Molecular imaging with targeted imaging probes can be used to evaluate vascular phenotype in cardiovascular disease. In the past funding period, we developed new tools for assessing endothelial activation and cellular adhesion using contrast-enhanced ultrasound (CEU) molecular imaging in order to detect and quantify high risk atherosclerotic disease. Because CEU molecular imaging can detect events that occur at the endothelial-blood pool interface with high sensitivity and temporal resolution, it is a potentially valuable asset in preclinical research than can be used to discover new disease-related pathways or to rapidly test new candidate therapies. The overall aim of this proposal is to leverage the technologies we have developed in order to better understand the role of platelets throughout the course of atherosclerotic plaque development. Platelet-endothelial interactions have been postulated to play an important early role in promoting atherosclerosis by potentiating the inflammatory response. These interactions have not been well characterized because of lack of appropriate tools for assessing platelet- endothelial interactions in vivo.
In Aim 1 CEU molecular imaging of platelet GPIb? and endothelial activation in a murine model of atherosclerosis will be used to temporally characterize platelet-endothelial interaction and endothelial inflammatory activation at different stages of plaque development. Mechanism for platelet adhesion will also be investigated by: (a) imaging the effects of inhibitors to the molecular pathways that may mediate platelet-endothelial or platelet-monocyte complexes, and (b) direct molecular imaging of potential mediators such as dysregulated von Willebrand factor. Since increased oxidative stress is a likely common mediator of endothelial activation and platelet adhesion, in Aim 2, we will determine whether platelet-endothelial interactions at various stages of atherosclerosis are modifiable by potent anti-oxidant therapies (NADPH-oxidase inhibitors, catalase mimetics, or stable transfection with single chain antibodies against oxidized lipoproteins). CEU molecular imaging will be an important biologic readout for these studies.
In Aim 3, we will evaluate endothelial-platelet interactions and endothelial inflammatory activation in primates by studying obese, insulin- resistant, and atherosclerotic rhesus macaques. In these studies CEU molecular imaging will be combined with targeted radionuclide imaging of vascular lipid oxidation. Treatment effects of NADPH oxidase inhibitors will again be used to determine the regulatory role of oxidative stress. Successful completion of these studies will provide important new information on atherosclerosis pathophysiology which can be targeted for therapy.
Platelets may not only be involved in the formation of blood clots that culminate in heart attack and stroke in patients with atherosclerotic lesions, but may also play a role much earlier In the development of atherosclerotic disease by interacting with the vessel wall. Oxidative stress may play an important role in promoting platelet attachment to the vessel wall. We propose to use ultrasound molecular imaging mouse and monkey models of atherosclerosis to determine the degree and mechanisms of platelet adhesion to the vessel wall, and to determine whether treatment with potent anti-oxidants reduces these events.
|Lindner, Jonathan R; Link, Jeanne (2018) Molecular Imaging in Drug Discovery and Development. Circ Cardiovasc Imaging 11:e005355|
|Lindner, Jonathan R (2018) Cause or Effect? Microvascular Dysfunction in Insulin-Resistant States. Circ Cardiovasc Imaging 11:e007725|
|Ozawa, Koya; Packwood, William; Varlamov, Oleg et al. (2018) Molecular Imaging of VWF (von Willebrand Factor) and Platelet Adhesion in Postischemic Impaired Microvascular Reflow. Circ Cardiovasc Imaging 11:e007913|
|Atkinson, Tamara; Packwood, William; Xie, Aris et al. (2018) Assessment of Novel Antioxidant Therapy in Atherosclerosis by Contrast Ultrasound Molecular Imaging. J Am Soc Echocardiogr 31:1252-1259.e1|
|Moccetti, Federico; Weinkauf, Craig C; Davidson, Brian P et al. (2018) Ultrasound Molecular Imaging of Atherosclerosis Using Small-Peptide Targeting Ligands Against Endothelial Markers of Inflammation and Oxidative Stress. Ultrasound Med Biol 44:1155-1163|
|Tsimikas, Sotirios (2018) In search of a physiological function of lipoprotein(a): causality of elevated Lp(a) levels and reduced incidence of type 2 diabetes. J Lipid Res 59:741-744|
|Moccetti, Federico; Brown, Eran; Xie, Aris et al. (2018) Myocardial Infarction Produces Sustained Proinflammatory Endothelial Activation in Remote Arteries. J Am Coll Cardiol 72:1015-1026|
|Tsimikas, Sotirios; Fazio, Sergio; Ferdinand, Keith C et al. (2018) NHLBI Working Group Recommendations to Reduce Lipoprotein(a)-Mediated Risk of Cardiovascular Disease and Aortic Stenosis. J Am Coll Cardiol 71:177-192|
|Lindner, Jonathan R (2018) Microvascular Dysfunction and Clinical Outcomes. Circ Cardiovasc Imaging 11:e008381|
|Senders, Max L; Que, Xuchu; Cho, Young Seok et al. (2018) PET/MR Imaging of Malondialdehyde-Acetaldehyde Epitopes With a Human Antibody Detects Clinically Relevant Atherothrombosis. J Am Coll Cardiol 71:321-335|
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