Removal of endothelial surface-associated von villebrand factor suppresses accelerate datherosclerosis after myocardial infarction.

Abstract

BACKGROUND:

Thromboinflammation involving platelet adhesion to endothelial surface-associated von Willebrand factor (VWF) has been implicated in the accelerated progression of non-culprit plaques after MI. The aim of this study was to use arterial endothelial molecular imaging to mechanistically evaluate endothelial-associated VWF as a therapeutic target for reducing remote plaque activation after myocardial infarction (MI).

METHODS:

Hyperlipidemic mice deficient for the low-density lipoprotein receptor and Apobec-1 underwent closed-chest MI and were treated chronically with either: (i) recombinant ADAMTS13 which is responsible for proteolytic removal of VWF from the endothelial surface, (ii) N-acetylcysteine (NAC) which removes VWF by disulfide bond reduction, (iii) function-blocking anti-factor XI (FXI) antibody, or (iv) no therapy. Non-ischemic controls were also studied. At day 3 and 21, ultrasound molecular imaging was performed with probes targeted to endothelial-associated VWF A1-domain, platelet GPIbα, P-selectin and vascular cell adhesion molecule-1 (VCAM-1) at lesion-prone sites of the aorta. Histology was performed at day 21.

RESULTS:

Aortic signal for P-selectin, VCAM-1, VWF, and platelet-GPIbα were all increased several-fold (p < 0.01) in post-MI mice versus sham-treated animals at day 3 and 21. Treatment with NAC and ADAMTS13 significantly attenuated the post-MI increase for all four molecular targets by > 50% (p < 0.05 vs. non-treated at day 3 and 21). On aortic root histology, mice undergoing MI versus controls had 2-4 fold greater plaque size and macrophage content (p < 0.05), approximately 20-fold greater platelet adhesion (p < 0.05), and increased staining for markers of platelet transforming growth factor-β1 signaling. Accelerated plaque growth and inflammatory activation was almost entirely prevented by ADAMTS13 and NAC. Inhibition of FXI had no significant effect on molecular imaging signal or plaque morphology.

CONCLUSIONS:

Plaque inflammatory activation in remote arteries after MI is strongly influenced by VWF-mediated platelet adhesion to the endothelium. These findings support investigation into new secondary preventive therapies for reducing non-culprit artery events after MI.

• Authors: Koya Ozawa, William Packwood, Matthew A Muller, Yue Qi, Aris Xie, Oleg Varlamov, Owen J McCarty, Dominic Chung, José A López, Jonathan R Lindner
• Journal: Journal of translational medicine (J Transl Med) Vol. 22 Issue 1 Pg. 412 (May 01 2024) ISSN: 1479-5876 [Electronic] England
• PMID: 38693516 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural)
• Copyright: © 2024. The Author(s).

Chemical References

• von Willebrand Factor
• ADAMTS13 Protein
• Vascular Cell Adhesion Molecule-1
• P-Selectin
• Acetylcysteine

Topics

• Animals
• von Willebrand Factor (metabolism)
• Myocardial Infarction (pathology, complications)
• ADAMTS13 Protein (metabolism)
• Vascular Cell Adhesion Molecule-1 (metabolism)
• Mice
• Plaque, Atherosclerotic (pathology)
• P-Selectin (metabolism)
• Endothelial Cells (metabolism, drug effects)
• Male
• Molecular Imaging
• Aorta (pathology, drug effects)
• Acetylcysteine (pharmacology, therapeutic use)
• Mice, Inbred C57BL