Delayed cardioprotective effects of WY-14643 are associated with inhibition of MMP-2 and modulation of Bcl-2 family proteins through PPAR-α activation in rat hearts subjected to global ischaemia–reperfusion

2013 ◽  
Vol 91 (8) ◽  
pp. 608-616 ◽  
Author(s):  
Eleftheria Barlaka ◽  
Veronika Ledvényiová ◽  
Eleftheria Galatou ◽  
Miroslav Ferko ◽  
Slávka Čarnická ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Matrix Metalloproteinase ◽  
Left Ventricular ◽  
Matrix Metalloproteinase 2 ◽  
Heme Oxygenase 1 ◽  
Mrna Levels ◽  
Acute Ischaemia ◽  
Ischaemia Reperfusion ◽  
Rat Hearts ◽  
Selective Ligand

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors regulating cardiac lipid metabolism and energy homeostasis. Although the activation of PPARs has been implicated in cardioprotection, the molecular mechanisms are largely unexplored. In this study, we aimed to investigate the effect of the PPAR-α agonist WY-14643 (WY), mimicking a delayed effect of preconditioning in rat hearts exposed to acute ischaemia–reperfusion (I/R) 24 h later, and to define whether antioxidative and antiapoptotic mechanisms are involved. Treatment with WY markedly attenuated post-ischaemic contractile dysfunction (as evidenced by the reduced infarct size), the higher left ventricular developed pressure (LVDP) recovery, and the decreased occurrence of arrhythmias. These effects were abolished in the presence of the PPAR-α antagonist MK886. Heme oxygenase-1, a key antioxidative enzyme implicated in cytoprotection, was upregulated in response to WY at baseline, but was markedly reduced after I/R, indicating reduced oxidative stress. WY treatment was also associated with decreased mRNA levels and enzymatic activity of matrix metalloproteinase-2, and increased ratios of Bcl-2:Bax proteins. These results indicate that PPAR-α activation by its selective ligand WY may confer delayed preconditioning-like protection in rat hearts subjected to I/R by modulating oxidative stress, activation of matrix metalloproteinase-2, and expression of Bcl-2 and Bax.

PPAR-alpha activation as a preconditioning-like intervention in rats in vivo confers myocardial protection against acute ischaemia–reperfusion injury: involvement of PI3K–Akt

2012 ◽  
Vol 90 (8) ◽  
pp. 1135-1144 ◽  
Author(s):  
Táňa Ravingerová ◽  
Slávka Čarnická ◽  
Martina Nemčeková ◽  
Veronika Ledvényiová ◽  
Adriana Adameová ◽  
...  
Keyword(s):  
Target Genes ◽  
Left Ventricular ◽  
Metabolic Effects ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Akt Inhibitor ◽  
Ischaemia Reperfusion Injury ◽  
Acute Ischaemia ◽  
Ischaemia Reperfusion

Peroxisome proliferator-activated receptors (PPAR) regulate the expression of genes involved in lipid metabolism, energy production, and inflammation. Their role in ischaemia–reperfusion (I/R) is less clear, although research indicates involvement of PPARs in some forms of preconditioning. This study aimed to explore the effects of PPAR-α activation on the I/R injury and potential cardioprotective downstream mechanisms involved. Langendorff-perfused hearts of rats pretreated with the selective PPAR-α agonist WY-14643 (WY, pirinixic acid; 3 mg·(kg body mass)·day–1; 5 days) were subjected to 30 min ischaemia – 2 h reperfusion with or without the phosphatidylinositol 3-kinase (PI3K)–Akt inhibitor wortmannin for the evaluation of functional (left ventricular developed pressure, LVDP) recovery, infarct size (IS), and reperfusion-induced arrhythmias. A 2-fold increase in baseline PPAR-α mRNA levels (qPCR) in the WY-treated group and higher post-I/R PPAR-α levels compared with those in untreated controls were accompanied by similar changes in the expression of PPAR-α target genes PDK4 and mCPT-1, regulating glucose and fatty acid metabolism, and by enhanced Akt phosphorylation. Post-ischaemic LVDP restoration in WY-treated hearts reached 60% ± 9% of the pre-ischaemic values compared with 24% ± 3% in the control hearts (P < 0.05), coupled with reduced IS and incidence of ventricular fibrillation that was blunted by wortmannin. Results indicate that PPAR-α up-regulation may confer preconditioning-like protection via metabolic effects. Downstream mechanisms of PPAR-α-mediated cardioprotection may involve PI3K–Akt activation.

