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ABSTRACT: OBJECTIVES: CD4CD25 regulatory T cells (Tregs) play a key role in the prevention of various inflammatory and autoimmune disorders by suppressing immune responses. The beneficial effect of statins on myocardial ischemia-reperfusion injury (IRI) depends in part on their immunomodulatory and anti-inflammatory mechanisms. We aimed to determine whether Tregs contribute to statin-induced cardioprotection against myocardial IRI. METHODS: Thirty-two rats were divided into four groups: sham, ischemia-reperfusion (IR), rosuvastatin (RSV)/IR, and mevalonic acid (MVA)+RSV/IR. Myocardial IR was induced by a 30-min coronary occlusion, followed by a 48-h reperfusion. RSV (5 mg/kg) was administered intravenously 18 h before IR. The rats were killed after 48-h reperfusion. Serum cardiac troponin I (cTnI) was measured by ELISA, infiltration of inflammatory cells in myocardium by hematoxylin and eosin staining, expression of FoxP3 protein by western blotting, accumulation of Tregs in myocardium by immunohistochemical examination, and infarct size by TTC staining. RESULTS: Significant elevation in serum cTnI, enlarged infarct size, and marked infiltration of inflammatory cells in myocardium were observed in the IR group. The administration of RSV significantly reduced the serum cTnI level, attenuated the accumulation of inflammatory cells, decreased infarct size, and increased the FoxP3 expression and Treg accumulation in myocardium compared with the IR group. The combination of RSV and MVA pretreatment partially abolished the anti-inflammatory and infarct size-limiting effects and completely reversed Treg accumulation in myocardium induced by RSV. The accumulation of inflammatory cells was negatively correlated with FoxP3 expression and Treg accumulation in the ischemic myocardium. CONCLUSION: RSV pretreatment was associated with more Treg accumulation, less inflammatory response, and myocardial injury, suggesting that such cardioprotection against IRI was partially mediated by Treg-negative modulation of inflammation response, probably through the HMG-CoA reductase pathway.
Coronary artery disease 03/2013; · 1.56 Impact Factor
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ABSTRACT: To investigate the role of connexin 43-formed hemichannels in cell volume regulation induced by simulated ischemia/reperfusion (SI/R).
Mouse cardiomyocytes isolated on a Langendorff apparatus with enzyme solution were aliquoted into control, SI/R and SI/R +octanol groups. Calcein-AM was used to stain the cells and the cell volume was measured with confocal microscope by stack scanning. Trypan blue was used to measure the cell viability after the treatments.
Calcein-AM staining and cofocal microscopy yielded stable and reproducible results for cell volume measurement. Mouse cardiomyocytes subjected to simulated SI/R showed obvious cell swelling as compared with the control cells [(126∓6)% vs 100%, P<0.05], and octanol preconditioning significantly attenuated the cell swelling [(113∓6)%, P<0.05]. SI/R caused a significant reduction of the cell viability compared to the control cells [(19∓2)% vs (45∓3)%, P<0.01], and octanol preconditioning obviously reduced the viability of the cells with SI/R challenge [(31∓2)%, P<0.01].
Connexin 43-formed hemichannels are involved in the regulation of cardiomyocyte volumes induced by SI/R challenge, and octanol can alleviate the cell swelling to enhance the viability of the cardiomyocytes following SI/R.
Nan fang yi ke da xue xue bao = Journal of Southern Medical University 10/2012; 32(10):1419-22.
