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Disrupting the EMMPRIN (CD147)-cyclophilin A interaction reduces infarct size and preserves systolic function after myocardial ischemia and reperfusion.

ABSTRACT: Inflammation and proteolysis crucially contribute to myocardial ischemia and reperfusion injury. The extracellular matrix metalloproteinase inducer EMMPRIN (CD147) and its ligand cyclophilin A (CyPA) may be involved in both processes. The aim of the study was to characterize the role of the CD147 and CyPA interplay in myocardial ischemia/reperfusion (I/R) injury.Immunohistochemistry showed enhanced expression of CD147 and CyPA in myocardial sections from human autopsies of patients who had died from acute myocardial infarction and from mice at 24 hours after I/R. At 24 hours and 7 days after I/R, the infarct size was reduced in CD147(+/-) mice vs CD147(+/+) mice (C57Bl/6), in mice (C57Bl/6) treated with monoclonal antibody anti-CD147 vs control monoclonal antibody, and in CyPA(-/-) mice vs CyPA(+/+) mice (129S6/SvEv), all of which are associated with reduced monocyte and neutrophil recruitment at 24 hours and with a preserved systolic function at 7 days. The combination of CyPA(-/-) mice with anti-CD147 treatment did not yield further protection compared with either inhibition strategy alone. In vitro, treatment with CyPA induced monocyte chemotaxis in a CD147- and phosphatidylinositol 3-kinase-dependent manner and induced monocyte rolling and adhesion to endothelium (human umbilical vein endothelial cells) under flow in a CD147-dependent manner.CD147 and its ligand CyPA are inflammatory mediators after myocardial ischemia and reperfusion and represent potential targets to prevent myocardial I/R injury.

SUBMITTER: Seizer P

PROVIDER: S-EPMC3113549 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Disrupting the EMMPRIN (CD147)-cyclophilin A interaction reduces infarct size and preserves systolic function after myocardial ischemia and reperfusion.

Seizer Peter P Ochmann Carmen C Schönberger Tanja T Zach Sebastian S Rose Melanie M Borst Oliver O Klingel Karin K Kandolf Reinhard R MacDonald H Robson HR Nowak Romana A RA Engelhardt Stefan S Lang Florian F Gawaz Meinrad M May Andreas E AE

Arteriosclerosis, thrombosis, and vascular biology 20110324 6

<h4>Objective</h4>Inflammation and proteolysis crucially contribute to myocardial ischemia and reperfusion injury. The extracellular matrix metalloproteinase inducer EMMPRIN (CD147) and its ligand cyclophilin A (CyPA) may be involved in both processes. The aim of the study was to characterize the role of the CD147 and CyPA interplay in myocardial ischemia/reperfusion (I/R) injury.<h4>Methods and results</h4>Immunohistochemistry showed enhanced expression of CD147 and CyPA in myocardial sections ...[more]

PMID: 21441138

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Project description:Postconditioning and cyclosporine A prevent mitochondrial permeability transition pore opening providing cardioprotection during ischemia/reperfusion. Whether microvascular obstruction is affected by these interventions is largely unknown. Pigs subjected to coronary occlusion for 1 h followed by 3 h of reperfusion were assigned to control (n = 8), postconditioning (n = 9) or cyclosporine A intravenous infusion 10-15 min before the end of ischemia (n = 8). Postconditioning was induced by 8 cycles of repeated 30-s balloon inflation and deflation. After 3 h of reperfusion magnetic resonance imaging, triphenyltetrazolium chloride/Evans blue staining and histopathology were performed. Microvascular obstruction (MVO, percentage of gadolinium-hyperenhanced area) was measured early (3 min) and late (12 min) after contrast injection. Infarct size with double staining was smaller in cyclosporine (46.2 ± 3.1%, P = 0.016) and postconditioning pigs (47.6 ± 3.9%, P = 0.008) versus controls (53.8 ± 4.1%). Late MVO was significantly reduced by cyclosporine (13.9 ± 9.6%, P = 0.047) but not postconditioning (23.6 ± 11.7%, P = 0.66) when compared with controls (32.0 ± 16.9%). Myocardial blood flow in the late MVO was improved with cyclosporine versus controls (0.30 ± 0.06 vs 0.21 ± 0.03 ml/g/min, P = 0.002) and was inversely correlated with late-MVO extent (R(2) = 0.93, P < 0.0001). Deterioration of left ventricular ejection fraction (LVEF) between baseline and 3 h of reperfusion was smaller with cyclosporine (-7.9 ± 2.4%, P = 0.008) but not postconditioning (-12.0 ± 5.5%, P = 0.22) when compared with controls (-16.4 ± 5.5%). In the three groups, infarct size (β = -0.69, P < 0.001) and late MVO (β = -0.33, P = 0.02) were independent predictors of LVEF deterioration following ischemia/reperfusion (R(2) = 0.73, P < 0.001). Despite both cyclosporine A and postconditioning reduce infarct size, only cyclosporine A infusion had a beneficial effect on microvascular damage and was associated with better preserved LV function when compared with controls.

Project description:OBJECTIVE:The occurrence of intramyocardial hemorrhage (IMH) and microvascular obstruction (MVO) in myocardial infarction (MI), known as severe ischemia/reperfusion injury (IRI), has been associated with adverse remodeling. APT102, a soluble human recombinant ecto-nucleoside triphosphate diphosphohydrolase-1, can hydrolyze extracellular nucleotides to attenuate their prothrombotic and proinflammatory effects. The purpose of this study was to temporally evaluate the therapeutic effect of APT102 on IRI in rats and to elucidate the evolution of IRI in the acute stage using cardiovascular magnetic resonance imaging (CMRI). MATERIALS AND METHODS:Fifty-four rats with MI, induced by ligation of the origin of the left anterior descending coronary artery for 60 minutes, were randomly divided into the APT102 (n = 27) or control (n = 27) group. Intravenous infusion of APT102 (0.3 mg/kg) or placebo was administered 15 minutes before reperfusion, and then 24 hours, 48 hours, 72 hours, and on day 4 after reperfusion. CMRI was performed at 24 hours, 48 hours, 72 hours, and on day 5 post-reperfusion using a 7T system and the hearts were collected for histopathological examination. Cardiac function was quantified using cine imaging and IMH/edema using T2 mapping, and infarct/MVO using late gadolinium enhancement. RESULTS:The extent of infarction (p < 0.001), edema (p < 0.001), IMH (p = 0.013), and MVO (p = 0.049) was less severe in the APT102 group than in the control group. IMH size at 48 hours was significantly greater than that at 24 hours, 72 hours, and 5 days after reperfusion (all p < 0.001). The left ventricular ejection fraction (LVEF) was significantly greater in the APT102 group than in the control group (p = 0.006). There was a negative correlation between LVEF and IMH (r = -0.294, p = 0.010) and a positive correlation between IMH and MVO (r = 0.392, p < 0.001). CONCLUSION:APT102 can significantly alleviate damage to the ischemic myocardium and microvasculature. IMH size peaked at 48 hours post reperfusion and IMH is a downstream consequence of MVO. IMH may be a potential therapeutic target to prevent adverse remodeling in MI.

Dataset Information

Disrupting the EMMPRIN (CD147)-cyclophilin A interaction reduces infarct size and preserves systolic function after myocardial ischemia and reperfusion.

Publications

Disrupting the EMMPRIN (CD147)-cyclophilin A interaction reduces infarct size and preserves systolic function after myocardial ischemia and reperfusion.

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