P361Protection against myocardial infarction and no-reflow through preservation of vascular integrity by angiopoietin-like 4

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Abstract

Purpose

New strategies aimed at preventing the no-reflow phenomenon in acute myocardial infarction (AMI) represent a major medical need. Increased vascular permeability is an important contributor to no-reflow. Angiopoietins are pivotal modulators of cell-cell junctions and vascular integrity. We hypothesized that Angiopoietin-like protein 4 (ANGPTL4), which is induced by hypoxia, might modulate vascular integrity, infarct size and no-reflow in AMI.

Methods and Results

In a myocardial ischemia-reperfusion model, we showed increased no-reflow (19 ± 1% versus 11 ± 2%, p < 0.05) and increased infarct size (47 ± 3% versus 36 ± 3%, p < 0.01) in angptl4-deficient mice compared to control mice. In angptl4-deficient mice, AMI induced severe disruption of endothelial cell junctions as revealed by VE-cadherin staining in the heart. These defects were further evidenced using tail vein injection of 100nm diameter fluorescent beads which extravasated from the coronary vasculature only in angptl4-deficient mice. Similarly, hemorrhage and edema were significantly more severe in angptl4-deficient mice compared to control mice.

Methods and Results

We then characterized downstream signalling of ANGPTL4 that acts through Src-dependent dissociation of the VEGFR2/VE-Cadherin complex. We determined that decrease in VEGFR2 and VE-Cadherin expression and increase in Src kinase phosphorylation downstream of VEGFR2 were accentuated in the coronary microcirculation of angptl4-deficient mice. Both events led to altered VEGFR2/VE-Cadherin complexes and to disrupted adherens junctions in between endothelial cells of angptl4-deficient mice.

Methods and Results

We showed that recombinant human ANGPTL4 (rhANGPTL4) was able to rescue the more severe cardiac damages in angptl4-deficient mice. When injected in angptl4-deficient mice at 10μg/kg body weight 5 min before AMI, the infarct size was undistinguishable from that of control mice, showing that ANGPTL4 can rescue the knockout phenotype.

Methods and Results

Finally, we showed that rhANGPTL4 has therapeutic potential in reducing no-reflow, and infarct size after MI in rabbits. Infarct size (percentage area at risk) was 57 ± 5% in the control group and 34 ± 7% in the rhANGPTL4-treated group (p < 0.01), and the no-reflow was also significantly improved in the rhANGPTL4-treated group.

Conclusion

The present findings show that ANGPTL4 counteracts the VEGF-induced permeability observed in reperfused AMI, thereby diminishing the no-reflow phenomenon. Vasculoprotection through ANGPTL4 is therefore a relevant therapeutic approach in AMI as illustrated by the significant decrease in infarct size.

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