scholarly journals High Matrix Metalloproteinase Production Correlates with Immune Activation and Leukocyte Migration in Leprosy Reactional Lesions

2009 ◽  
Vol 78 (3) ◽  
pp. 1012-1021 ◽  
Author(s):  
Rosane M. B. Teles ◽  
Rose B. Teles ◽  
Thais P. Amadeu ◽  
Danielle F. Moura ◽  
Leila Mendonça-Lima ◽  
...  
Keyword(s):  
Matrix Metalloproteinase ◽  
Cultured Cells ◽  
Leukocyte Migration ◽  
Therapeutic Interventions ◽  
Matrix Metalloproteinase 2 ◽  
Mrna Levels ◽  
Membrane Breakdown ◽  
Tnf Α ◽  
Ifn Γ

ABSTRACT Gelatinases A and B (matrix metalloproteinase 2 [MMP-2] and MMP-9, respectively) can induce basal membrane breakdown and leukocyte migration, but their role in leprosy skin inflammation remains unclear. In this study, we analyzed clinical specimens from leprosy patients taken from stable, untreated skin lesions and during reactional episodes (reversal reaction [RR] and erythema nodosum leprosum [ENL]). The participation of MMPs in disease was suggested by (i) increased MMP mRNA expression levels in skin biopsy specimens correlating with the expression of gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α), (ii) the detection of the MMP protein and enzymatic activity within the inflammatory infiltrate, (iii) increased MMP levels in patient sera, and (iv) the in vitro induction of MMP-9 by Mycobacterium leprae and/or TNF-α. It was observed that IFN-γ, TNF-α, MMP-2, and MMP-9 mRNA levels were higher in tuberculoid than lepromatous lesions. In contrast, interleukin-10 and tissue inhibitor of MMP (TIMP-1) message were not differentially modulated. These data correlated with the detection of the MMP protein evidenced by immunohistochemistry and confocal microscopy. When RR and ENL lesions were analyzed, an increase in TNF-α, MMP-2, and MMP-9, but not TIMP-1, mRNA levels was observed together with stronger MMP activity (zymography/in situ zymography). Moreover, following in vitro stimulation of peripheral blood cells, M. leprae induced the expression of MMP-9 (mRNA and protein) in cultured cells. Overall, the present data demonstrate an enhanced MMP/TIMP-1 ratio in the inflammatory states of leprosy and point to potential mechanisms for tissue damage. These results pave the way toward the application of new therapeutic interventions for leprosy reactions.

Abstract 337: Activation of Myocardial AMP-activated Protein Kinase by Metformin Prevents Progression of Heart Failure in Dogs; Involvement of eNOS Activation

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Hideyuki Sasaki ◽  
Hiroshi Asanuma ◽  
Masashi Fujita ◽  
Hiroyuki Takahama ◽  
Masanori Asakura ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Heart Failure ◽  
Cell Death ◽  
Protein Kinase ◽  
Left Ventricular ◽  
Vehicle Group ◽  
Mrna Levels ◽  
Compound C ◽  
Amp Activated Protein Kinase

Background; Several studies have shown that metformin activates AMP-activated protein kinase (AMPK), which mediates potent cardioprotection against ischemia-reperfusion injury. AMPK is also activated in experimental failing myocardium, suggesting that activation of AMPK is beneficial for the pathophysiology of heart failure. We investigated whether metformin prevents oxidative stress-induced cell death in rat cardiomyocytes and attenuates the progression of heart failure in dogs. Methods and Results; The treatment with metformin (10 μmol/L) protected the rat cultured cardiomyocytes against cell death due to H 2 O 2 exposure (50 μmol/L) as indicated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), TUNEL staining, and flow cytometry. These effects were blunted by an AMPK inhibitor, compound-C (20 μmol/L), suggesting that the activation of AMPK decreased the extent of apoptosis-induced cell death due to H 2 O 2 exposure. Continuous rapid ventricular pacing (230/min for 4 weeks) in dogs caused heart failure and the treatment with metformin (100 mg/kg/day PO, n=8) decreased left ventricular (LV) end-diastolic dimension (32.8±0.4 vs. 36.5±1.0 mm, p< 0.01) and pressure (11.8±1.1 vs. 22±0.9 mmHg, p< 0.01), and increased LV fractional shortening (18.6±1.8 vs. 9.6±0.7 %, p< 0.01) along with enhanced phosphorylation of AMPK and the decreased the number of TUNEL-positive cells of the LV myocardium compared with the vehicle group (n=8). Interestingly, metformin increased the protein and mRNA levels of endothelial nitric oxide synthase of the LV myocardium and plasma nitric oxide levels. Metformin improved the plasma insulin resistance without increased myocardial GLUT-4 translocation. Furthermore, the subcutaneous administration of AICAR (50 mg/kg/every other day), another AMPK activator mediated the equivalent effects to metformin, strengthening the pivotal role of AMPK in reduction of apoptosis and prevention of heart failure. Conclusions; Activation of myocardial AMPK attenuated the oxidative stress-induced cardiomyocyte apoptosis and prevented the progression of heart failure in dogs, along with eNOS activation. Thus, metformin or AICAR may be applicable as a novel therapy for heart failure.

