Nutrition & Food Science
Permanent URI for this communityhttp://hdl.handle.net/1903/2267
null
Browse
2 results
Search Results
Item Identification and functional analysis of a biflavone as a novel inhibitor of TRPV4-dependent atherogenic process in macrophages(2021) Alharbi, Mazen Obaid; Rahaman, Shaik O.; Nutrition; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Cardiovascular 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.Item THE PROATHEROGENIC ROLE OF THE TRPV4 CALCIUM-PERMEABLE CHANNEL IN MACROPHAGES(2016) Merth, Michael; Rahaman, Shaid O; Nutrition; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Atherosclerosis is a multi-faceted chronic disease and one of the leading causes of cardiovascular diseases which attribute to 28.2% of all-cause mortality worldwide. Central tenets of atherogenesis are macrophage passage and transformation to foam cells. It is known that numerous macrophage membrane proteins regulate this process by controlling properties such as migration and binding and uptake of oxidized lipids. The focus of this study is to identify mechanisms by which the transient receptor potential (TRP) channel of the vanilloid subfamily, TRPV4, a calcium-permeable channel, regulates proatherogenic macrophage functions. The findings show TRPV4 is expressed and functional in macrophages, TRPV4 modulates macrophage migratory characteristics, oxidized low-density lipoprotein (oxLDL) uptake and foam cell formation is reliant on TRPV4-elicited Ca2+ influx, and the physiological inflammatory stimulus of lipopolysaccharide can mediate TRPV4 function. These results identified previously unknown components to macrophage migration and foam cell development. Collectively, these discoveries associate the TRPV4 channel with atherogenesis by identifying new regulators for macrophage phagocytosis and migration that are essential to atherosclerosis development.