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A Standardized Lindera obtusiloba Extract Improves Endothelial Dysfunction and Attenuates Plaque Development in Hyperlipidemic ApoE-Knockout Mice.

ABSTRACT: Lindera obtusiloba extract (LOE), a traditional herbal medicine used to enhance blood circulation and to reduce inflammation, induced NO-mediated endothelium-dependent relaxation, and reduced the formation of reactive oxygen species (ROS). The study investigated whether LOE improves endothelial dysfunction and reduces plaque inflammation and progression by inhibiting ROS generation in a mouse model of atherosclerosis. Eight-week-old apolipoprotein E-deficient (apoE^-/-) mice fed with a western diet (WD) were randomized into different groups by administering vehicle (0.5% carboxymethylcellulose (CMC)), LOE (100 mg/kg/day), or losartan (30 mg/kg/day) by gavage until the age of 28 weeks. Fourteen male C57BL/6 mice that were fed normal chow and treated with CMC were used as negative controls. Similar to losartan treatment, LOE treatment induced the concentration-dependent relaxation of aorta rings in WD-fed apoE^-/- mice. LOE treatment significantly reduced the vascular ROS formation and expression of NADPH oxidase subunits, including p22phox and p47phox. Compared with WD-fed apoE^-/- mice, mice exposed to chronic LOE treatment exhibited reductions in plaque inflammation-related fluorescence signals and atherosclerotic lesions. These effects were greater than those of losartan treatment. In conclusion, LOE treatment improves endothelial dysfunction and reduces plaque inflammation as well as lesion areas by reducing vascular NADPH oxidase-induced ROS generation in a mouse model of atherosclerosis.

SUBMITTER: Ihm SH

PROVIDER: S-EPMC8618780 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundChronic glucocorticoid excess has been linked to increased atherosclerosis and general cardiovascular risk in humans. The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) increases active glucocorticoid levels within tissues by catalyzing the conversion of cortisone to cortisol. Pharmacological inhibition of 11βHSD1 has been shown to reduce atherosclerosis in murine models. However, the cellular and molecular details for this effect have not been elucidated.Methodology/principal findingsTo examine the role of 11βHSD1 in atherogenesis, 11βHSD1 knockout mice were created on the pro-atherogenic apoE⁻/⁻ background. Following 14 weeks of Western diet, aortic cholesterol levels were reduced 50% in 11βHSD1⁻/⁻/apoE⁻/⁻ mice vs. 11βHSD1⁺/⁺/apoE⁻/⁻ mice without changes in plasma cholesterol. Aortic 7-ketocholesterol content was reduced 40% in 11βHSD1⁻/⁻/apoE⁻/⁻ mice vs. control. In the aortic root, plaque size, necrotic core area and macrophage content were reduced ∼30% in 11βHSD1⁻/⁻/apoE⁻/⁻mice. Bone marrow transplantation from 11βHSD1⁻/⁻/apoE⁻/⁻ mice into apoE⁻/⁻ recipients reduced plaque area 39-46% in the thoracic aorta. In vivo foam cell formation was evaluated in thioglycollate-elicited peritoneal macrophages from 11βHSD1⁺/⁺/apoE⁻/⁻ and 11βHSD1⁻/⁻/apoE⁻/⁻ mice fed a Western diet for ∼5 weeks. Foam cell cholesterol levels were reduced 48% in 11βHSD1⁻/⁻/apoE⁻/⁻ mice vs. control. Microarray profiling of peritoneal macrophages revealed differential expression of genes involved in inflammation, stress response and energy metabolism. Several toll-like receptors (TLRs) were downregulated in 11βHSD1⁻/⁻/apoE⁻/⁻ mice including TLR 1, 3 and 4. Cytokine release from 11βHSD1⁻/⁻/apoE⁻/⁻-derived peritoneal foam cells was attenuated following challenge with oxidized LDL.ConclusionsThese findings suggest that 11βHSD1 inhibition may have the potential to limit plaque development at the vessel wall and regulate foam cell formation independent of changes in plasma lipids. The diminished cytokine response to oxidized LDL stimulation is consistent with the reduction in TLR expression and suggests involvement of 11βHSD1 in modulating binding of pro-atherogenic TLR ligands.

Project description:Lindera obtusiloba Blume is the northernmost tree species in the family Lauraceae, and it is a key species in understanding the evolutionary history of this family. The species of L. obtusiloba in East Asia has diverged into the Northern and Southern populations, which are geographically separated by an arid belt. Though the morphological differences between populations have been observed and well documented, intraspecific variations at the plastomic level have not been systematically investigated to date. Here, ten chloroplast genomes of L. obtusiloba individuals were sequenced and analyzed along with three publicly available plastomes. Comparative plastomic analysis suggests that both the Northern and the Southern populations share similar overall structure, gene order, and GC content in their plastomes although the size of the plasome and the level of intraspecific variability do vary between the two populations. The Northern have relatively larger plastomes while the Southern population possesses higher intraspecific variability, which could be attributed to the complexity of the geological environments in the South. Phylogenomic analyses also support the split of the Northern and Southern clades among L. obtusiloba individuals. However, there is no obvious species boundary between var. obtusiloba and var. heterophylla in the Southern population, indicating that gene flow could still occur between these two varieties, and this could be used as a good example of reticulate evolution. It is also found that a few photosynthesis-related genes are under positive selection, which is mainly related to the geological and environmental differences between the Northern and the Southern regions. Our results provide a reference for phylogenetic analysis within species and suggest that phylogenomic analyses with a sufficient number of nuclear and chloroplast genomic target loci from widely distributed individuals could provide a deeper understanding of the population evolution of the widespread species.

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A Standardized Lindera obtusiloba Extract Improves Endothelial Dysfunction and Attenuates Plaque Development in Hyperlipidemic ApoE-Knockout Mice.

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