Publications by authors named "Nai-Feng Liu"

38 Publications

Periostin promotes arterial calcification through PPARγ-related glucose metabolism reprogramming.

Am J Physiol Heart Circ Physiol 2021 Apr 9. Epub 2021 Apr 9.

Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, P.R., China.

Extracellular matrix (ECM) exerts a list of biological functions, contributing to almost 30% of the osteogenic process. Periostin is a secreted protein that can alter ECM remodeling in response to vascular injury. However, the functional role of periostin in vascular calcification has yet to be fully described. Ex vivo, recombinant periostin accelerated thoracic aortas calcification, increased the expression of glycolysis key enzymes, and disturbed the normal oxidative phosphorylation (OXPHOS), which could be alleviated by the peroxisome proliferation-activated receptor γ (PPARγ) agonist pioglitazone. In vascular smooth muscle cells (VSMCs), recombinant periostin promoted VSMC-osteoblastic phenotype transition and calcium deposition, and suppressed PPARγ expression. Mechanistically, recombinant periostin caused over-activation of glycolysis and mitochondrial dysfunction in VSMCs, as assessed by extracellular acidification rate (ECAR), oxygen consumption rate, and mitochondrial respiratory chain complexes activities. Targeted glycolysis inhibitors reduced mitochondrial calcium overload, apoptosis, and periostin-induced VSMCs calcification. PPARγ agonists preserved glycolysis and OXPHOS in the stimulated microenvironment, and reversed periostin-promoted VSMC calcification. Furthermore, plasma periostin, lactate, and matrix Gla protein levels were measured in 274 patients who underwent computed tomography to determine coronary artery calcium score (Agatston score). Plasma periostin and lactate levels were both linked to an Agatston score of more than zero in patients with coronary artery calcification. There is also a positive correlation between plasma periostin and lactate levels. This study suggests that downregulation of PPARγ is involved in the mechanism by which periostin accelerates arterial calcification, partly through excessive glycolysis activation and unbalanced mitochondrial homeostasis.
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http://dx.doi.org/10.1152/ajpheart.01009.2020DOI Listing
April 2021

POSTN promotes diabetic vascular calcification by interfering with autophagic flux.

Cell Signal 2021 Jul 17;83:109983. Epub 2021 Mar 17.

Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, 87 Dingjiaqiao, Nanjing 210009, PR China. Electronic address:

Autophagy is a lysosomal degradative process that is closely related to the pathogenesis of vascular calcification. Recent evidence suggests that periostin (POSTN) is a unique extracellular matrix protein that is associated with diabetic vascular complications. The aim of current study is to investigate the role of POSTN in diabetic vascular calcification and the underlying mechanisms. Results showed that POSTN was highly upregulated in both calcified arteries of diabetic rats and AGEs-BSA mediated vascular smooth muscle cell (VSMC) calcification. POSTN blocked autophagic flux during the diabetic calcification process, as evidenced by increased protein expression of Beclin1, LC3-II, and P62, as well as the co-localization of LC3-II and LAMP1. Inhibition of POSTN alleviated AGEs-BSA-induced autophagic flux blockade, thereby attenuating AGEs-BSA-induced VSMC calcification. Mechanistically, the upregulation of POSTN impaired the fusion of autophagosomes and lysosome and resulted in the autophagic flux blockade in AGEs-BSA-treated VSMC. Furthermore, this autophagic blockade was intracellular ROS-dependent. In summary, this study uncovered a novel mechanism of POSTN in autophagy regulation of diabetic vascular calcification.
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http://dx.doi.org/10.1016/j.cellsig.2021.109983DOI Listing
July 2021

Mitochondria Homeostasis and Vascular Medial Calcification.

Calcif Tissue Int 2021 Mar 3. Epub 2021 Mar 3.

Department of Cardiology, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009, People's Republic of China.

Vascular calcification occurs highly prevalent, which commonly predicts adverse cardiovascular events. The pathogenesis of calcification, a complicated and multifactorial process, is incompletely characterized. Accumulating evidence shows that mitochondrial dysfunction may ultimately be more detrimental in the vascular smooth muscle cells (VSMCs) calcification. This review summarizes the role of mitochondrial dysfunction and metabolic reprogramming in vascular calcification, and indicates that metabolic regulation may be a therapeutic target in vascular calcification.
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http://dx.doi.org/10.1007/s00223-021-00828-1DOI Listing
March 2021

Metformin attenuates hyperlipidaemia-associated vascular calcification through anti-ferroptotic effects.

Free Radic Biol Med 2021 Mar 26;165:229-242. Epub 2021 Jan 26.

Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University 87 Dingjiaqiao, Nanjing, 210009, PR China. Electronic address:

Ferroptosis is a form of regulated cell death that involves metabolic dysfunction resulting from iron-dependent excessive lipid peroxidation. Elevated plasma levels of free fatty acids are tightly associated with cardiometabolic risk factors in patients with obesity, diabetes mellitus, and metabolic syndrome. Metformin (Met) is an antidiabetic drug with beneficial cardiovascular disease effects. The aim of this study was to determine the effects of Met on ferroptosis induced by lipid overload and the effects of these changes on vascular smooth muscle cells (VSMCs) calcification. We developed a hyperlipidaemia-related vascular calcification in vivo model with rats fed a high-fat diet combined with vitamin D3 plus nicotine, and palmitic acid (PA), the most abundant long-chain saturated fatty acid in plasma, was used to induce lipid overload and develop an oxidative stress-related calcification model in vitro. The results showed that Met inhibits hyperlipidaemia-associated calcium deposition in the rat aortic tissue. In vitro, treatment of VSMCs with PA stimulates ferroptosis concomitant with increased calcium deposition in VSMCs, while pretreatment with Met attenuates these effects. Furthermore, PA also promotes the protein expression of the extracellular matrix protein periostin (POSTN) and its secretion into the extracellular environment. More importantly, upregulation of POSTN increased the sensitivity of cells to ferroptosis. Mechanistically, upregulation of POSTN suppresses SLC7A11 expression through the inhibition of p53 in VSMCs, which contributes to a decrease in glutathione synthesis and therefore triggers ferroptosis. Interestingly, overexpression of p53 attenuates the inhibitory effect of POSTN on SLC7A11 expression, accompanied by increased Gpx4 expression. Furthermore, p53 knockdown suppresses Met-mediated anti-ferroptosis effects in PA-treated VSMCs, which may be related to the downregulation of SLC7A11 expression. In addition, supplementation of VSMCs with Met enhances the antioxidative capacity of VSMCs through Nrf2 signalling activation. Collectively, targeting POSTN in VSMCs may provide a new strategy for vascular calcification prevention or treatment.
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http://dx.doi.org/10.1016/j.freeradbiomed.2021.01.033DOI Listing
March 2021

PDK4 promotes vascular calcification by interfering with autophagic activity and metabolic reprogramming.

Cell Death Dis 2020 11 17;11(11):991. Epub 2020 Nov 17.

Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, 87 Dingjiaqiao, Nanjing, 210009, P.R. China.

