PCSK9 promotes arterial medial calcification

Lupo, Maria Giovanna; Bressan, A.; Donato, Maristella; Canzano, Paola; Camera, Marina; Poggio, Paolo; Greco, Maria Francesca; Garofalo, Mariangela; Martin, Sara De; Panighel, Giovanni; Ruscica, Massimiliano; Baragetti, Andrea; Bollati, Valentina; Faggin, Elisabetta; Rattazzi, Marcello; Catapano, Alberico L.; Ferri, Nicola

doi:10.1016/j.atherosclerosis.2022.01.015

Cited by 20 publications

(22 citation statements)

References 73 publications

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“…It has been demonstrated that this medication affects not only cholesterol concentrations, but also pro-inflammatory factor concentrations, resulting in a higher decrease in CVD risk than only reducing LDL concentrations [ 33 , 34 ]. Furthermore, additional research in people and animal models has found that statin treatment reduces proinflammatory cytokines, MMP-2, and MMP-9 levels considerably [ 35 , 36 , 37 , 38 ]. These treatments reduce the risk of cardiovascular disease by stabilizing the atherosclerotic plaque.…”

Section: Discussionmentioning

confidence: 99%

Impact of PCSK9 Inhibition on Proinflammatory Cytokines and Matrix Metalloproteinases Release in Patients with Mixed Hyperlipidemia and Vulnerable Atherosclerotic Plaque

2022

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Background: Atherosclerosis is a disorder in which, in addition to high cholesterol levels, several plasma factors play a significant role in its development. Among these cytokines and molecules are interleukin 6 (IL-6), interleukin 18 (IL-18), tumor necrosis factor α (TNF-α), metalloproteinase 2 (MMP-2), and metalloproteinase 9 (MMP-9), all of which may contribute to the stabilization of atherosclerotic plaque. The purpose of this study was to determine the effect of advanced lipid-lowering therapy on the levels of these determinants by utilizing proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors in patients with verified high-risk atherosclerotic plaque. Methods: The study involved patients with dyslipidemia who had the presence of unstable atherosclerotic plaque verified by ultrasonography and who were eligible to begin alirocumab treatment. The levels of IL-6, IL, 18, TNF-α, and MMPs were determined in this group before and after three months of therapy. Results: After treatment, a statistically significant decrease in concentrations of Il-18, Il-6, TNF-α (p < 0.001) and MMP-2 (p < 0.05) was observed. Additionally, we observed that the concentrations of these markers were significantly higher in the group of patients prior to initiating therapy than in the control group. Conclusions: Our study’s results suggest that PCSK-9 inhibitor therapy significantly reduces the concentration of factors influencing the stability of atherosclerotic plaque, which may explain their essential importance in reducing cardiovascular risk in patients receiving this treatment.

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Section: Discussionmentioning

confidence: 99%

Impact of PCSK9 Inhibition on Proinflammatory Cytokines and Matrix Metalloproteinases Release in Patients with Mixed Hyperlipidemia and Vulnerable Atherosclerotic Plaque

2022

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“…It has been proven that this therapy affects not only the concentration of cholesterol but also the concentration of pro-inflammatory factors, and thus causes a greater reduction of CVD risk than results from only lowering the concentration of LDL [ 38 , 39 ]. In addition, other studies conducted in humans and in animal models have also shown that statin therapy significantly lowers the levels of OPN, OPG, MMP-2, and MMP-9 [ 40 , 41 , 42 , 43 ]. These actions stabilize the atherosclerotic plaque, thus reducing the CVD risk.…”

Section: Discussionmentioning

confidence: 99%

Impact of Alirocumab on Release Markers of Atherosclerotic Plaque Vulnerability in Patients with Mixed Hyperlipidemia and Vulnerable Atherosclerotic Plaque

