20(<i>S</i>)-Protopanaxadiol decreases atherosclerosis in ApoE KO mice by increasing the levels of LDLR and inhibiting its binding with PCSK9

Huang, Yewei; Zhang, Meng; Wang, Litian; Nie, Yan; Yang, Jinbo; Meng, Wen-Luer; Sheng, Jun

doi:10.1039/d2fo00392a

Cited by 8 publications

(4 citation statements)

References 42 publications

(65 reference statements)

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“…Previously, we have shown that the primary mechanism of 20( S )-PPD in alleviating AS in ApoE KO mice involves increasing LDLR levels and inhibiting its binding with PCSK9. 36 20( S )-PPT has an additional hydroxyl group at the C-6 position compared to 20( S )-PPD. The presence of this additional hydroxyl group results in a lower plasma protein-binding rate of the PPT-type ginsenoside than that of the PPD-type ginsenoside, 37 which will be rapidly absorbed and eliminated from the body.…”

Section: Discussionmentioning

confidence: 99%

r20 (S)-protopanaxatriol improves atherosclerosis by inhibiting low-density lipoprotein receptor degradation in ApoE KO mice

Huang,

Luo,

Zhang

et al. 2024

Journal of Cardiovascular Pharmacology

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Atherosclerosis (AS) is a chronic progressive disease caused by various factors and causes various cerebrovascular and cardiovascular diseases (CVDs). Reducing the plasma levels of low-density lipoprotein-cholesterol (LDL-C) is the primary goal in preventing and treating AS. Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) plays a crucial role in regulating LDL-C metabolism. Panax notoginseng has potent lipid-reducing effects and protects against CVDs, and its saponins induce vascular dilatation, inhibit thrombus formation, and are used in treating CVDs. However, the anti-AS effect of the secondary metabolite, 20(S) protopanaxatriol (20(S)-PPT), remains unclear. In this study, the anti-AS effect and molecular mechanism of 20(S)-PPT were investigated in vivo and in vitro by western blotting, real time-polymerase chain reaction (RT-PCR), Enzyme-linked Immunosorbent Assay (ELISA), immunofluorescence staining, and other assays. The in vitro experiments revealed that 20(S)-PPT reduced the levels of PCSK9 in the supernatant of HepG2 cells, upregulated low density lipoprotein receptor (LDLR) protein levels, promoted LDL uptake by HepG2 cells, and reduced PCSK9 mRNA transcription by upregulating the levels of FoxO3 protein and mRNA and decreasing the levels of HNF1α and SREBP2 protein and mRNA. The in vivo experiments revealed that 20(S)-PPT upregulated aortic αSMA expression, increased the stability of atherosclerotic plaques, and reduced aortic plaque formation induced by a high-cholesterol fed in ApoE-/- mice (HCF group). Additionally, 20(S)PPT reduced the aortic expression of CD68, reduced inflammation in the aortic root, and alleviated the hepatic lesions in the HCF group. The study revealed that 20(S)-PPT inhibited LDLR degradation via PCSK9 to alleviate AS.

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Section: Discussionmentioning

confidence: 99%

r20 (S)-protopanaxatriol improves atherosclerosis by inhibiting low-density lipoprotein receptor degradation in ApoE KO mice

Huang,

Luo,

Zhang

et al. 2024

Journal of Cardiovascular Pharmacology

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“… 134 Similarly, for ApoE −/− mice sustained on an HCD, the SIRT1 activator demonstrated an effect against atherosclerosis by lowering blood PCSK9 levels while augmenting LDLR levels. 135 , 136 Moreover, PCSK9 has also been implicated in the processes of platelet activation and thrombosis. 137 It has been evidenced that PCSK9 fosters platelet clustering, activation, and expansion as well as thrombosis by the interaction with CD36 on the surface of platelets and triggering a subsequent p38 mitogen-activated protein kinase (MAPK)/cytosolic phospholipase A2 (cPLA2)/cyclooxygenase 1 (COX-1)/thromboxane A2 (TXA2) signaling cascade.…”