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ABSTRACT: Ischemic postconditioning (IPC) is cardioprotective against ischemia-reperfusion injury which impairs the myocardial micro-environment and reduces the survival of transplanted cells. We tested the hypothesis that IPC may improve the survival of transplanted cells and enhance their therapeutic effects. In this study, bone marrow-derived mesenchymal stem cells (BMSCs) from Sprague-Dawley rats were infected with lentivirus carrying green fluorescent protein (GFP) gene. The left main coronary arteries of rats were occluded for a 30-min ischemia, followed by a 72 h or 28 d reperfusion. IPC was induced by 3 cycles of 10s reperfusion and 10s ischemia before sustained reperfusion. GFP-BMSCs were intramyocardially injected at 2h reperfusion. At 70 h after transplantation, IPC treatment increased the level of interleukin-10, B-cell leukemia-lymphoma-2 (BCL-2), and vascular endothelial and basic fibroblast growth factor (VEGF and bFGF), and decreased the level of tumor necrosis factor-α, interleukin-1β and BCL-2-associated X protein by ELISA or PCR or western blotting. The BMSCs therapy with IPC produced more surviving GFP-positive cells than the BMSCs therapy alone by fluorescent staining [at 70 h, (90 ± 14)/mm(2) vs. (61 ± 12)/mm(2), and at 28 days, (55 ± 14)/mm(2) vs. (26 ± 8)/mm(2), P<0.01, respectively]. At 28 days, it, when compared with the Control, IPC treatment, and BMSCs therapy, demonstrated higher left ventricular ejection fraction by echocardiography (62%± 8%, 69%± 6%, and 75%± 4% vs. 82%± 4%, P<0.05, respectively), higher expression of VEGF and bFGF by western blotting and PCR, less myocardial fibrosis by Masson's trichrome staining, and higher capillary density by immunohistochemistry. These results suggest that ischemic postconditioning promotes the survival of transplanted cells and enhances their repair of infarcted myocardium through paracrine mechanisms.
Journal of Molecular and Cellular Cardiology 06/2011; 51(5):839-47. · 5.17 Impact Factor
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ABSTRACT: to investigate the combined effect of rosuvastatin (RSV) and ischemic postconditioning (PC) on myocardial ischemia-reperfusion (I/R) injury in a type 2 diabetic rat model.
type 2 diabetic (induced by streptozotocin plus nicotinamide) rats, undergoing 30 min ischemia and 120 min reperfusion, were divided into six groups (n = 10 each): Sham, I/R without other interventions, RSV before reperfusion, PC with 3 cycles of 10 s reperfusion and 10 s ischemia, RSV + PC and RSV + PC + PI3-K inhibitor LY294002. Myocardial infarct size (IS), ultrastructural change and myocardial expression of phosphorylated eNOS/total eNOS were determined.
IS and ultrastructural damages were all significantly reduced and myocardial eNOS phosphorylation was significantly increased in RSV and PC groups compared with the I/R group (all P < 0.05) these beneficial effects were further enhanced by RSV + PC (all P < 0.05 vs. RSV and PC, respectively). The beneficial effects were significantly attenuated by PI3K inhibitor LY294002.
the results indicate that RSV + PC could alleviate myocardial ischemia-reperfusion injury in this type 2 diabetic model by activating PI3K/AKT/eNOS signaling pathway.
Zhonghua xin xue guan bing za zhi [Chinese journal of cardiovascular diseases] 09/2010; 38(9):814-8.
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ABSTRACT: To investigate the effect of survivin (SVV)-engineered mesenchymal stem cells (MSCs) on post-infarction cardiac performance and remodelling in rats.
Mesenchymal stem cells from male Sprague-Dawley rat bone marrow were infected with the self-inactive lentiviral vector GFP-wre-CMV/LTR and Flap-Ubiqutin promoter (GCFU) carrying green fluorescent protein (GFP) gene and SVV recombinant vector (GCFU-SVV). In vitro, modification with SVV increased the secretion of vascular endothelial growth factor (VEGF) by 1.28-fold under hypoxic conditions. In vivo, after permanent left anterior descending artery occlusion, rats were randomized (n = 18 per group) to receive intra-myocardial injections of 100 microL of phosphate-buffered saline without cells (group vehicle) or containing 2 million MSC(GFP) (group MSC(GFP)) or MSC(SVV) (group MSC(SVV)) cells. Cellular survival assessed by reverse transcriptase-polymerase chain reaction for GFP in the MSC(SVV) group was 2.5-fold higher at 7 days and 4.3-fold higher at 28 days after transplantation than in the MSC(GFP) group. When compared with transplantation with MSC(GFP), transplantation with MSC(SVV) further upregulated VEGF expression at 7 and 28 days after myocardial infarction (MI), increased capillary density by 38%, reduced the infarct size by 12.7%, significantly inhibited collagen deposition, and further improved cardiac function at 28 days after MI.