Pyruvate dehydrogenase kinase 4 (PDK4) is an important mitochondrial matrix enzyme in cellular energy regulation. Previous studies suggested that PDK4 is increased in the calcified vessels of patients with atherosclerosis and is closely associated with mitochondrial function, but the precise regulatory mechanisms remain largely unknown. This study aims to investigate the role of PDK4 in vascular calcification and the molecular mechanisms involved. Using a variety of complementary techniques, we found impaired autophagic activity in the process of vascular smooth muscle cells (VSMCs) calcification, whereas knocking down PDK4 had the opposite effect. PDK4 drives the metabolic reprogramming of VSMCs towards a Warburg effect, and the inhibition of PDK4 abrogates VSMCs calcification. Mechanistically, PDK4 disturbs the integrity of the mitochondria-associated endoplasmic reticulum membrane, concomitantly impairing mitochondrial respiratory capacity, which contributes to a decrease in lysosomal degradation by inhibiting the V-ATPase and lactate dehydrogenase B interaction. PDK4 also inhibits the nuclear translocation of the transcription factor EB, thus inhibiting lysosomal function. These changes result in the interruption of autophagic flux, which accelerates calcium deposition in VSMCs. In addition, glycolysis serves as a metabolic adaptation to improve VSMCs oxidative stress resistance, whereas inhibition of glycolysis by 2-deoxy-D-glucose induces the apoptosis of VSMCs and increases the calcium deposition in VSMCs. Our results suggest that PDK4 plays a key role in vascular calcification through autophagy inhibition and metabolic reprogramming.
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http://dx.doi.org/10.1038/s41419-020-03162-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673024PMC
November 2020

Lactate accelerates vascular calcification through NR4A1-regulated mitochondrial fission and BNIP3-related mitophagy.

Apoptosis 2020 06;25(5-6):321-340

Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, People's Republic of China.

Arterial media calcification is related to mitochondrial dysfunction. Protective mitophagy delays the progression of vascular calcification. We previously reported that lactate accelerates osteoblastic phenotype transition of VSMC through BNIP3-mediated mitophagy suppression. In this study, we investigated the specific links between lactate, mitochondrial homeostasis, and vascular calcification. Ex vivo, alizarin S red and von Kossa staining in addition to measurement of calcium content, RUNX2, and BMP-2 protein levels revealed that lactate accelerated arterial media calcification. We demonstrated that lactate induced mitochondrial fission and apoptosis in aortas, whereas mitophagy was suppressed. In VSMCs, lactate increased NR4A1 expression, leading to activation of DNA-PKcs and p53. Lactate induced Drp1 migration to the mitochondria and enhanced mitochondrial fission through NR4A1. Western blot analysis of LC3-II and p62 and mRFP-GFP-LC3 adenovirus detection showed that NR4A1 knockdown was involved in enhanced autophagy flux. Furthermore, NR4A1 inhibited BNIP3-related mitophagy, which was confirmed by TOMM20 and BNIP3 protein levels, and LC3-II co-localization with TOMM20. The excessive fission and deficient mitophagy damaged mitochondrial structure and impaired respiratory function, determined by mPTP opening rate, mitochondrial membrane potential, mitochondrial morphology under TEM, ATP production, and OCR, which was reversed by NR4A1 silencing. Mechanistically, lactate enhanced fission but halted mitophagy via activation of the NR4A1/DNA-PKcs/p53 pathway, evoking apoptosis, finally accelerating osteoblastic phenotype transition of VSMC and calcium deposition. This study suggests that the NR4A1/DNA-PKcs/p53 pathway is involved in the mechanism by which lactate accelerates vascular calcification, partly through excessive Drp-mediated mitochondrial fission and BNIP3-related mitophagy deficiency.
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http://dx.doi.org/10.1007/s10495-020-01592-7DOI Listing
June 2020

Lactate accelerates calcification in VSMCs through suppression of BNIP3-mediated mitophagy.

Cell Signal 2019 06 6;58:53-64. Epub 2019 Mar 6.

Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, PR China. Electronic address:

Arterial media calcification is one of the major complications of diabetes mellitus, which is related to oxidative stress and apoptosis. Mitophagy is a special regulation of mitochondrial homeostasis and takes control of intracellular ROS generation and apoptotic pathways. High circulating levels of lactate usually accompanies diabetes. The potential link between lactate, mitophagy and vascular calcification is investigated in this study. Lactate treatment accelerated VSMC calcification, evaluated by measuring the calcium content, ALP activity, RUNX2, BMP-2 protein levels, and Alizarin red S staining. Lactate exposure caused excessive intracellular ROS generation and VSMC apoptosis. Lactate also impaired mitochondrial function, determined by mPTP opening rate, mitochondrial membrane potential and mitochondrial biogenesis markers. Western blot analysis of LC3-II and p62 and mRFP-GFP-LC3 adenovirus detection for autophagy flux revealed that lactate blocked autophagy flux. LC3-II co-staining with LAMP-1 and autophagosome quantification revealed lactate inhibited autophagy. Furthermore, lactate inhibited mitophagy, which was confirmed by TOMM20 and BNIP3 protein levels, LC3-II colocalization with BNIP3 and TEM assays. In addition, BNIP3-mediated mitophagy played a protective role against VSMC calcification in the presence of lactate. This study suggests that lactate accelerates osteoblastic phenotype transition of VSMC and calcium deposition partly through the BNIP3-mediated mitophagy deficiency induced oxidative stress and apoptosis.
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http://dx.doi.org/10.1016/j.cellsig.2019.03.006DOI Listing
June 2019

Impact of smoking on all-cause mortality and cardiovascular events in patients after coronary revascularization with a percutaneous coronary intervention or coronary artery bypass graft: a systematic review and meta-analysis.

Coron Artery Dis 2019 08;30(5):367-376

Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing.

Although cigarette smoking is an independent risk factor for cardiovascular disease, inconsistent results have been published in the literature on its impacts on the cardiovascular health of patients after coronary revascularization with a percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG). We performed a comprehensive electronic database search through July 2018. Studies reporting the risk estimates of all-cause mortality and cardiovascular outcomes in patients after coronary revascularization with PCI or CABG on the basis of smoking status were selected. Multivariate-adjusted relative risks (RRs) and 95% confidence intervals (CIs) were pooled using random-effects models with inverse variance weighting. Data from 37 records including 126 901 participants were finally collected. Overall, the pooled RR (95% CI) associated with cigarette smoking was 1.26 (95% CI: 1.09-1.47) for all-cause mortality, 1.08 (95% CI: 0.92-1.28) for major adverse cardiovascular events, 0.96 (95% CI: 0.69-1.35) for cardiovascular mortality and 1.15 (95% CI: 0.81-1.64) for myocardial infarction. The increased risk of all-cause mortality was also observed in former smokers compared with those who had never smoked (RR: 1.19; 95% CI: 1.03-1.38). Furthermore, the negative effects of cigarette smoking on all-cause mortality were also observed in most subgroups. Cigarette smoking has been shown to increase the likelihood of all-cause mortality in patients after coronary revascularization with PCI or CABG. Smoking cessation is essential for PCI or CABG patients to manage their coronary artery disease.
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http://dx.doi.org/10.1097/MCA.0000000000000711DOI Listing
August 2019

Involvement of brain-derived neurotrophic factor in exercise‑induced cardioprotection of post-myocardial infarction rats.

Int J Mol Med 2018 Nov 24;42(5):2867-2880. Epub 2018 Aug 24.

Department and Institute of Cardiology, Zhongda Hospital, Medical School of Southeast University, Nanjing, Jiangsu 210009, P.R. China.

