Introduction 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. Methods and results 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 versus CD147+/+ mice (C57Bl/6), in mice (C57Bl/6) treated with mAb anti-CD147 vs. control mAb, and in CyPA−/− mice vs. CyPA+/+ mice (129S6/SvEv), all of which being associated with reduced monocyte and neutrophil recruitment at 24h and with a preserved systolic function at 7 days. Combination of CyPA−/− mice with anti-CD147 treatment did not yield further protection in comparison to either inhibition strategy alone. In vitro, treatment with CyPA induced monocyte chemotaxis in a CD147- and PI3-kinase dependent manner and induced monocyte rolling and adhesion to endothelium (HUVEC) under flow in a CD147-dependent manner. Conclusion CD147 and its ligand CyPA are inflammatory mediators after myocardial ischemia and reperfusion and represent potential targets to prevent myocardial I/R injury.

Platelets play a critical role in the pathophysiology of reperfusion, sepsis, and cardiovascular diseases. In a multiple step process, they adhere to activated endothelium and release proinflammatory cytokines thereby promoting the inflammatory process. Glycoprotein VI (GPVI) is the major collagen receptor on the platelet surface and triggers platelet activation and primary hemostasis. Activation of GPVI leads to stable platelet adhesion and degranulation of platelet granules. However, GPVI is critically involved in platelet adhesion to activated endothelium without exposure of subendothelial matrix. Earlier studies show that the soluble GPVI-Fc binds to collagen and protects mice from atherosclerosis and decreases neointima proliferation after arterial injury. Here, we show for the first time that recombinant GPVI-Fc binds to activated endothelium mainly via vitronectin and prevents platelet/endothelial interaction. Administration of GPVI-Fc reduced infarct size and preserved cardiac function in a mouse model of myocardial infarction. This process was associated with reduced GPVI-induced platelet degranulation and release of proinflammatory cytokines in vitro and in vivo. Taken together, administration of GPVI-Fc offers a novel strategy to control platelet-mediated inflammation and to preserve myocardial function following myocardial infarction.

Background-CXCR4-positive bone marrow cells (BMCs) are critically involved in cardiac repair mechanisms contributing to preserved cardiac function. Stromal cell-derived factor-1 (SDF-1) is the most prominent BMC homing factor known to augment BMC engraftment, which is a limiting step of stem cell-based therapy. After myocardial infarction, SDF-1 expression is rapidly upregulated and promotes myocardial repair. Methods and Results-We have established a bifunctional protein consisting of an SDF-1 domain and a glycoprotein VI (GPVI) domain with high binding affinity to the SDF-1 receptor CXCR4 and extracellular matrix proteins that become exposed after tissue injury. SDF1-GPVI triggers chemotaxis of CXCR4-positive cells, preserves cell survival, enhances endothelial differentiation of BMCs in vitro, and reveals proangiogenic effects in ovo. In a mouse model of myocardial infarction, administration of the bifunctional protein leads to enhanced recruitment of BMCs, increases capillary density, reduces infarct size, and preserves cardiac function. Conclusions-These results indicate that administration of SDF1-GPVI may be a promising strategy to treat myocardial infarction to promote myocardial repair and to preserve cardiac function. (Circulation. 2012;125:685-696.)Key Words: GPVI Ⅲ myocardial infarction Ⅲ cells Ⅲ SDF-1 Ⅲ tissue repair I n recent years, extensive efforts have been made to identify mechanisms to promote myocardial repair and regeneration. 1,2 It has been increasingly recognized that bone marrow (BM)-derived progenitor cells (BMCs) participate in cardiac repair mechanisms and regeneration and contribute to function recovery after myocardial infarction (MI). Elevated levels of BMCs in patients with cardiovascular disease are associated with a reduced risk of death from cardiovascular complications. 3,4 The isolation of putative BMCs was first described in the late 1990s, 5 and it has become evident that circulating BMCs significantly contribute to the regeneration of vascular integrity and support locally induced repair mechanisms of resident endothelial cells. 6 In vivo studies in mice and rats provide evidence that vascular homing of BMCs improves endothelial regeneration and preserves myocardial function after transient coronary ischemia. [7][8][9] Myocardial BMC transplantation into immunodeficient mice induces sustained humoral effects and leads to increased mobilization of endogenous BM-derived or progenitor cells that are incorporated into sites of neovascularization and myocardial repair. 10 Clinical Perspective on p 696Progressive adverse left ventricular (LV) remodeling after MI is the pathomorphological substrate of postinfarction heart failure and reduced survival. 11 Cell therapy for patients with acute MI has been evaluated in the past by various clinical studies. In some studies, intracoronary administration of BMCs has been found to improve recovery of LV contractile function in patients with acute MI. [12][13][14] Other clinical studies did not show a beneficial effect of intracorona...

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Myocardial ischemia und subsequent reperfusion is followed by a complex sequence of pathophysiological responses involving inflammatory cell infiltration and cytokine release as well as postinfarction wound healing and myocardial tissue remodeling. With the development of gene targeted mice the contribution of individual gene products to the pathophysiology of myocardial ischemia and reperfusion can be defined leading to an increasing interest in the widely-used mouse model of myocardial infarction. This methological paper describes in detail the required equipment, surgical instruments, drugs and additional material, the methods of anesthesia and analgesia, the procedures involved in preparation of the animal, tracheotomy, intubation, thoracotomy, occlusion of the left descending artery, removal of the heart, determination of infarct size, analysis of cardiac functional parameters with echocardiography and magnetic resonance imaging (MRI) as well as determination of the morphological consequences utilizing gelatin zymography, histology and immunohistochemistry.

Summary. Background:  Bone‐marrow‐derived progenitor cells are important in myocardial repair mechanisms following prolonged ischemia. Cell‐based therapy of diseased myocardium is limited by a low level of tissue engraftment. Objectives:  The aim of this study was the development of the bifunctional protein αCD133–glycoprotein (GP)VI as an effective treatment for supporting vascular and myocardial repair mechanisms. Results:  We have generated and characterized a bifunctional molecule (αCD133–GPVI) that binds both to the subendothelium of the injured microvasculature and to CD133+ progenitor cells with high affinity. αCD133–GPVI enhances progenitor cell adhesion to extracellular matrix proteins and differentiation into mature endothelial cells. In vivo studies showed that αCD133–GPVI favors adhesion of circulating progenitor cells to the injured vessel wall (intravital microscopy). Also, treatment of mice undergoing experimental myocardial infarction with αCD133–GPVI‐labeled progenitor cells reduces infarction size and preserves myocardial function. Conclusions:  The bifunctional trapping protein αCD133–GPVI represents a novel and promising therapeutic option for limiting heart failure of the ischemic myocardium.