Disrupting the EMMPRIN (CD147)–Cyclophilin A Interaction Reduces Infarct Size and Preserves Systolic Function After Myocardial Ischemia and Reperfusion

Abstract

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.

Targeting Extracellular Cyclophilins Ameliorates Disease Progression in Experimental Biliary Atresia

“…Indeed, the inflammatory response in BA, both in the mouse model and in humans, is associated with infiltration by neutrophils, which form inflammatory foci around the areas of bile duct obstruction (21)(22)(23). Modulation of neutrophil infiltration by the inhibition of extracellular cyclophilins or their receptor CD147 has been reported in rheumatoid arthritis (38,39), lung inflammation (14) and myocardial ischemia and reperfusion injury (40). The decreased migration of neutrophils and other inflammatory cells to the liver may explain the decreased levels of IL-6 observed in MM284-treated animals in our study.…”

Intracellular cyclophilin A is an important Ca2+ regulator in platelets and critically involved in arterial thrombus formation

“…28 Animal studies were approved by the local authorities (regional board Tübingen) and conducted according to German law for the welfare of animals.…”

“…8,[28][29][30] Briefly, murine blood from the retroorbital plexus was collected and centrifuged at 640g for 5 minutes at room temperature. To obtain platelet-rich plasma, the supernatant was centrifuged at 260g for 6 minutes.…”

“…[19][20][21][22][23][24] Recent studies provide evidence that CyPA is also present in the cytoplasm of platelets and can be released from granules upon platelet activation to bind to endothelial cells, monocytes, and macrophages via the CyPA receptor EMMPRIN (CD147), thereby inducing a signaling cascade into the target cell (eg, degranulation or expression of matrix metalloproteinases. 19,23,[25][26][27][28] The function of intracellular CyPA in platelets has not yet been explored.In the present study, we show for the first time that CyPA deficiency leads to multiple platelet activation defects caused by strongly reduced Ca 2ϩ mobilization from intracellular stores and Ca 2ϩ entry from the extracellular space. Our results identify CyPA as a powerful Ca 2ϩ regulator in platelets.…”

The Expression of Cyclophilin A in Ovarian Endometrioma: Its Correlation with Recurrence and Vascularity

“…However, many previous studies have demonstrated that CyPA knockdown serves to protect individuals from the detrimental effects of inflammation associated with many diseases, including atherosclerosis , ischemia/reperfusion injury (Seizer et al 2011), and tumor growth in vivo (Li et al 2008).…”