Exercise induces a number of benefits, including angiogenesis in post‑myocardial infarction (MI); however, the underlying mechanisms have not been fully clarified. Neurotrophic brain‑derived neurotrophic factor (BDNF) serves a protective role in certain adult cardiac diseases through its specific receptor, BDNF/NT‑3 growth factors receptor (TrkB). The present study explored the mechanisms by which exercise improves cardiac function, with a focus on the involvement of the BDNF/TrkB axis. MI rats were assigned to Sham, sedentary, exercise, exercise with K252a (a TrkB inhibitor), and exercise with NG‑nitro‑L‑arginine methyl ester (L‑NAME) groups. The exercise group was subjected to 8 weeks of treadmill running. The results demonstrated that the rats in the exercise group exhibited increased myocardial angiogenesis and improved cardiac function, which was attenuated by K252a. Exercise induced activation of the BDNF/TrkB axis in the ischaemic myocardium and increased serum BDNF levels were abated by exposure to L‑NAME. Improvements in angiogenesis and left ventricular function exhibited a positive association, with changes in serum BDNF. In the in vitro experiments, human umbilical vein endothelial cells were exposed to shear stress (SS) of 12 dyn/cm2 to mimic the effects of exercise training on vascular tissue. An increased tube‑forming capacity, and a nitric oxide (NO)‑dependent prolonged activation of the BDNF/TrkB‑full‑length axis over 12 h, but not the TrkB‑truncated axis, was observed. The SS‑related angiogenic response was attenuated by TrkB inhibition. Overall, these results demonstrate that exercise confers certain aspects of its cardioprotective effects through the activation of the BDNF/TrkB axis in an NO‑dependent manner, a process in which fluid‑induced SS may serve a crucial role.
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http://dx.doi.org/10.3892/ijmm.2018.3841DOI Listing
November 2018

Advanced glycation end products accelerate calcification in VSMCs through HIF-1α/PDK4 activation and suppress glucose metabolism.

Sci Rep 2018 09 13;8(1):13730. Epub 2018 Sep 13.

Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, P.R. China.

Arterial media calcification is associated with diabetes mellitus. Previous studies have shown that advanced glycation end products (AGEs) are responsible for vascular smooth muscle cell (VSMC) calcification, but the underlying mechanisms remain unclear. Hypoxia-inducible factor-1α (HIF-1α), one of the major factors during hypoxia, and pyruvate dehydrogenase kinase 4 (PDK4), an important mitochondrial matrix enzyme in cellular metabolism shift, have been reported in VSMC calcification. The potential link among HIF-1α, PDK4, and AGEs-induced vascular calcification was investigated in this study. We observed that AGEs elevated HIF-1α and PDK4 expression levels in a dose-dependent manner and that maximal stimulation was attained at 24 h. Two important HIF-1α-regulated genes, vascular endothelial growth factor A (VEGFA) and glucose transporter 1 (GLUT-1), were significantly increased after AGEs exposure. Stabilization or nuclear translocation of HIF-1α increased PDK4 expression. PDK4 inhibition attenuated AGEs-induced VSMC calcification, which was evaluated by measuring the calcium content, alkaline phosphatase (ALP) activity and runt-related transcription factor 2 (RUNX2) expression levels and by Alizarin red S staining. In addition, the glucose consumption, lactate production, key enzymes of glucose metabolism and oxygen consumption rate (OCR) were decreased during AGEs-induced VSMC calcification. In conclusion, this study suggests that AGEs accelerate vascular calcification partly through the HIF-1α/PDK4 pathway and suppress glucose metabolism.
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http://dx.doi.org/10.1038/s41598-018-31877-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6137084PMC
September 2018

Restoring mitochondrial biogenesis with metformin attenuates β-GP-induced phenotypic transformation of VSMCs into an osteogenic phenotype via inhibition of PDK4/oxidative stress-mediated apoptosis.

Mol Cell Endocrinol 2019 01 29;479:39-53. Epub 2018 Aug 29.

Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, 87 Dingjiaqiao, Nanjing 210009, PR China. Electronic address:

Mitochondrial abnormalities have long been observed in the development of vascular calcification. Metformin, a member of the biguanide class of antidiabetic drugs, has recently received attention owing to new findings regarding its protective role in cardiovascular disease. Since the precise control of mitochondrial quantity and quality is critical for the survival and function of vascular smooth muscle cells (VSMCs), maintaining mitochondrial homeostasis may be a potential protective factor for VSMCs against osteoblast-like phenotypic transition. However, limited studies have been reported in this area. Here, we investigated the role of metformin in the phenotypic transformation of VSMCs, as well as its intracellular signal transduction pathways. We demonstrated that supplementation with metformin restored the β-glycerophosphate (β-GP)-mediated impairment of mitochondrial biogenesis in VSMCs, as evidenced by an increased mitochondrial DNA copy number, a restored mitochondrial membrane potential (MMP), and upregulated mitochondrial biogenesis-related gene expression, whereas the AMP-activated protein kinase (AMPK) inhibitor compound C suppressed these effects. We also observed that overexpression of pyruvate dehydrogenase kinase 4 (PDK4), an important mitochondrial matrix enzyme in cellular energy metabolism, exacerbated β-GP-induced oxidative stress and subsequent apoptosis in VSMCs but that these effects were suppressed by dichloroacetate, a widely reported PDK4 inhibitor. More importantly, enhanced mitochondrial biogenesis attenuated the β-GP-induced phenotypic transformation of VSMCs into an osteogenic phenotype through inhibition of the PDK4/oxidative stress-mediated apoptosis pathway, whereas disruption of mitochondrial biogenesis by zidovudine aggravated β-GP-induced apoptosis in VSMCs. In addition, inhibition of autophagy by small interfering RNA targeting Atg5 reduced mitochondrial biogenesis in VSMCs. In summary, we uncovered a novel mechanism by which metformin attenuates the phenotypic transformation of VSMCs into an osteogenic phenotype via inhibition of the PDK4/oxidative stress-mediated apoptosis pathway, and mitochondrial homeostasis is involved in this process.
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http://dx.doi.org/10.1016/j.mce.2018.08.012DOI Listing
January 2019

Association of genetic polymorphisms in vascular endothelial growth factor with susceptibility to coronary artery disease: a meta-analysis.

BMC Med Genet 2018 07 4;19(1):108. Epub 2018 Jul 4.

Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, 87 Dingjiaqiao, Nanjing, 210009, People's Republic of China.

Background: Single nucleotide polymorphisms (SNPs) located in the vascular endothelial growth factor (VEGF) gene may be correlated with the susceptibility to coronary artery disease (CAD) - although results have been controversial. The aim of this meta-analysis is to clarify the effects of VEGF -2578A/C (rs699947), -1154G/A (rs1570360), +405C/G (rs2010963), and + 936C/T (rs3025039) polymorphisms on CAD risk.

Methods: Pooled odds ratio (OR) and corresponding 95% confidence intervals (CIs) were calculated to estimate the strength of the association between VEGF gene polymorphisms and CAD risk. Fixed- or random-effects model was used depending on the heterogeneity between studies.

Results: In total, 13 eligible articles containing 29 studies were analysed. The pooled analysis indicated that the VEGF gene polymorphisms of rs699947, rs2010963, and rs3025039 were associated with an increased risk of CAD, whereas no significant associations were observed with the rs1570360 polymorphism. A subgroup analysis stratified by ethnicity revealed that the rs699947 and rs3025039 polymorphisms were associated with CAD risk in Asian populations. In addition, stratification by control source indicated an increased risk of CAD susceptibility with the rs699947 polymorphism for population-based studies of reduced heterogeneity.

