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Assessment of Novel Antioxidant Therapy in Atherosclerosis by Contrast Ultrasound Molecular Imaging.

ABSTRACT: BACKGROUND:Ultrasound molecular imaging was used to evaluate the therapeutic effects of antioxidant therapy with EUK-207, which has superoxide dismutase and catalase activities, on suppressing high-risk atherosclerotic features. METHODS:Mice with age-dependent atherosclerosis produced by deletion of the low-density lipoprotein receptor and Apobec-1 were studied at 20 and 40 weeks of age. EUK-207 or vehicle was administered for the preceding 8 weeks. Therapy for 28 weeks was also studied for 40-week-old mice. Ultrasound molecular imaging of the thoracic aorta was performed with contrast agents targeted to endothelial P-selectin, von Willebrand factor A1-domain, and platelet glycoprotein Ib? or control agent. Aortic plaque area and macrophage content were assessed by histology. RESULTS:In 20-week-old double-knockout mice, EUK-207 compared with sham therapy produced only nonsignificant trends for reduction in molecular imaging signal for endothelial P-selectin, von Willebrand factor A1-domain, and platelet adhesion. At 40 weeks, EUK-207 given for 8 or 28 weeks significantly (P < .05) reduced signal for all three endothelial-associated events essentially to background levels, with the exception of glycoprotein Ib? signal after 8 weeks (P = .06). On aortic histology, EUK-207 therapy for 8 weeks did not affect plaque area or macrophage content at either age. However, EUK-207 for 28 weeks almost completely suppressed plaque development (350 ± 258 vs 4 ± 6 × 103 ?m2, P = .014) and macrophage content (136 ± 103 vs 3 ± 2 × 103 ?m2, P = .002) compared with control mice at 40 weeks. CONCLUSIONS:Molecular imaging can be used to assess vascular responses to antioxidants and has demonstrated that certain antioxidants reduce vascular endothelial activation and platelet adhesion, but reductions in plaque size and macrophage content occurs only with long-duration therapy that is started early.

SUBMITTER: Atkinson T

PROVIDER: S-EPMC6218294 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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Assessment of Novel Antioxidant Therapy in Atherosclerosis by Contrast Ultrasound Molecular Imaging.

Atkinson Tamara T Packwood William W Xie Aris A Liang Sherry S Qi Yue Y Ruggeri Zaverio Z Lopez Jose J Davidson Brian P BP Lindner Jonathan R JR

Journal of the American Society of Echocardiography : official publication of the American Society of Echocardiography 20180911 11

<h4>Background</h4>Ultrasound molecular imaging was used to evaluate the therapeutic effects of antioxidant therapy with EUK-207, which has superoxide dismutase and catalase activities, on suppressing high-risk atherosclerotic features.<h4>Methods</h4>Mice with age-dependent atherosclerosis produced by deletion of the low-density lipoprotein receptor and Apobec-1 were studied at 20 and 40 weeks of age. EUK-207 or vehicle was administered for the preceding 8 weeks. Therapy for 28 weeks was also s ...[more]

PMID: 30213420

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Project description:Platelet-endothelial interactions have been linked to increased inflammatory activation and a prothrombotic state in atherosclerosis. The interaction between von Willebrand factor (vWF)-A1 domain and platelet glycoprotein (GP) Ib/IX plays a significant role in mediating the adhesion of platelets to the injured endothelium. In the present study, contrast-enhanced ultrasound (CEU) molecular imaging with microbubbles bearing the vWF-A1 domain was performed to non-invasively monitor activated platelets on the vascular endothelium in the procession of atherosclerosis. A targeted CEU contrast agent was prepared by attaching the vWF-A1 domain to the shell of microbubbles (MbA1). Rat isotype control antibody was used to produce control (Mbctrl) microbubbles. The binding of MbA1 and Mbctrl to activated platelets was assessed in in vitro flow chamber experiments. Apolipoprotein E (ApoE-/-) deficient mice were studied as a model of atherosclerosis. At 8, 16 and 32 weeks of age, CEU molecular imaging of the proximal aorta with MbA1 and Mbctrl was performed and the imaging signals from microbubbles were quantified. Atherosclerotic lesion severity and platelets on the endothelial surface were assessed by histology and immunohistochemistry. In in vitro flow chamber studies, attachment of MbA1 to activated platelets on culture dishes was significantly greater than that of Mbctrl across a range of shear stresses (P<0.05). The attachment of Mbctrl was sparse and not related to the aggregated platelets. As lesion development progressed in the ApoE-/- mice, molecular imaging of activated platelets demonstrated selective signal enhancement of MbA1 (P<0.05 vs. Mbctrl) at all ages. Selective signal enhancement from MbA1 increased from 8 to 32 weeks of age. Immunohistochemistry for GPIIb revealed the presence of platelets on the endothelial cell surface in each group of ApoE-/- mice and that the degree of platelet deposits was age-dependent. The results of the present study indicated that non-invasive CEU molecular imaging with targeted microbubbles bearing the vWF-A1 domain could not only detect activated platelets on the vascular endothelium but also indicate lesion severity in atherosclerosis.

Dataset Information

Assessment of Novel Antioxidant Therapy in Atherosclerosis by Contrast Ultrasound Molecular Imaging.

Publications

Assessment of Novel Antioxidant Therapy in Atherosclerosis by Contrast Ultrasound Molecular Imaging.

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