Transplantation with SVV-engineered MSCs by lentiviral vector leads to better prognosis for MI by enhancing cellular survival.
European Journal of Heart Failure 11/2009; 11(11):1023-30. · 4.90 Impact Factor
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ABSTRACT: It remains unknown whether brief occlusion and relaxation of remote non-infarct-related coronary arteries limits infarct size. We tested the hypothesis that repetitive, brief, non-infarcting ischemia in one remote myocardial region, applied before sustained reperfusion to another intra-cardiac vasculature following infarcting ischemia, attenuates ischemia-reperfusion injury.
In anesthetized open-chest rats, the left main coronary artery (LCA) was occluded for 30 min followed by sustained relaxation for 120 min. All rats were randomly allocated to six groups (n=8): Control: without other interventions; Intra-cardiac remote ischemic post-conditioning (R-Post): before LCA relaxation, 3 cycles of 10 s ischemia by occluding the circumflex branch and 10 s reperfusion by relaxing it were applied; Atractyloside (Atr): given intravenously with atractyloside, an opener of the mitochondrial permeability transition pore; R-Post + Atr; Classical ischemic post-conditioning (Post): 3 cycles of 10 s reperfusion followed by 10 s ischemia were applied before 120 min of LCA relaxation; Sham: without LCA occlusion. We evaluated infarct size, cardiac function, cardiomyocyte ultrastructure and inflammatory processes.
Compared with Control, at the end of sustained reperfusion, R-Post and Post had smaller infarcts (respectively, 49%+/-5% vs. 32%+/-6% and 26%+/-5%, p<0.05), higher left ventricular +/-dP/dt(max), slighter ultrastructural damage, lower malondialdehyde activity and higher superoxide dismutase activity in plasma and myocardium, and lower myeloperoxidase activity in myocardium. R-Post-induced cardioprotection was abrogated by atractyloside.
Intra-cardiac remote ischemic post-conditioning attenuates myocardial ischemia-reperfusion injury, and inhibition of the mitochondrial permeability transition pore opening may be involved in this cardioprotection.
Scandinavian cardiovascular journal: SCJ 04/2009; 43(6):386-94. · 1.07 Impact Factor
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ABSTRACT: The effect of inhibiting mitochondrial permeability transition (MPT) on cardioprotection induced by ischaemic postconditioning remains debatable. The aim of the present study was to investigate whether ischaemic postconditioning attenuates cardiomyocyte ultrastructure injury and apoptosis by blocking MPT.
Sprague-Dawley rats were randomly allocated to eight groups (n = 12) including sham without ischaemia (I), control given 30 min 1 and 5 min or 120 min reperfusion (R), postconditioning (Post) treated the same as control and 3 cycles of 10 s R and 10 s I before R, preconditioning (Pre) treated the same as control and 3 cycles of 5 min 1 and 5 min R before 30 min 1, and other groups treated the same as control or Post and given cyclosporin A (CsA) or atractyloside (Atr). Infarct size was evaluated by TTC, ultrastructure by electron microscope, MPT by spectrophotometry, and apoptosis by TUNEL. Compared with the control treatment, the Post, CsA and Pre treatments had smaller infarct size, less reduction in optical density at 540 nm (OD540) for MPT (20.2% +/- 2.3% versus 12.1% +/- 1.8%, 11.2% +/- 3.3% and 12.1% +/- 5.6%, P < 0.01, respectively), lower mitochondrial score (2.09 +/- 0.27 versus 1.27 +/- 0.27, 0.97 +/- 0.26 and 1.28 +/- 0.32, P < 0.01, respectively) and percentage of apoptosis (34.9% +/- 2.6% versus 17.5% +/- 1.7%, 17.6% +/- 2.1% and 17.2% +/- 2.1%, P < 0.01, respectively). Post-induced cardioprotection was abrogated by Atr and failed to be enhanced by CsA.
Blockage of MPT may be involved in attenuation of ultrastructure injury and apoptosis by ischaemic postconditioning.
Acta cardiologica 07/2008; 63(3):377-87. · 0.61 Impact Factor