Conclusions: In summary, we concluded that the VEGF gene polymorphisms rs699947, rs2010963, and rs3025039 are correlated with an elevated CAD risk.
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http://dx.doi.org/10.1186/s12881-018-0628-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6031176PMC
July 2018

Associations between gene polymorphisms and coronary artery disease: evidence based on an updated and cumulative meta-analysis.

Biosci Rep 2018 Feb 19. Epub 2018 Feb 19.

Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, 87 Ding Jiaqiao, Nanjing, P.R.China, Nanjing, 210009, China

Lipoprotein lipase (LPL) is widely linked to lipid and lipoprotein metabolism, but its effects on coronary artery disease (CAD) are not clearly elucidated. The aim of this study was to clarify the association between gene polymorphisms and CAD susceptibility. The pooled odds ratio (OR) and 95% confidence interval (CI) were calculated to estimate the strength of the relationship between gene polymorphisms and CAD risk. Comprehensive electronic databases, including PubMed, EMBASE, Web of Science, and the Cochrane Library, were systematically searched. A total of 45 records containing 80 eligible studies were analyzed. The results indicated an increased risk between the D9N polymorphism and susceptibility to CAD in the dominant genetic model (AA + GA vs. GG: OR = 1.46, 95% CI = 1.14-1.87), whereas the HindIII polymorphism showed a protective effect against CAD under all tested models (GG+GT vs. TT: OR = 0.85, 95% CI = 0.75-0.97; GG vs. TT + TG: OR = 0.62, 95% CI = 0.47-0.83; G vs. T: OR = 0.81, 95% CI = 0.71-0.92). No significant association was identified for the N291S and PvuII polymorphisms. Stratification analysis by ethnicity suggested a significant correlation between the S447X polymorphism and CAD susceptibility in Caucasians under the dominant and allele genetic models. In summary, our meta-analysis indicated that the D9N polymorphism was associated with an increased risk of CAD, whereas the S447X and HindIII polymorphisms showed protective effects. There was no association observed between the N291S and PvuII polymorphisms and CAD risk.
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http://dx.doi.org/10.1042/BSR20171642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5857905PMC
February 2018

Comparative efficacy of pharmacological interventions for contrast-induced nephropathy prevention after coronary angiography: a network meta-analysis from randomized trials.

Int Urol Nephrol 2018 Jun 5;50(6):1085-1095. Epub 2018 Feb 5.

Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, 87 Dingjiaqiao, Nanjing, 210009, People's Republic of China.

Background: Contrast-induced nephropathy (CIN) is the major complication related to contrast media administration in patients after coronary angiography (CAG). However, inconsistent results have been published in the literature regarding the effects of pharmacological drugs on CIN prevention. We conducted a network meta-analysis to evaluate the relative efficacy of pharmacological interventions for the prevention of CIN.

Methods: We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from inception to July 2017. We included any randomized controlled trials of eleven pharmacological interventions that reported the prevention of CIN.

Results: We identified 3850 records through database searches, of which 107 studies comprising 21,450 participants were finally identified. Compared with intravenous saline, intravenous saline plus pharmacological drugs including statin [relative risk (RR) 0.57; 95% credibility interval (CrI) 0.39 to 0.83], N-acetylcysteine (NAC) (RR 0.84; 95% CrI, 0.71 to 0.98), vitamin and its analogues (RR 0.66; 95% CrI 0.45 to 0.97), brain natriuretic peptide (BNP) and its analogues (RR 0.46; 95% CrI 0.30 to 0.70), prostaglandin analogues (RR 0.37; 95% CrI 0.18 to 0.76), NAC plus sodium bicarbonate (SB) (RR 0.60; 95% CrI 0.39 to 0.90), and statin plus NAC (RR 0.39; 95% CrI 0.21 to 0.70), have helped to reduce the incidence of CIN in patients after CAG. The top four ranked treatments were statin plus NAC, BNP and its analogues, statin, and vitamin and its analogues, respectively. NAC plus intravenous saline was associated with lower incidence of short-term all-cause mortality than intravenous saline alone (RR 0.62; 95% CI, 0.40 to 0.96; P = 0.03). However, no evidence indicated that any of the pharmacological drugs were associated with a reduced requirement for dialysis and major adverse cardiac and cerebrovascular events (MACCE).

Conclusions: Statin plus NAC plus intravenous saline seems to be the most effective treatment for the prevention of CIN in patients after CAG. NAC plus intravenous saline may have a protective role against short-term all-cause mortality. However, none of these drugs has effectively decreased the requirement for dialysis and MACCE.
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http://dx.doi.org/10.1007/s11255-018-1814-0DOI Listing
June 2018

A Folate-Conjugated Dual-Modal Fluorescent Magnetic Resonance Imaging Contrast Agent that Targets Activated Macrophages In Vitro and In Vivo.

J Biomed Nanotechnol 2016 Dec;12(12):2161-71

Mucin-1 (MUC1), a transmembrane glycoprotein is aberrantly expressed on ∼90% of breast cancer and is an excellent target for nanoparticulate targeted imaging. In this study, the development of a dye-doped NIR emitting mesoporous silica nanoparticles platform conjugated to tumor-specific MUC1 antibody (ab-tMUC1-NIR-MSN) for in vivo optical detection of breast adenocarcinoma tissue is reported. The structural properties, the in vitro and in vivo performance of this nanoparticle-based probe were evaluated. In vitro studies showed that the MSN-based optical imaging nanoprobe is non-cytotoxic and targets efficiently mammary cancer cells overexpressing human tMUC1 protein. In vivo experiments with female C57BL/6 mice indicated that this platform accumulates mainly in the liver and did not induce short-term toxicity. In addition, we demonstrated that the ab-tMUC1-NIR-MSN nanoprobe specifically detects mammary gland tumors overexpressing human tMUC1 in a human MUC1 transgenic mouse model.
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http://dx.doi.org/10.1166/jbn.2016.2316DOI Listing
December 2016

Nε-carboxymethyl-lysine promotes calcium deposition in VSMCs via intracellular oxidative stress-induced PDK4 activation and alters glucose metabolism.

Oncotarget 2017 Dec 1;8(68):112841-112854. Epub 2017 Dec 1.

Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing 210009, P.R. China.

Diabetes and vascular calcification are intrinsically linked. We previously reported that advanced glycation end products (AGEs) accelerate calcium deposition in vascular smooth muscle cells (VSMCs) via excessive oxidative stress. However, the underlying mechanism remains poorly understood. Pyruvate dehydrogenase kinase 4 (PDK4) is an important mitochondrial matrix enzyme in cellular energy metabolism. Since hyperactivation of PDK4 has been reported in calcified vessels and in patients with diabetes mellitus, inhibition of PDK4 expression may be a strategy for the prevention of diabetic vascular calcification. In this study, we used a rat VSMC model to investigate the role of PDK4 in diabetic vascular calcification and further explore the underlying mechanisms. We observed that Nε-carboxymethyl-lysine (CML), which is a major immunogen of AGEs, accelerated calcium deposition in VSMCs through PDK4 activation. An elevated level of reactive oxygen species (ROS) acted as a signal transduction intermediate to increase PDK4 expression. Either inhibition of PDK4 expression or RAGE (receptor for AGEs) blockade attenuated CML-induced VSMC calcification, as shown by decreased alkaline phosphatase (ALP) activity and runt-related transcription factor 2 (RUNX2) expression. Glucose consumption and lactate production were increased during CML-induced VSMC calcification. Importantly, CML accelerates glycolysis in VSMCs via a PDK4-dependent pathway. In conclusion, this study demonstrates a novel mechanism by which CML promotes VSMC calcification via PDK4 activation and alters glucose metabolism in VSMCs.
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http://dx.doi.org/10.18632/oncotarget.22835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5762555PMC
December 2017

Association of RAGE gene Gly82Ser polymorphism with coronary artery disease and ischemic stroke: A systematic review and meta-analysis.

