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Questions {❓}

• Baidoshvili A, Krijnen PA, Kupreishvili K, Ciurana C, Bleeker W, Nijmeijer R, Visser CA, Visser FC, Meijer CJ, Stooker W, Eijsman L, van Hinsbergh VW, Hack CE, Niessen HW, Schalkwijk CG (2006) N(epsilon)-(carboxymethyl)lysine depositions in intramyocardial blood vessels in human and rat acute myocardial infarction: a predictor or reflection of infarction?
• Baroldi G, Marzilli M, L’Abbate A, Arbustini E (1990) Coronary occlusion: cause or consequence of acute myocardial infarction?

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         headline:Loss of DPP4 activity is related to a prothrombogenic status of endothelial cells: implications for the coronary microvasculature of myocardial infarction patients
         description:Pro-coagulant and pro-inflammatory intramyocardial (micro)vasculature plays an important role in acute myocardial infarction (AMI). Currently, inhibition of serine protease dipeptidyl peptidase 4 (DPP4) receives a lot of interest as an anti-hyperglycemic therapy in type 2 diabetes patients. However, DPP4 also possesses anti-thrombotic properties and may behave as an immobilized anti-coagulant on endothelial cells. Here, we studied the expression and activity of endothelial DPP4 in human myocardial infarction in relation to a prothrombogenic endothelial phenotype. Using (immuno)histochemistry, DPP4 expression and activity were found on the endothelium of intramyocardial blood vessels in autopsied control hearts (n = 9). Within the infarction area of AMI patients (n = 73), this DPP4 expression and activity were significantly decreased, coinciding with an increase in Tissue Factor expression. In primary human umbilical vein endothelial cells (HUVECs), Western blot analysis and digital imaging fluorescence microscopy revealed that DPP4 expression was strongly decreased after metabolic inhibition, also coinciding with Tissue Factor upregulation. Interestingly, inhibition of DPP4 activity with diprotin A also enhanced the amount of Tissue Factor encountered and induced the adherence of platelets under flow conditions. Ischemia induces loss of coronary microvascular endothelial DPP4 expression and increased Tissue Factor expression in AMI as well as in vitro in HUVECs. Our data suggest that the loss of DPP4 activity affects the anti-thrombogenic nature of the endothelium.
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      description:Pro-coagulant and pro-inflammatory intramyocardial (micro)vasculature plays an important role in acute myocardial infarction (AMI). Currently, inhibition of serine protease dipeptidyl peptidase 4 (DPP4) receives a lot of interest as an anti-hyperglycemic therapy in type 2 diabetes patients. However, DPP4 also possesses anti-thrombotic properties and may behave as an immobilized anti-coagulant on endothelial cells. Here, we studied the expression and activity of endothelial DPP4 in human myocardial infarction in relation to a prothrombogenic endothelial phenotype. Using (immuno)histochemistry, DPP4 expression and activity were found on the endothelium of intramyocardial blood vessels in autopsied control hearts (n = 9). Within the infarction area of AMI patients (n = 73), this DPP4 expression and activity were significantly decreased, coinciding with an increase in Tissue Factor expression. In primary human umbilical vein endothelial cells (HUVECs), Western blot analysis and digital imaging fluorescence microscopy revealed that DPP4 expression was strongly decreased after metabolic inhibition, also coinciding with Tissue Factor upregulation. Interestingly, inhibition of DPP4 activity with diprotin A also enhanced the amount of Tissue Factor encountered and induced the adherence of platelets under flow conditions. Ischemia induces loss of coronary microvascular endothelial DPP4 expression and increased Tissue Factor expression in AMI as well as in vitro in HUVECs. Our data suggest that the loss of DPP4 activity affects the anti-thrombogenic nature of the endothelium.
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            address:
               name:Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
               type:PostalAddress
            type:Organization
            name:ICaR-VU
            address:
               name:ICaR-VU, Amsterdam, The Netherlands
               type:PostalAddress
            type:Organization
      name:Jessica A. Sipkens
      affiliation:
            name:VU University Medical Center
            address:
               name:Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
               type:PostalAddress
            type:Organization
            name:ICaR-VU
            address:
               name:ICaR-VU, Amsterdam, The Netherlands
               type:PostalAddress
