CK-MB more than 5.0 ng/ml, was less in the PGE1 group than in the control group (30 vs. 54%; 13 vs. 31%, respectively; P < 0.05). Lipo-PGE1 was well tolerated and there were no serious adverse events or side-effects.

Conclusions: Lipo-PGE1 treatment appears to reduce myocardial injury following elective PCI in angina patients.
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http://dx.doi.org/10.2459/JCM.0b013e32834bb47cDOI Listing
November 2011
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