Medicine (Baltimore) 2016 Dec;95(49):e5593

Department of Cardiology Department of Nephrology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, PR China.

Background: The receptor for advanced glycosylation end products (RAGE) has been widely linked to diabetic atherosclerosis, but its effects on coronary artery disease (CAD) and ischemic stroke (IS) remain controversial. The Gly82Ser polymorphism is located in the ligand-binding V domain of RAGE, suggesting a possible influence of this variant on RAGE function. The aim of the present study is to clarify the association between the RAGE Gly82Ser polymorphism and susceptibility to CAD and IS.

Methods: Eligible studies were identified through a comprehensive literature search. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the association of Gly82Ser polymorphism with CAD and IS risk. Fixed- or random-effects model was used depending on the heterogeneity between studies. A funnel plot and Egger linear regression test were applied to assess publication bias. We also performed subgroup analyses to investigate potential sources of heterogeneity.

Results: A total of 16 eligible articles containing 18 studies were analyzed. The pooled analysis indicated that the Gly82Ser polymorphism significantly increased CAD risk in recessive and homozygous genetic models (SS vs GS + GG: OR = 1.34, 95% CI = 1.09-1.64; SS vs GG: OR = 1.38, 95% CI = 1.12-1.71). A significant association between the Gly82Ser polymorphism and IS risk was observed in all tested models except the heterozygous genetic model (GS + SS vs GG: OR = 1.20, 95% CI = 1.04-1.38; SS vs GS + GG: OR = 2.20, 95% CI = 1.74-2.78; SS vs GG: OR = 2.23, 95% CI = 1.72-2.91; S vs G: OR = 1.32, 95% CI = 1.05-1.65). Subgroup analysis suggested an association between CAD and IS risk and the Gly82Ser polymorphism in the Chinese population, but not in the non-Chinese population.

Conclusions: The current meta-analysis suggests that the RAGE Gly82Ser polymorphism is associated with an increased risk of CAD and IS, especially in the Chinese population. However, better-designed studies with larger sample sizes are needed to validate the results.
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http://dx.doi.org/10.1097/MD.0000000000005593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5266052PMC
December 2016

Associations between XRCC1 Gene Polymorphisms and Coronary Artery Disease: A Meta-Analysis.

PLoS One 2016 21;11(11):e0166961. Epub 2016 Nov 21.

Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, 87 Dingjiaqiao, Nanjing, 210009, P.R. China.

Genetic variations that influence DNA repair efficiency may contribute to coronary artery disease (CAD) susceptibility. Previous studies have investigated whether there was evidence of an association between polymorphisms at the X-ray repair cross complementing 1 (XRCC1) gene and susceptibility to CAD, but findings have been inconclusive. We identified eligible studies through a comprehensive literature search to determine whether an association exists between XRCC1 gene polymorphisms and CAD susceptibility. Findings were assessed using the odds ratio (OR) and corresponding 95% confidence interval (CI), which were calculated using a fixed- or random-effects model, based on the heterogeneity of the studies. Ten eligible studies were finally included in this meta-analysis. Our pooled analysis found that XRCC1 polymorphisms were significantly associated with CAD susceptibility under recessive (Arg194Trp: OR = 1.47, 95% CI = 1.13-1.93; Arg399Gln: OR = 1.45, 95% CI = 1.12-1.89), homozygous (Arg194Trp: OR = 1.37, 95% CI = 1.03-1.81; Arg399Gln: OR = 1.56, 95% CI = 1.19-2.05), and allele (Arg399Gln: OR = 1.18, 95% CI = 1.06-1.32) genetic models. Following subgroup analysis by ethnicity, in Asian populations, we found evidence of associations between the XRCC1 Arg194Trp polymorphism and CAD under recessive and homozygous genetic models, and between the XRCC1 Arg399Gln polymorphism and CAD under recessive, homozygous, and allele genetic models. Subgroup analysis stratified by control source revealed associations between the Arg194Trp and Arg399Gln polymorphisms and susceptibility to CAD under recessive and homozygous modes of inheritance, respectively. In addition, subgroup analysis stratified by sample size found that findings of the Arg194Trp polymorphism in large sample sizes were comparable to those found using pooled eligible studies. Based on our meta-analysis, we concluded that the XRCC1 gene polymorphisms, Arg194Trp and Arg399Gln, are associated with CAD susceptibility, specifically in Asian populations. However, additional, comprehensive and well-designed studies are warranted to confirm these findings.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0166961PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5117741PMC
June 2017

Left ventricular subclinical dysfunction associated with myocardial deformation changes in obstructive sleep apnea patients estimated by real-time 3D speckle-tracking echocardiography.

Sleep Breath 2016 Mar 24;20(1):135-44. Epub 2015 May 24.

Department of Cardiology, Zhongda Hospital, Southeast University School of Medicine, Nanjing, China.

Background: Previous studies have demonstrated that patients with obstructive sleep apnea (OSA) may develop left ventricular (LV) diastolic dysfunction. We aimed to study whether OSA patients have LV regional systolic dysfunction with myocardial deformation changes, despite a normal LV ejection fraction, using real-time 3D speckle-tracking echocardiography (Rt3D-STE).

Methods: Seventy-eight patients with OSA and no comorbidities were studied. They were divided into the following three groups according to the apnea-hypopnea index (AHI): 5~15/h as group I (mild OSA, 26 cases), 15~30/h as group II (moderate OSA, 29 cases), and ≥30/h as group III (severe OSA, 23 cases). Thirty gender-age-matched normal subjects were included as controls. The parameters of LV diastolic function were acquired with traditional echocardiography. The LV myocardial deformation parameters were obtained, including the longitudinal (LS), circumferential (CS), radial (RS), and area (AS) strains, with Rt3D-STE.

Results: LV global systolic function was normal in all patients, but diastolic function was impaired in groups II and III (E/E' was 9.6 ± 2.8 and 10.4 ± 2.5, respectively, p < 0.0001). The global LS and AS were significantly reduced in groups II and III compared with the controls and group I (LS 15.9 ± 1.4 % and 14.8 ± 1.5 % vs 18.2 ± 1.7 % and 17.8 ± 1.5 %; AS 27.4 ± 1.8 % and 24.9 ± 2.3 % vs 33.4 ± 2.2 % and 32.7 ± 2.9 %, respectively, p < 0.0001), but the global CS and RS were significantly reduced only in group III (17.3 ± 1.4 % and 43.1 ± 6.5 % vs 19.6 ± 1.6 % and 55.4 ± 4.0 %, respectively, <0.0001). The severity of OSA was significantly associated with the LV global AS value (r = -0.80, p < 0.0001), LS (r = -0.64, p < 0.0001), CS (r = -0.51, p < 0.0001), and RS (r = -0.62, p < 0.0001).