scholarly journals Hesperidin Prevents Nitric Oxide Deficiency-Induced Cardiovascular Remodeling in Rats via Suppressing TGF-β1 and MMPs Protein Expression

2018 ◽  
Author(s):  
Putcharawipa Maneesai ◽  
Sarawoot Bunbupha ◽  
Prapassorn Potue ◽  
Thewarid Berkban ◽  
Upa Kukongviriyapan ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Tumor Necrosis Factor ◽  
Matrix Metalloproteinase ◽  
Protein Expression ◽  
Wall Thickness ◽  
Tumor Necrosis ◽  
Left Ventricular ◽  
Matrix Metalloproteinase 2 ◽  
Cardiovascular Remodeling ◽  
Necrosis Factor

Hesperidin is a major flavonoid isolated from citrus fruits that exhibits several biological activities. This study aims to evaluate the effect of hesperidin on cardiovascular remodeling induced by N-nitro L-arginine methyl ester (L-NAME) in rats.&nbsp; Male Sprague-Dawley rats were treated with L-NAME (40 mg/kg); L-NAME plus hesperidin (15 mg/kg), or hesperidin (30 mg/kg), or captopril (2.5 mg/kg) for five weeks (n = 8/group). Hesperidin or captopril significantly prevented the development of hypertension in L-NAME rats.&nbsp; Moreover, hesperidin or captopril alleviated L-NAME-induced cardiac remodeling; increases in wall thickness, cross sectional area (CSA) and fibrosis of left ventricular (LV), and vascular remodeling; increases in wall thickness, CSA, vascular smooth muscle cells and collagen deposition in the aorta. These were associated with reduced oxidative stress markers, tumor necrosis factor-alpha (TNF-&alpha;), transforming growth factor-beta 1 (TGF-&beta;1) and enhancing plasma nitric oxide metabolite (NOx) in L-NAME treated groups. Furthermore, up-regulation of tumor necrosis factor receptor type 1 (TNF-R1) and TGF-&beta;1 protein expression and the over-expression of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) were suppressed in L-NAME rats treated with hesperidin or captopril. These data suggested that hesperidin had cardioprotective effects in L-NAME hypertensive rats. The possible mechanism may involve its antioxidant and anti-inflammatory effects.

Differential regulation of MMP-2, TIMP-2 and IL-6 in valve replacement versus CABG patients

Perfusion ◽  
2002 ◽  
Vol 17 (6) ◽  
pp. 435-439 ◽  
Author(s):  
Masazumi Watanabe ◽  
Satoru Hasegawa ◽  
Nagahisa Ohshima ◽  
Hiroyuki Tanaka ◽  
Tohru Sakamoto ◽  
...  
Keyword(s):  
Cardiac Surgery ◽  
Matrix Metalloproteinase ◽  
Left Ventricular ◽  
Matrix Metalloproteinase 2 ◽  
Arterial Blood ◽  
Aortic Replacement ◽  
Lv Mass ◽  
Lv Remodeling ◽  
Baseline Levels ◽  
Cabg Patients

Background: Extracellular matrix degradation may play an important role in left ventricular (LV) remodeling. It has been reported that matrix metalloproteinase-2 (MMP-2) is activated under mechanical stress conditions. Therefore, we examined the release of MMP-2, its inhibitor and interleukin-6 (IL-6), which affects MMPs, in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB). Methods: Arterial blood samples were obtained from 20 patients undergoing cardiac surgery and six patients with descending aortic replacement (as noncardiac control) with CPB. Samples were assayed for plasma MMP-2, tissue inhibitors of matrix metalloproteinase-2 (TIMP-2) and IL-6 concentration. Results: Plasma MMP-2 concentrations in the valvular disease patients were greater than in other patients ( p < 0.05) and correlated with the LV mass (r= 0.810, p < 0.0001) prior to the operation. Plasma MMP-2 concentrations decreased during CPB and gradually recovered to the baseline levels after CPB. Plasma TIMP-2 concentrations increased significantly during and after CPB in a biphasic manner. Plasma IL-6 concentrations also increased significantly during CPB ( p < 0.05 versus baseline levels). Conclusion: Plasma MMP-2 concentrations reflect the state of the left ventricle, and changes in plasma MMP-2 and TIMP-2 concentrations during CPB may play an important role in LV remodeling after cardiac surgery.

