Peripheral blood mononuclear cells (MNC) enhance cardiac recovery and repair after myocardial infarction (MI). The SDF-1α/CXCR4 axis plays a major role in cell homing to infarcted myocardium and is... Show morePeripheral blood mononuclear cells (MNC) enhance cardiac recovery and repair after myocardial infarction (MI). The SDF-1α/CXCR4 axis plays a major role in cell homing to infarcted myocardium and is negatively regulated by CD26. Therefore, we studied the expression of CD26 during MI and its effects on cardiac function. Blood samples from forty-two patients who underwent a primary percutaneous coronary intervention (PCI) for a first ST-elevated MI were collected during primary PCI, 1 week and 3 months after MI. Soluble CD26 (sCD26) and membrane bound CD26 expression on MNCs (mncCD26) were determined. Left ventricular function and infarct size were measured within 1 day, 1 week and 3 months follow up by magnetic resonance imaging. One week post MI, sCD26 was down regulated compared to baseline, while mncCD26 was higher at baseline and 1 week compared to 3 months. Increased mncCD26 expression at 1 week after MI was associated with decreased overall recovery of left ventricular function as measured by left ventricular end systolic volume index. Furthermore, the in vitro migration capacity of MNCs to SDF-1α was decreased 1 week post MI and the migration capacity to SDF-1α was negatively correlated with mncCD26 expression. CD26 inhibition with sitagliptin - a drug currently used in diabetic patients - resulted in improved in vitro migration capacities of MNCs. In conclusion, our preliminary results suggest that high cellular CD26 expression decreases the migration of MNCs towards SDF-1α and high cellular CD26 expression negatively influences cardiac function post MI. Treating patients shortly post MI with sitagliptin to inhibit CD26 may therefore increase MNC homing to the infarct area and could improve cardiac recovery and repair. Show less
Post, S.; Post, M.C.; Branden, B.J. van den; Eefting, F.D.; Goumans, M.J.; Stella, P.R.; ... ; Doevendans, P.A. 2012
Cardiac cushion formation is crucial for both valvular and septal development. Disruption in this process can lead to valvular and septal malformations, which constitute the largest part of... Show moreCardiac cushion formation is crucial for both valvular and septal development. Disruption in this process can lead to valvular and septal malformations, which constitute the largest part of congenital heart defects. One of the signaling pathways that is important for cushion formation is the TGFβ superfamily. The involvement of TGFβ and BMP signaling pathways in cardiac cushion formation has been intensively studied using chicken in vitro explant assays and in genetically modified mice. In this review, we will summarize and discuss the role of TGFβ and BMP signaling components in cardiac cushion formation. Show less
Genetic and molecular studies suggest that activin receptor-like kinase 1 (ALK1), a transforming growth factor β (TGF-β) type I receptor and endoglin, a TGF-β co-receptor, play an essential role in... Show moreGenetic and molecular studies suggest that activin receptor-like kinase 1 (ALK1), a transforming growth factor β (TGF-β) type I receptor and endoglin, a TGF-β co-receptor, play an essential role in vascular development and pathological angiogenesis. Several agents that interfere with ALK1 and endoglin function are currently in clinical trials for anti-angiogenic activity in cancer therapy. One of these agents, PF-03446962 (anti-hALK1 antibody), shows promising results in the clinic. However, its effects on endothelial cell function and mechanism of action are unclear. Here we demonstrate that anti-hALK1 antibody selectively recognizes human ALK1. The anti hALK1-antibody interfered with bone morphogenetic protein 9 (BMP9)-induced signaling in endothelial cells. Consistent with this notion, anti-hALK1 antibody was found to compete highly efficiently with the binding of the ALK1 ligand BMP9 to ALK1. Moreover, it prevented BMP9-dependent recruitment of co-receptor endoglin into this angiogenesis-mediating signaling complex. In addition, we demonstrated that anti-hALK1 antibody inhibited endothelial cell sprouting, but did not directly interfere with vascular endothelial growth factor (VEGF) signaling, VEGF-induced proliferation and migration of endothelial cells. Finally, we demonstrated that BMP9 in serum is essential for endothelial sprouting and that anti-hALK1 antibody inhibits this potently. Our data suggest that both the VEGF-VEGFR and the BMP9-ALK1 pathways are essential for stimulating angiogenesis, and targeting both pathways simultaneously is an attractive strategy to overcome resistance to anti-angiogenesis therapy. Show less