Conclusions: Patients with moderate and severe OSA tended to have both LV diastolic dysfunction and abnormalities in regional systolic function with myocardial deformation changes, in spite of the normal LV ejection fraction. Myocardial strains of the LV were negatively correlated with the AHI. Rt-3DST had important clinical significance in the early evaluation of cardiac dysfunction in OSA patients.
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http://dx.doi.org/10.1007/s11325-015-1197-8DOI Listing
March 2016

Evaluation of left ventricular function by three-dimensional speckle-tracking echocardiography in patients with myocardial bridging of the left anterior descending coronary artery.

J Am Soc Echocardiogr 2015 Jun 18;28(6):674-82. Epub 2015 Mar 18.

Department of Cardiology, Zhongda Hospital, Southeast University School of Medicine, Nanjing, China. Electronic address:

Background: To understand the influence of myocardial bridging (MB) on left ventricular (LV) function, myocardial function was studied in patients with MB of the left anterior descending coronary artery (LAD) using three-dimensional speckle-tracking echocardiography (STE).

Methods: Left anterior descending coronary artery MB was diagnosed by coronary angiography in 82 subjects. Patients were divided into three groups according to the percentage of systolic narrowing of the compressed segment: 30% to 49% was defined as group I (24 patients), 50% to 74% as group II (28 patients), and ≥75% as group III (30 patients). Thirty gender- and age-matched normal subjects were included as controls. Left ventricular myocardial deformation was estimated by three-dimensional STE.

Results: Left ventricular ejection fractions were normal in all patients, but diastolic function was impaired in groups II and III (E/E' ratio, 9 ± 3 and 10 ± 3, respectively). The amplitudes of longitudinal strain (LS) and area strain (AS) of the LAD territory was significantly reduced in groups II and III compared with controls and group I (LS, -15 ± 2% and -12 ± 1% vs -19 ± 2% and -18 ± 2%; AS, -22 ± 2% and -13 ± 2% vs -33 ± 4% and -33 ± 3%; P < .0001), but the amplitudes of circumferential and radial strain showed no intergroup differences. Longitudinal strain and AS were significantly lower in patients with fractional flow reserve < 0.75 than in those with fractional flow reserve ≥ 0.75 (P < .0001), with relative preservation of circumferential and radial strain. The severity of LAD compression was significantly associated with AS and LS of the LAD territory (r = -0.92 and r = -0.84, respectively, P < .0001), but the correlations with circumferential and radial strain were modest (r = -0.36 and r = -0.32, respectively, P < .05).

Conclusions: With the increasing severity of systolic compression of the mural coronary artery, LV diastolic function and regional systolic deformation (AS and LS) of the MB perfusion territory were reduced. Three-dimensional STE can detect subtle myocardial dysfunction in patients with MB.
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http://dx.doi.org/10.1016/j.echo.2015.02.012DOI Listing
June 2015

Coronary tortuosity is associated with reversible myocardial perfusion defects in patients without coronary artery disease.

Chin Med J (Engl) 2012 Oct;125(19):3581-3

Department of Cardiology, Zhongda Hospital, Southeast University, Nanjing, Jiangsu 210009, China.

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October 2012

Erythropoietin attenuates cardiac dysfunction by increasing myocardial angiogenesis and inhibiting interstitial fibrosis in diabetic rats.

Cardiovasc Diabetol 2012 Sep 7;11:105. Epub 2012 Sep 7.

Department and Institute of Cardiology, Zhongda Hospital, Medical School of Southeast University, 87 Dingjiaqiao street, Nanjing 210009, China.

Background: Recent studies revealed that erythropoietin (EPO) has tissue-protective effects in the heart by increasing vascular endothelial growth factor (VEGF) expression and attenuating myocardial fibrosis in ischemia models. In this study, we investigated the effect of EPO on ventricular remodeling and blood vessel growth in diabetic rats.

Methods: Male SD rats were randomly divided into 3 groups: control rats, streptozotocin (STZ)-induced diabetic rats, and diabetic rats treated with 1000 U/kg EPO by subcutaneous injection once per week. Twelve weeks later, echocardiography was conducted, and blood samples were collected for counting of peripheral blood endothelial progenitor cells (EPCs). Myocardial tissues were collected, quantitative real-time PCR (RT-PCR) was used to detect the mRNA expression of VEGF and EPO-receptor (EPOR), and Western blotting was used to detect the protein expression of VEGF and EPOR. VEGF, EPOR, transforming growth factor beta (TGF-β), and CD31 levels in the myocardium were determined by immunohistochemistry. To detect cardiac hypertrophy, immunohistochemistry of collagen type I, collagen type III, and Picrosirius Red staining were performed, and cardiomyocyte cross-sectional area was measured.

Results: After 12 weeks STZ injection, blood glucose increased significantly and remained consistently elevated. EPO treatment significantly improved cardiac contractility and reduced diastolic dysfunction. Rats receiving the EPO injection showed a significant increase in circulating EPCs (27.85 ± 3.43%, P < 0.01) compared with diabetic untreated animals. EPO injection significantly increased capillary density as well as EPOR and VEGF expression in left ventricular myocardial tissue from diabetic rats. Moreover, EPO inhibited interstitial collagen deposition and reduced TGF-β expression.

Conclusions: Treatment with EPO protects cardiac tissue in diabetic animals by increasing VEGF and EPOR expression levels, leading to improved revascularization and the inhibition of cardiac fibrosis.
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http://dx.doi.org/10.1186/1475-2840-11-105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3527329PMC
September 2012

Fatty acid desaturase 1 polymorphisms are associated with coronary heart disease in a Chinese population.

Chin Med J (Engl) 2012 Mar;125(5):801-6

Department of Epidemiology and Biostatistics, Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 210029, China.

Background: A recent genome-wide association study in Caucasians revealed that three loci (rs174547 in fatty acid desaturase 1 (FADS1), rs2338104 near mevalonate kinase/methylmalonic aciduria, cobalamin deficiency, cblB type (MVK/MMAB) and rs10468017 near hepatic lipase (LIPC)) influence the plasma concentrations of high-density lipoprotein-cholesterol (HDL-C) and triglycerides (TG). However, there are few reports on the associations between these polymorphisms and plasma lipid concentrations in Chinese individuals. This study aimed to evaluate the associations between these three polymorphisms with HDL-C and TG concentrations, as well as coronary heart disease (CHD) susceptibility in Chinese individuals.

Methods: We conducted a population-based case-control study in Chinese individuals to evaluate the associations between these three polymorphisms and HDL-C and TG concentrations, and also evaluated their associations with susceptibility to CHD. Genotypes were determined using polymerase chain reaction-restriction fragment length polymorphism assays and TaqMan genotyping assays.

Results: We found significant differences in TG and HDL-C concentrations among the TT, TC and CC genotypes of FADS1 rs174547 (P=0.017 and 0.003, respectively, multiple linear regression). The CC variant of rs174547 was significantly associated with hyperlipidemia compared with the TT variant (adjusted odds ratio (OR)=1.71, 95% confidence intervals (CI): 1.16-2.54). The FADS1 rs174547 CC variant was also associated with significantly increased CHD risk compared with the TT and TC variant (adjusted OR=1.53, 95%CI: 1.01-2.31), and the effect was more evident among nonsmokers and females. The polymorphisms rs2338104 and rs10468017 did not significantly influence HDL-C or TG concentrations in this Chinese population.

