Identification and functional analysis of a biflavone as a novel inhibitor of TRPV4-dependent atherogenic process in macrophages

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dc.contributor.advisorRahaman, Shaik O.en_US
dc.contributor.authorAlharbi, Mazen Obaiden_US
dc.contributor.departmentNutritionen_US
dc.contributor.publisherDigital Repository at the University of Marylanden_US
dc.contributor.publisherUniversity of Maryland (College Park, Md.)en_US
dc.date.accessioned2021-07-13T05:34:34Z
dc.date.available2021-07-13T05:34:34Z
dc.date.issued2021en_US
dc.description.abstractCardiovascular disease is the major cause of death throughout the world. Atherosclerosis, a chronic inflammatory disease of large arteries, is the major contributor to the growing burden of cardiovascular disease-related mortality and morbidity throughout the world. During early atherogenesis, as a result of inflammation and endothelial dysfunction, monocytes transmigrate into the aortic intimal areas, and differentiate into lipid-laden macrophage foam cells, a critical process in atherosclerosis. Numerous natural compounds such as flavonoids and polyphenols are known to have anti-inflammatory and anti-atherogenic properties. Transient receptor potential vanilloid 4 (TRPV4), a non-selective Ca2+-permeant ion channel and a mechanosensor, is widely expressed in diverse cell types including macrophages. Accumulating reports from our laboratory and others on TRPV4 recognized this plasma membrane receptor/channel as an essential modulator of various physiological functions in cardiac, pulmonary, urinary, skeletal, digestive system, and central and peripheral nervous systems. Thus, it is expected that aberrant regulation of TRPV4 activity may lead to multiple pathological conditions such as cardiovascular disease, pulmonary disease, inflammation, neurological disorders, inflammatory bowel disease and wound healing. Previous studies by our group and others have reported that TRPV4 can be activated by numerous mechanical and biochemical stimuli including shear stress, osmolarity, temperature, and growth factors, as well as by alterations in matrix stiffness in vitro and in vivo. Recently, we reported that oxidized low-density lipoprotein-mediated and matrix stiffness-induced macrophage foam cell formation, a critical pathological process in atherosclerosis, is regulated in a TRPV4-dependent manner. Given that TRPV4 is a mechanosensitive channels and mechanical factors like hypertension, disrupted laminar flow of blood, and matrix stiffening are recognized pro-atherogenic factors, makes TRPV4 an important target for therapeutic intervention of atherosclerosis. The objectives of this proposal is to: i) identify natural inhibitor (s) of TRPV4 utilizing a fluorometric imaging plate reader-supported Ca2+ influx assay, ii) functionally characterize the identified compound, and iii) determine the mechanisms by which the identified compound blocks pro-atherogenic/inflammatory TRPV4 activity in macrophages. We expect that the results of this study may strengthen the rationale for the use of natural compounds for developing therapeutic and/or chemopreventive molecules.en_US
dc.identifierhttps://doi.org/10.13016/d15m-zuyj
dc.identifier.urihttp://hdl.handle.net/1903/27368
dc.language.isoenen_US
dc.subject.pqcontrolledBiologyen_US
dc.subject.pqcontrolledBiochemistryen_US
dc.subject.pqcontrolledCellular biologyen_US
dc.subject.pquncontrolledAtherosclerosisen_US
dc.subject.pquncontrolledCalcium Signalingen_US
dc.subject.pquncontrolledFoam Cellen_US
dc.subject.pquncontrolledGinkgetinen_US
dc.subject.pquncontrolledMacrophageen_US
dc.subject.pquncontrolledTRPV4en_US
dc.titleIdentification and functional analysis of a biflavone as a novel inhibitor of TRPV4-dependent atherogenic process in macrophagesen_US
dc.typeDissertationen_US

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