Section: The Role Of Pcsk9 In Various Disordersmentioning

confidence: 99%

Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside

Bao,

Liang,

Chang

et al. 2024

Sig Transduct Target Ther

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Proprotein convertase subtilisin/kexin type 9 (PCSK9) has evolved as a pivotal enzyme in lipid metabolism and a revolutionary therapeutic target for hypercholesterolemia and its related cardiovascular diseases (CVD). This comprehensive review delineates the intricate roles and wide-ranging implications of PCSK9, extending beyond CVD to emphasize its significance in diverse physiological and pathological states, including liver diseases, infectious diseases, autoimmune disorders, and notably, cancer. Our exploration offers insights into the interaction between PCSK9 and low-density lipoprotein receptors (LDLRs), elucidating its substantial impact on cholesterol homeostasis and cardiovascular health. It also details the evolution of PCSK9-targeted therapies, translating foundational bench discoveries into bedside applications for optimized patient care. The advent and clinical approval of innovative PCSK9 inhibitory therapies (PCSK9-iTs), including three monoclonal antibodies (Evolocumab, Alirocumab, and Tafolecimab) and one small interfering RNA (siRNA, Inclisiran), have marked a significant breakthrough in cardiovascular medicine. These therapies have demonstrated unparalleled efficacy in mitigating hypercholesterolemia, reducing cardiovascular risks, and have showcased profound value in clinical applications, offering novel therapeutic avenues and a promising future in personalized medicine for cardiovascular disorders. Furthermore, emerging research, inclusive of our findings, unveils PCSK9’s potential role as a pivotal indicator for cancer prognosis and its prospective application as a transformative target for cancer treatment. This review also highlights PCSK9’s aberrant expression in various cancer forms, its association with cancer prognosis, and its crucial roles in carcinogenesis and cancer immunity. In conclusion, this synthesized review integrates existing knowledge and novel insights on PCSK9, providing a holistic perspective on its transformative impact in reshaping therapeutic paradigms across various disorders. It emphasizes the clinical value and effect of PCSK9-iT, underscoring its potential in advancing the landscape of biomedical research and its capabilities in heralding new eras in personalized medicine.

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“…In particular, PPD has been shown the ability to bind to the extracellular domain of LDLR, effectively inhibiting the interaction between PCSK9 and LDLR. This results in increased LDLR protein levels in HepG2 cells and liver tissue from high‐fat fed ApoE −/− mice, alleviating hepatic steatosis and lipid droplet accumulation, as well as ameliorating atherosclerosis (Huang, Zhang, et al, 2022). Gypenoside, similar to ginsenosides, has a dammarane‐like structure and shows promise as an anti‐atherogenic agent.…”

Section: Mechanism Of Saponins In the Treatment Of Atherosclerosismentioning

confidence: 99%

Saponins as therapeutic candidates for atherosclerosis

Lv,

Wang,

Zeng

et al. 2024

Phytotherapy Research

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Drug development for atherosclerosis, the underlying pathological state of ischemic cardiovascular diseases, has posed a longstanding challenge. Saponins, classified as steroid or triterpenoid glycosides, have shown promising therapeutic potential in the treatment of atherosclerosis. Through an exhaustive examination of scientific literature spanning from May 2013 to May 2023, we identified 82 references evaluating 37 types of saponins in terms of their prospective impacts on atherosclerosis. These studies suggest that saponins have the potential to ameliorate atherosclerosis by regulating lipid metabolism, inhibiting inflammation, suppressing apoptosis, reducing oxidative stress, and modulating smooth muscle cell proliferation and migration, as well as regulating gut microbiota, autophagy, endothelial senescence, and angiogenesis. Notably, ginsenosides exhibit significant potential and manifest essential pharmacological attributes, including lipid‐lowering, anti‐inflammatory, anti‐apoptotic, and anti‐oxidative stress effects. This review provides a comprehensive examination of the pharmacological attributes of saponins in atherosclerosis, with particular emphasis on their role in the regulation of lipid metabolism regulation and anti‐inflammatory effects. Thus, saponins may warrant further investigation as a potential therapy for atherosclerosis. However, due to various reasons such as low oral bioavailability, the clinical application of saponins in the treatment of atherosclerosis still needs further exploration.

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20(S)-Protopanaxadiol decreases atherosclerosis in ApoE KO mice by increasing the levels of LDLR and inhibiting its binding with PCSK9

Abstract: Chinese medicinal and edible plants such as Panax notoginseng and ginseng are widely used for the treatment of Atherosclerosis (AS). AS is the main pathological basis of cardiac-cerebral vascular disease,...

Cited by 8 publications

References 42 publications

r20 (S)-protopanaxatriol improves atherosclerosis by inhibiting low-density lipoprotein receptor degradation in ApoE KO mice

r20 (S)-protopanaxatriol improves atherosclerosis by inhibiting low-density lipoprotein receptor degradation in ApoE KO mice

Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside

Saponins as therapeutic candidates for atherosclerosis

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