2022

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Background and Objectives: Atherosclerosis is a disease in the pathogenesis of which plasma factors apart from elevated cholesterol levels play a keyrole. Such factors include osteopontin (OPN), osteoprotegerin (OPG), and metalloproteinases (MMPs), which are factors that may be responsible for the stabilization of atherosclerotic plaque. The aim of this study was to assess the effect of modern lipid-lowering therapy by using proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitor on the concentrations of these factors. Materials and Methods: The study included people suffering from dyslipidemia who were eligible to start alirocumab therapy. In this group, the concentrations of OPN, OPG, and MMPs were assessed before the initiation of therapy and after three months of its duration. Results: In the study, we observed a statistically significant reduction in the concentrations of OPN, OPG (p < 0.001), and metalloproteinase 2 (MMP-2) (p < 0.05) after the applied therapy. Moreover, we noticed that in the group of patients soon to start alirocumab therapy, the concentrations of these factors were higher compared to the control group (p < 0.001). Conclusions: The results of our study show that therapy with alirocumab significantly reduces the concentration of factors that affect atherosclerotic plaque vulnerability, which may explain their important role in reducing cardiovascular risk in patients undergoing this therapy.

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“…Conversely, PCSK9 has already been strongly linked to CVD, both from genetic and functional aspects, being a major target for control of hyperlipidemia and vascular disease in clinical practice, which therefore lowered its novelty for our study. Nevertheless, recent reports showed that PCSK9 can be found not only in hepatocytes, but in different cell types typically present within the diseased vascular wall and associated with various processes essential for CVD that go beyond its involvement in degradation of the LDLr, such as inflammation, calcification and thrombosis ( Ferri et al, 2012 ; Ding et al, 2015 ; Li et al, 2017 ; Ding et al, 2020 ; Liu et al, 2020 ; Macchi et al, 2021 ; Qi et al, 2021 ; Lupo et al, 2022 ). Here we were able to confirm and extend these findings, as our study shows for the first time that despite the low mRNA expression levels observed in vascular biopsies, PCSK9 protein was abundant.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic potential of the Proprotein Convertase Subtilisin/Kexin family in vascular disease

et al. 2022

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Proprotein convertase subtilisin/kexins (PCSKs) constitute a family of nine related proteases: PCSK1-7, MBTPS1, and PCSK9. Apart from PCSK9, little is known about PCSKs in cardiovascular disease. Here, we aimed to investigate the expression landscape and druggability potential of the entire PCSK family for CVD. We applied an integrative approach, combining genetic, transcriptomic and proteomic data from three vascular biobanks comprising carotid atherosclerosis, thoracic and abdominal aneurysms, with patient clinical parameters and immunohistochemistry of vascular biopsies. Apart from PCSK4, all PCSK family members lie in genetic regions containing variants associated with human cardiovascular traits. Transcriptomic analyses revealed that FURIN, PCSK5, MBTPS1 were downregulated, while PCSK6/7 were upregulated in plaques vs. control arteries. In abdominal aneurysms, FURIN, PCSK5, PCSK7, MBTPS1 were downregulated, while PCSK6 was enriched in diseased media. In thoracic aneurysms, only FURIN was significantly upregulated. Network analyses of the upstream and downstream pathways related to PCSKs were performed on the omics data from vascular biopsies, revealing mechanistic relationships between this protein family and disease. Cell type correlation analyses and immunohistochemistry showed that PCSK transcripts and protein levels parallel each other, except for PCSK9 where transcript was not detected, while protein was abundant in vascular biopsies. Correlations to clinical parameters revealed a positive association between FURIN plaque levels and serum LDL, while PCSK6 was negatively associated with Hb. PCSK5/6/7 were all positively associated with adverse cardiovascular events. Our results show that PCSK6 is abundant in plaques and abdominal aneurysms, while FURIN upregulation is characteristic for thoracic aneurysms. PCSK9 protein, but not the transcript, was present in vascular lesions, suggesting its accumulation from circulation. Integrating our results lead to the development of a novel 'molecular' 5D framework. Here, we conducted the

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PCSK9 promotes arterial medial calcification

Cited by 20 publications

References 73 publications

Impact of PCSK9 Inhibition on Proinflammatory Cytokines and Matrix Metalloproteinases Release in Patients with Mixed Hyperlipidemia and Vulnerable Atherosclerotic Plaque

Impact of PCSK9 Inhibition on Proinflammatory Cytokines and Matrix Metalloproteinases Release in Patients with Mixed Hyperlipidemia and Vulnerable Atherosclerotic Plaque

Impact of Alirocumab on Release Markers of Atherosclerotic Plaque Vulnerability in Patients with Mixed Hyperlipidemia and Vulnerable Atherosclerotic Plaque

Therapeutic potential of the Proprotein Convertase Subtilisin/Kexin family in vascular disease

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