Conclusion: rs174547 in FADS1 may contribute to the susceptibility of CHD by altering HDL-C and TG levels in Chinese individuals.
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March 2012

Efficiently tracking of stem cells in vivo using different kinds of superparamagnetic iron oxide in swine with myocardial infarction.

Chin Med J (Engl) 2011 Apr;124(8):1199-204

Department of Cardiovascular Research Center, Zhongda Hospital, Southeast University, Nanjing, Jiangsu, China.

Background: Superparamagnetic iron oxide (SPIO) particles have shown much promise as a means to visualize labeled cells using molecular magnetic resonance imaging (MRI). Micrometer-sized superparamagnetic iron oxide (MPIO) particles and nanometer-sized ultrasmall superparamagnetic iron oxide (USPIO) are two kinds of SPIO widely used for monitoring stem cells migration. Here we compare the efficiency of two kinds of SPIO during the use of stem cells to treat acute myocardial infarction (AMI).

Methods: An AMI model in swine was created by 60 minutes of balloon occlusion of the left anterior descending coronary artery. Two kinds of SPIO particles were used to track after intracoronary delivered 10(7) magnetically labeled mesenchymal stem cells (MR-MSCs). The distribution and migration of the MR-MSCs were assessed with the use of 3.0T MR scanner and then the results were confirmed by histological examination.

Results: MR-MSCs appeared as a local hypointense signal on T₂*-weighted MRI and there was a gradual loss of the signal intensity after intracoronary transplantation. All of the hypointense signals in the USPIO-labeled group were found on T₂*-weighted MRI, contrast to noise ratio (CNR) decreased in the MPIO-labeled group (16.07 ± 5.85 vs. 10.96 ± 1.34) and USPIO-labeled group (11.72 ± 1.27 vs. 10.03 ± 0.96) from 4 to 8 weeks after transplantation. However, the hypointense signals were not detected in MPIO-labeled group in two animals. MRI and the results were verified by histological examination.

Conclusions: We demonstrated that two kinds of SPIO particles in vitro have similar labeling efficiency and viability. USPIO is more suitable for labeling stem cells when they are transplanted via a coronary route.
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April 2011

Effects of heme oxygenase-1 gene modulated mesenchymal stem cells on vasculogenesis in ischemic swine hearts.

Chin Med J (Engl) 2011 Feb;124(3):401-7

Department of Cardiology, Zhongda Hospital, Southeast University, Nanjing, Jiangsu 210009, China.

Background: Mesenchymal stem cells (MSCs) transplantation may partially restore heart function in the treatment of acute myocardial infarction (AMI). The aim of this study was to explore the beneficial effects of MSCs modified with heme xygenase-1 (HO-1) on post-infarct swine hearts to determine whether the induction of therapeutic angiogenesis is modified by the angiogenic cytokines released from the implanted cells.

Methods: In vitro, MSCs were divided into four groups: (1) non-transfected MSCs (MSCs group), (2) MSCs transfected with the pcDNA3.1-Lacz plasmid (Lacz-MSCs group), (3) MSCs transfected with pcDNA3.1-hHO-1 (HO-1-MSCs group), and (4) MSCs transfected with pcDNA3.1-hHO-1 and pretreatment with an HO inhibitor, tin protoporphyrin (SnPP) (HO-1-MSCs + SnPP group). Cells were cultured in an airtight incubation bottle for 24 hours, in which the oxygen concentration was maintained at < 1%, followed by 12 hours of reoxygenation. After hypoxia/reoxygen treatment, ELISA was used to measure transforming growth factor (TGF-β) and fibroblast growth factor (FGF-2) in the supernatant. In vivo, 28 Chinese mini-pigs were randomly allocated to the following treatment groups: (1) control group (saline), (2) Lacz-MSCs group, (3) HO-1-MSCs group, and (4) HO-1-MSCs + SnPP group. About 1 × 10(7) of autologous stem cells or an identical volume of saline was injected intracoronary into porcine hearts 1 hour after MI. Magnetic resonance imaging (MRI) assay and postmortem analysis were assessed four weeks after stem cell transplantation.

Results: Post hypoxia/reoxygenation in vitro, TGF-β in the supernatant was significantly increased in the HO-1-MSCs ((874.88 ± 68.23) pg/ml) compared with Lacz-MSCs ((687.81 ± 57.64) pg/ml, P < 0.001). FGF-2 was also significantly increased in the HO-1-MSCs ((1106.48 ± 107.06) pg/ml) compared with the Lacz-MSCs ((853.85 ± 74.44) pg/ml, P < 0.001). In vivo, at four weeks after transplantation, HO-1 gene transfer increased the capillary density in the peri-infarct area compared with the Lacz-MSCs group (14.24 ± 1.66/HPFs vs. 11.51 ± 1.34/HPFs, P < 0.001). Arteriolar density was also significantly higher in HO-1-MSCs group than in the Lacz-MSCs group (7.86 ± 2.00/HPFs vs. 6.45 ± 1.74/HPFs, P = 0.001). At the same time, the cardiac function was significantly improved in the HO-1-MSCs group compared with the Lacz-MSCs group ((53.17 ± 3.55)% vs. (48.82 ± 2.98)%, P < 0.05). However, all these effects were significantly abrogated by SnPP.

Conclusion: MSCs provided a beneficial effect on cardiac function after ischemia/reperfusion by the induction of therapeutic angiogenesis, and this effect was amplified by HO-1 overexpression.
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February 2011

Fluvastatin attenuates myocardial interstitial fibrosis and cardiac dysfunction in diabetic rats by inhibiting over-expression of connective tissue growth factor.

Chin Med J (Engl) 2011 Jan;124(1):89-94

Department of Cardiology, Zhongda Hospital, Southeast University, Nanjing, Jiangsu 210009, China.

Background: Diabetic myocardiopathy is characterized by myocardial interstitial fibrosis and cardiac dysfunction. Statins were found to exert protective effects on cardiovascular disease by suppressing activation of small G proteins, independently of their lipid-lowering effect. The study investigated the effect of fluvastatin on myocardial interstitial fibrosis, cardiac function and mechanism of its action in diabetic rats.

Methods: Twenty-four male SD rats were randomly assigned to 3 groups: control rats (n = 8), streptozotocin (STZ)-induced diabetic rats (n = 8), and diabetic rats treated with fluvastatin (administered fluvastatin orally, 10 mg/kg body weight per day, n = 8). Twelve weeks later, miniature cardiac catheter was inserted into the left ventricle to conduct hemodynamic examination. Then myocardium tissues were collected, collagen content was detected by picro-sirius red staining, real-time quantitative reverse transcription polymerase chain reaction (RT-PCR) was used to detect the mRNA expression of connective tissue growth factor (CTGF), and Western blotting was used to detect the protein expression of CTGF. Rho activity was determined by pull-down assay.