            type:Organization
      name:Floris P. van Alphen
      affiliation:
            name:Academic Medical Center, University of Amsterdam
            address:
               name:Department Molecular Cell Biology, Sanquin Research, Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
               type:PostalAddress
            type:Organization
      name:Alexander B. A. Vonk
      affiliation:
            name:VU University Medical Center
            address:
               name:Department of Cardiac Surgery, VU University Medical Center, Amsterdam, The Netherlands
               type:PostalAddress
            type:Organization
            name:ICaR-VU
            address:
               name:ICaR-VU, Amsterdam, The Netherlands
               type:PostalAddress
            type:Organization
      name:Suat Simsek
      affiliation:
            name:Medical Center Alkmaar
            address:
               name:Department of Internal Medicine, Medical Center Alkmaar, Alkmaar, The Netherlands
               type:PostalAddress
            type:Organization
      name:Christof Meischl
      affiliation:
            name:VU University Medical Center
            address:
               name:Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
               type:PostalAddress
            type:Organization
            name:ICaR-VU
            address:
               name:ICaR-VU, Amsterdam, The Netherlands
               type:PostalAddress
            type:Organization
      name:Casper G. Schalkwijk
      affiliation:
            name:University of Maastricht
            address:
               name:Department of Internal Medicine, University of Maastricht, Maastricht, The Netherlands
               type:PostalAddress
            type:Organization
      name:Jaap D. van Buul
      affiliation:
            name:Academic Medical Center, University of Amsterdam
            address:
               name:Department Molecular Cell Biology, Sanquin Research, Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
               type:PostalAddress
            type:Organization
      name:Victor W. M. van Hinsbergh
      affiliation:
            name:VU University Medical Center
            address:
               name:Department of Physiology, VU University Medical Center, Amsterdam, The Netherlands
               type:PostalAddress
            type:Organization
            name:ICaR-VU
            address:
               name:ICaR-VU, Amsterdam, The Netherlands
               type:PostalAddress
            type:Organization
      name:Hans W. M. Niessen
      affiliation:
            name:VU University Medical Center
            address:
               name:Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
               type:PostalAddress
            type:Organization
            name:VU University Medical Center
            address:
               name:Department of Cardiac Surgery, VU University Medical Center, Amsterdam, The Netherlands
               type:PostalAddress
            type:Organization
            name:ICaR-VU
            address:
               name:ICaR-VU, Amsterdam, The Netherlands
               type:PostalAddress
            type:Organization
PostalAddress:
      name:Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
      name:ICaR-VU, Amsterdam, The Netherlands
      name:Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
      name:ICaR-VU, Amsterdam, The Netherlands
      name:Department of Pathology, University of Kuopio, Kuopio, Finland
      name:Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
      name:ICaR-VU, Amsterdam, The Netherlands
      name:Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
      name:ICaR-VU, Amsterdam, The Netherlands
      name:Department Molecular Cell Biology, Sanquin Research, Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
      name:Department of Cardiac Surgery, VU University Medical Center, Amsterdam, The Netherlands
      name:ICaR-VU, Amsterdam, The Netherlands
      name:Department of Internal Medicine, Medical Center Alkmaar, Alkmaar, The Netherlands
      name:Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
      name:ICaR-VU, Amsterdam, The Netherlands
      name:Department of Internal Medicine, University of Maastricht, Maastricht, The Netherlands
      name:Department Molecular Cell Biology, Sanquin Research, Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
      name:Department of Physiology, VU University Medical Center, Amsterdam, The Netherlands
      name:ICaR-VU, Amsterdam, The Netherlands
      name:Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands
      name:Department of Cardiac Surgery, VU University Medical Center, Amsterdam, The Netherlands
      name:ICaR-VU, Amsterdam, The Netherlands

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