scholarly journals Cardiac matrix metalloproteinase-2 expression independently induces marked ventricular remodeling and systolic dysfunction

2007 ◽  
Vol 292 (4) ◽  
pp. H1847-H1860 ◽  
Author(s):  
Marina R. Bergman ◽  
John R. Teerlink ◽  
Rajeev Mahimkar ◽  
Luyi Li ◽  
Bo-Qing Zhu ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Matrix Metalloproteinase ◽  
Ventricular Remodeling ◽  
Systolic Function ◽  
Systolic Dysfunction ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Matrix Metalloproteinase 2 ◽  
Membrane Type ◽  
Volume Relation

Although enhanced cardiac matrix metalloproteinase (MMP)-2 synthesis has been associated with ventricular remodeling and failure, whether MMP-2 expression is a direct mediator of this process is unknown. We generated transgenic mice expressing active MMP-2 driven by the α-myosin heavy chain promoter. At 4 mo MMP-2 transgenic hearts demonstrated expression of the MMP-2 transgene, myocyte hypertrophy, breakdown of Z-band registration, lysis of myofilaments, disruption of sarcomere and mitochondrial architecture, and cardiac fibroblast proliferation. Hearts from 8-mo-old transgenic mice displayed extensive myocyte disorganization and dropout with replacement fibrosis and perivascular fibrosis. Older transgenic mice also exhibited a massive increase in cardiac MMP-2 expression, representing recruitment of endogenous MMP-2 synthesis, with associated expression of MMP-9 and membrane type 1 MMP. Increases in diastolic [control (C) 33 ± 3 vs. MMP 51 ± 12 μl; P = 0.003] and systolic (C 7 ± 2 vs. MMP 28 ± 14 μl; P = 0.003) left ventricular (LV) volumes and relatively preserved stroke volume (C 26 ± 4 vs. MMP 23 ± 3 μl; P = 0.16) resulted in markedly decreased LV ejection fraction (C 78 ± 7% vs. MMP 48 ± 16%; P = 0.0006). Markedly impaired systolic function in the MMP transgenic mice was demonstrated in the reduced preload-adjusted maximal power (C 240 ± 84 vs. MMP 78 ± 49 mW/μl2; P = 0.0003) and decreased end-systolic pressure-volume relation (C 7.5 ± 1.5 vs. MMP 4.7 ± 2.0; P = 0.016). Expression of active MMP-2 is sufficient to induce severe ventricular remodeling and systolic dysfunction in the absence of superimposed injury.

scholarly journals Homocysteine Exposure Impairs Myocardial Resistance to Ischaemia Reperfusion and Oxidative Stress

2015 ◽  
Vol 37 (6) ◽  
pp. 2265-2274 ◽  
Author(s):  
Amer Almashhadany ◽  
Dareuosh Shackebaei ◽  
Thomas Van der Touw ◽  
Graham L. Jones ◽  
M.-Saadeh Suleiman ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Calcium Transient ◽  
Rate Pressure Product ◽  
Rat Cardiomyocytes ◽  
Ischaemia Reperfusion ◽  
Rat Hearts ◽  
Before And After ◽  
Cardiomyocyte Contractility ◽  
Perfused Rat Hearts ◽  
And Oxidative Stress

Background/Aims: Hyperhomocysteinaemia is recognised as a strong independent risk factor for developing cardiovascular disease. This study investigated how an acute homocysteine dose affected cardiac performance during ischaemia reperfusion and cardiomyocyte contractility and morphology under normal conditions and during oxidative stress. Methods: Cardiac function was measured in isolated and perfused rat hearts before and after 40 minutes' global normothermic ischaemia. Where used, 0.1 mM L-homocysteine was present prior to, and throughout ischaemia, before wash out after 10 minutes' reperfusion. Calcium transients under normal conditions and changes in contractile synchronicity during oxidative stress (exposure to 0.2 mM H2O2) were measured in freshly isolated rat cardiomyocytes incubated for 60 minutes ± 0.1 mM L-homocysteine. Results: During ischaemia reperfusion 0.1 mM L-homocysteine significantly reduced the rate pressure product during reperfusion (10,038 ± 749 vs. 5955 ± 567 mmHg bpm, p < 0.001), but did not affect time to ischaemic contracture. Incubation of freshly isolated cardiomyocytes with 0.1 mM L-homocysteine significantly decreased the amplitude of the calcium transient and slowed the time to half relaxation. Conclusions: These findings suggest that homocysteine exposure affected myocardial recovery from ischaemia and contractile homeostasis although the exact mechanisms for these changes remain to be determined.

