Reduction in Vasa Vasorum Angiogenesis by Lp-PLA2 Selective Inhibitor Through The HIF-1α and VEGF Expression Under Dyslipidemic Conditions in Atherosclerosis Pathogenesis

Heriansyah, Teuku; Nafisatuzzamrudah, Nafisa; Aini, Fitria Nugraha; Ridwan, Muhammad; Primardhika, Rozah F; Wijayanti, Maya; Bekti, Rachmad Sarwo; Wihastuti, Titin Andri

doi:10.2174/1871525716666181105151429

Cited by 8 publications

(5 citation statements)

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“…With a series of eligible compounds available at present, scientists would be admired if they exerted more effort in exploring the role of Lp‐PLA2 in diseases other than atherosclerosis, particularly, in microvascular diseases that may be more sensitive to Lp‐PLA2 inhibition. In addition, the large pool of data generated from clinical trials provides numerous opportunities for comprehensive data mining, which may be beneficial to understanding the biological consequences of Lp‐PLA2 inhibition and help us to learn a profound and valuable lesson from the failure of darapladib . To conclude, we anticipate that the story of Lp‐PLA2 will continue.…”

Section: Discussion and Prospectsmentioning

confidence: 99%

“…In addition, the large pool of data generated from clinical trials provides numerous opportunities for comprehensive data mining, which may be beneficial to understanding the biological consequences of Lp-PLA2 inhibition and help us to learn a profound and valuable lesson from the failure of darapladib. [279][280][281][282][283][284][285][286][287][288] To conclude, we anticipate that the story of Lp-PLA2 will continue.…”

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confidence: 99%

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Lipoprotein‐associated phospholipase A2: The story continues

Huang

Wang

Shen

2019

Medicinal Research Reviews

121

140

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Inflammation is thought to play an important role in the pathogenesis of vascular diseases. Lipoprotein‐associated phospholipase A2 (Lp‐PLA2) mediates vascular inflammation through the regulation of lipid metabolism in blood, thus, it has been extensively investigated to identify its role in vascular inflammation‐related diseases, mainly atherosclerosis. Although darapladib, the most advanced Lp‐PLA2 inhibitor, failed to meet the primary endpoints of two large phase III trials in atherosclerosis patients cotreated with standard medical care, the research on Lp‐PLA2 has not been terminated. Novel pathogenic, epidemiologic, genetic, and crystallographic studies regarding Lp‐PLA2 have been reported recently, while novel inhibitors were identified through a fragment‐based lead discovery strategy. More strikingly, recent clinical and preclinical studies revealed that Lp‐PLA2 inhibition showed promising therapeutic effects in diabetic macular edema and Alzheimer's disease. In this review, we not only summarized the knowledge of Lp‐PLA2 established in the past decades but also emphasized new findings in recent years. We hope this review could be valuable for helping researchers acquire a much deeper insight into the nature of Lp‐PLA2, identify more potent and selective Lp‐PLA2 inhibitors, and discover the potential indications of Lp‐PLA2 inhibitors.

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Section: Discussion and Prospectsmentioning

confidence: 99%

mentioning

confidence: 99%

Lipoprotein‐associated phospholipase A2: The story continues

Huang

Wang

Shen

2019

Medicinal Research Reviews

121

140

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“…The hypoxia condition induces the HIF-1α expression (Wong et al, 2017;Jain et al, 2018). HIF-1α referred to as "master switch for hypoxia gene expression" is a DNA-binding transcription factor closely associated with specific nuclear cofactors (Fong, 2015;Ferns and Heikal, 2017;Yao et al, 2017;Heriansyah et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

Effect and Mechanism of Si-Miao-Yong-An on Vasa Vasorum Remodeling in ApoE−/− Mice with Atherosclerosis Vulnerable Plague

Zhang

et al. 2021

Front. Pharmacol.

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Objective: To observe the effect of Si-Miao-Yong-An (SMYA) on atherosclerosis (AS) vulnerable plaques, and to further explore the mechanism by vasa vasorum (VV) angiogenesis and maturation as an entry point.Methods: SPF-class healthy male ApoE−/− mice were randomized into model group, simvastatin group and SMYA group, and C57BL/6 mice were used as the control group. After 8 weeks of intervention, the pathological morphology of plaque was observed by HE staining; the VV density in plaque and aortic adventitia were observed by immunohistochemistry; VV maturation was measured by double-labelling immunofluorescence; the critical proteins of HIF-1α-Apelin/APJ and Ang-1/Tie signal pathways were detected by western blotting.Results: SMYA decreased the plaque area and the ratio of plaque to lumen area; increased the minimum thickness of fibrous cap and its effect was greater than simvastatin. SMYA suppressed the VV neovascularization; promoted smooth muscle cells recruitment and VV maturation, which maintained plaque stability; its effect was obviously superior to simvastatin. SMYA deceased the expression of HIF-1α, Apelin, APJ, Phospho-MEK1/2 (Ser217/221), Phospho-p44/42 MAPK (Erk1/2) (Thr202/Tyr204), Phospho-p70 S6 Kinase (Thr421/Ser424), Ang-2 and Tie-2; it also increased the expression of Ang-1, Phospho-Akt (Ser473), Phospho-FOXO1 (Ser256) and Survivin.Conclusions: SMYA can decrease the AS plaque area in ApoE−/− mice, suppress the VV neovascularization and promote the VV maturation, and stabilize AS vulnerable plaque. The mechanism could be regulating the HIF-1α-Apelin/APJ and Ang-1/Tie signal pathways.

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“…Lipoprotein-associated phospholipase A2 (Lp-PLA2), which mainly circulates a complex of LDL and HDL in the blood AS, can hydrolyze oxidized phospholipids in ox-LDL to produce pro-inflammatory lipids, and then produce various AS-causing effects. It also promotes the production of related cytokines [ [34] , [35] , [36] ]. However, Lp-PLA2 expression was upregulated in AS plaques, and its expression was enhanced in the Mφ of fibrous caps of vulnerable plaques [ 37 ].…”

Section: Inflammatory Markers In the Pathogenesis And Clinical Diagno...mentioning

confidence: 99%

Exploring the mechanism of atherosclerosis and the intervention of traditional Chinese medicine combined with mesenchymal stem cells based on inflammatory targets

Sun,

Liu,

Fan

et al. 2023

Heliyon

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Reduction in Vasa Vasorum Angiogenesis by Lp-PLA2 Selective Inhibitor Through The HIF-1α and VEGF Expression Under Dyslipidemic Conditions in Atherosclerosis Pathogenesis

Cited by 8 publications

References 0 publications

Lipoprotein‐associated phospholipase A2: The story continues

Lipoprotein‐associated phospholipase A2: The story continues

Effect and Mechanism of Si-Miao-Yong-An on Vasa Vasorum Remodeling in ApoE−/− Mice with Atherosclerosis Vulnerable Plague

Exploring the mechanism of atherosclerosis and the intervention of traditional Chinese medicine combined with mesenchymal stem cells based on inflammatory targets

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