Results: After 12 weeks, the left ventricular systolic pressure (LVSP) and maximum rate of left ventricular (LV) pressure rise and fall (+dP/dt max and -dP/dt max) were significantly lower and left ventricular end diastolic pressure (LVEDP) was higher in the diabetic rats than those in the control rats (P < 0.01). Moreover, in LV myocardial tissue of diabetic rats the collagen content, fibronectin, mRNA and protein expression of CTGF and the activity of RhoA were all significantly increased compared with the control rats (P < 0.01). Administration of fluvastain obviously improved the cardiac function of diabetic rats, attenuated fibronectin expression, mRNA and protein expression of CTGF and the activity of RhoA in LV myocardium of diabetic rats.

Conclusions: Fluvastatin attenuates cardiac dysfunction and myocardial interstitial fibrosis of diabetic rat by inhibiting activity of RhoA to down-regulate the overexpression of CTGF, and Rho/Rho-kinase pathway may be an important target in the treatment of diabetic cardiomyopathy.
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January 2011

[Clinical impact and underlying mechanism of clopidogrel response variability].

Zhonghua Xin Xue Guan Bing Za Zhi 2010 Aug;38(8):759-62

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August 2010

The level of connective tissue growth factor in sera of patients with hepatitis B virus strongly correlates with stage of hepatic fibrosis.

Viral Immunol 2010 Feb;23(1):71-8

Center of Clinical Laboratory Medicine, Zhongda Hospital, Southeast University, Nanjing, China.

Connective tissue growth factor (CTGF) plays a crucial role in the formation and development of hepatic fibrosis. The aim of this study was to establish a method for CTGF determination in order to investigate the level of CTGF in the sera of patients with hepatitis B virus, and to assess the correlation between CTGF concentration and stage of hepatic fibrosis. A CTGF C-terminal region gene was obtained by RT-PCR of human mesangial kidney cells and inserted into pET-32a((+)) vector. Recombinant protein was obtained by expression and purification of the fused protein. Polyclonal and monoclonal antibodies were prepared to establish a sandwich ELISA method. CTGF levels in 18 healthy serum samples and 83 serum samples from patients with hepatitis B virus were assessed. A simple, sensitive, and noninvasive method of determining CTGF levels was successfully established. CTGF levels in the sera of patients with hepatitis B were significantly increased compared controls (p < 0.001). There was a strong correlation between CTGF concentration and fibrotic stage (r = 0.8906, p < 0.005). No significant association was found between CTGF level and the grade of hepatic inflammation (p > 0.05). The area under the receiver operating characteristic (ROC) curves of CTGF was 0.681 for identification of significant fibrosis, and 0.759 for the diagnosis of middle- and late-stage fibrosis. Accuracy of CTGF assessment was independent of age, renal function, liver function, platelet count, or other biochemical markers of liver fibrosis (all p > 0.05). No significant correlation was found between CTGF and several humoral factors associated with liver fibrosis (all p > 0.05). The levels of CTGF in the sera of patients with hepatitis B were strongly associated with the stages of hepatic fibrosis, and CTGF may become a useful diagnostic aid in assessing hepatic fibrosis.
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http://dx.doi.org/10.1089/vim.2009.0067DOI Listing
February 2010

[Effects of autologous mesenchymal stem cells transfected with heme oxygenase-1 gene transplantation on ischemic Swine hearts].

Zhonghua Xin Xue Guan Bing Za Zhi 2009 Aug;37(8):692-5

Department of Cardiology, Zhongda Hospital, Southeast University, Nanjing 210009, China.

Objective: To observe the effect of intracoronary transfer of autologous HO-1 overexpressed MSCs in porcine model of myocardial ischemia (1 h)/reperfusion.

Methods: Apoptosis was assayed and cytokine concentrations in supernatant were measured in cells exposed to hypoxia-reoxygen in vitro. In vivo, Chinese male mini-pigs were allocated to the following treatment groups: control group (saline), MSCs group (MSCs), MSCs transfected with pcDNA3.1-nHO-1 (HO-1-MSCs). 1 x 10(7) of autologous stem cells or identical volume of saline was injected intracoronary into porcine hearts 1 h after ischemia. MRI assay and postmortem analysis were assessed 3 months after stem cell transplantation.

Results: In vitro, cell apoptosis rate post hypoxia-reoxygen was significantly reduced in HO-1-MSCs group (30.30% +/- 7.64%) compared with that in MSCs group (56.93% +/- 4.68%, P < 0.001) and LacZ-MSCs group (55.88% +/- 4.38%, P < 0.001), VEGF was also significantly upregulated in HO-1-MSCs group [(768.44 +/- 78.38) pg/ml] compared with that in MSCs group [(555.27 +/- 67.67) pg/ml, P < 0.001] and LacZ-MSCs group [(522.97 +/- 71.45) pg/ml, P < 0.001]. In vivo, cardiac function was significantly improved in both MSCs transplantation groups compared to saline group (all P < 0.05 vs.saline) and the left ventricular ejection fraction was significantly higher in HO-1-MSCs group compared with that in MSCs group at 3 months after transplantation (53.50% +/- 2.09% vs. 49.54% +/- 2.74%, P = 0.017), capillary density in the peri-infarct area was also significantly higher in HO-1-MSC group than that in MSCs group [(14.59 +/- 2.39)/HPF vs. (11.78 +/- 2.48)/HPF, P = 0.033].

Conclusions: Efficacy of HO-1 overexpressed MSCs on improving cardiac function and promoting angiogenesis was greater than those by MSCs in this porcine ischemia/reperfusion model.
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August 2009

Effects of advanced glycosylation end products and rosiglitazone on the expression and secretion of galectin-3 in human renal mesangial cells.

Chin Med J (Engl) 2009 May;122(9):1067-71

Department of Endocrinology, Zhongda Hospital, Southeast University, Nanjing, Jiangsu, China.

Background: Galectin-3 is the most recently identified advanced glycosylation end products (AGEs) binding protein. This study aimed to investigate the effects of AGEs and rosiglitazone on the expression and secretion of galectin-3 in cultured human renal mesangial cells (HRMCs).

Methods: HRMCs were incubated with different concentrations of AGE-bovine serum albumin (BSA) (0, 50, 100, 200, and 400 mg/L) for different time (0, 24, 36, 48, and 72 hours), and exposed to AGE-BSA in the presence of different concentrations of rosiglitazone (1, 10, and 100 micromol/L). The mRNA and protein expression of galectin-3 in HRMCs were analyzed by reverse transcription polymerase chain reaction (RT-PCR) and Western blotting. The culture medium of HRMCs was collected and concentrated, and the content of galectin-3 in the medium was detected by Western blotting.

Results: Both RT-PCR and Western blotting revealed that AGE-BSA up-regulated the expression of galectin-3 in HRMCs in a concentration- (P < 0.05) and time-dependent (P < 0.05) manner compared with the control. Compared with the control, AGE-BSA elevated the content of galectin-3 in the culture medium of HRMCs time- and concentration-dependently (P < 0.05, respectively). Both protein and mRNA expression of galectin-3, and its content in the medium of HRMCs exposed to different concentrations of rosiglitazone in the presence of AGE-BSA were increased compared with those of cells exposed to AGE-BSA alone (P < 0.05). Rosiglitazone increased the expression and secretion of galectin-3 in a dose-dependent manner (P < 0.05).

Conclusions: AGEs up-regulates the expression and secretion of galectin-3 in HRMCs. Rosiglitazone further enhances the upregulation of galectin-3 in HRMCs induced by AGEs, which suggests that rosiglitazone may play a role of reno-protection via up-regulation of galectin-3.
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May 2009