Selective spatiotemporal induction of matrix metalloproteinase-2 and matrix metalloproteinase-9 transcription after myocardial infarction

2006 ◽  
Vol 291 (5) ◽  
pp. H2216-H2228 ◽  
Author(s):  
Rupak Mukherjee ◽  
Joseph T. Mingoia ◽  
James A. Bruce ◽  
Jeffrey S. Austin ◽  
Robert E. Stroud ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Matrix Metalloproteinase ◽  
Spatial Relation ◽  
Left Ventricular ◽  
Matrix Metalloproteinase 2 ◽  
Dependent Manner ◽  
Gene Promoters ◽  
Promoter Activation ◽  
Reporter Mice ◽  
Lv Remodeling

Myocardial remodeling after myocardial infarction (MI) is associated with increased levels of the matrix metalloproteinases (MMPs). Levels of two MMP species, MMP-2 and MMP-9, are increased after MI, and transgenic deletion of these MMPs attenuates post-MI left ventricular (LV) remodeling. This study characterized the spatiotemporal patterns of gene promoter induction for MMP-2 and MMP-9 after MI. MI was induced in transgenic mice in which the MMP-2 or MMP-9 promoter sequence was fused to the β-galactosidase reporter, and reporter level was assayed up to 28 days after MI. Myocardial localization with respect to cellular sources of MMP-2 and MMP-9 promoter induction was examined. After MI, LV diameter increased by 70% ( P < 0.05), consistent with LV remodeling. β-Galactosidase staining in MMP-2 reporter mice was increased by 1 day after MI and increased further to 64 ± 6% of LV epicardial area by 7 days after MI ( P < 0.05). MMP-2 promoter activation occurred in fibroblasts and myofibroblasts in the MI region. In MMP-9 reporter mice, promoter induction was detected after 3 days and peaked at 7 days after MI (53 ± 6%, P < 0.05) and was colocalized with inflammatory cells at the peri-infarct region. Although MMP-2 promoter activation was similarly distributed in the MI and border regions, activation of the MMP-9 promoter was highest at the border between the MI and remote regions. These unique findings visually demonstrated that activation of the MMP-2 and MMP-9 gene promoters occurs in a distinct spatial relation with reference to the MI region and changes in a characteristic time-dependent manner after MI.

Copper decreases gene expression of TNF-α, IL-10, and of matrix metalloproteinases MMP-2 and MMP-9 in isolated perfused rat livers

Biologia ◽  
2007 ◽  
Vol 62 (3) ◽  
Author(s):  
Albena Alexandrova ◽  
Elena Bandžuchová ◽  
Anton Kebis ◽  
Marián Kukan ◽  
Daniel Kuba
Keyword(s):  
Oxidative Stress ◽  
Gene Expression ◽  
Matrix Metalloproteinase ◽  
Oxidative Dna Damage ◽  
Interleukin 10 ◽  
Matrix Metalloproteinase 2 ◽  
Necrosis Factor Alpha ◽  
Tissue Samples ◽  
Tnf Α ◽  
Rat Livers

AbstractCopper is known to induce oxidative stress in a number of models. It was shown that many pathophysiological events were associated with oxidative stress. Further, oxidative stress can increase gene expression of cytokines and of metalloproteinases. We previously found that copper toxic effects in isolated perfused rat livers were associated with significant oxidative stress (as assessed by lipid peroxidation, protein oxidation and oxidative DNA damage, particularly at concentration of 0.03 mM of Cu2+ in the perfusate). Here we investigated gene expression of tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10); matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9) in frozen liver tissue samples by the real-time PCR assay. Compared to controls, copper at concentration of 0.01 mM did not affect gene expression of TNF-α, IL-10, MMP-2 and MMP-9, whereas copper at concentration of 0.03 mM significantly decreased gene expression of all the four TNF-α, IL-10, MMP-2 and MMP-9 by 69%, 81%, 43%, and 62%, respectively. These results suggest that copper-induced oxidative stress in the isolated rat liver can lead to the suppression of gene expression. Because TNF-α and metalloproteinases are involved also in liver regeneration, the suppression of these genes by copper may be one of the mechanisms by which acute intoxication of animals and humans with copper may impair regenerative capability of the liver.

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