The impact of the PCSK-9/VLDL-Receptor axis on inflammatory cell polarization

Arellano, Maria Luisa Barcena de; Estepa, Misael; Marx, Louis; Breiter, Anne; Haritonow, Natalie; Stawowy, Philipp

doi:10.1016/j.cyto.2022.156077

Cited by 7 publications

(4 citation statements)

References 62 publications

(62 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Viral envelope glycoproteins directly interact with host cell receptors and mediate virus-host membrane fusion [ 5 ], and, therefore, represent key factors in determining host cell tropism. SARS-CoV-2 infection reshapes cholesterol metabolism via gene activation and increased host metabolism activity [ 71 ], and depends on the presence of cholesterol-rich lipid raft and endosomal acidification [ 72 ]. However, the respective possible implication of the two proprotein convertases SKI-1/S1P and PCSK9, which regulate lipid metabolism and LDL-cholesterol levels [ 34 ] in SARS-CoV-2 infection has not yet been addressed.…”

Section: Discussionmentioning

confidence: 99%

SKI-1/S1P Facilitates SARS-CoV-2 Spike Induced Cell-to-Cell Fusion via Activation of SREBP-2 and Metalloproteases, Whereas PCSK9 Enhances the Degradation of ACE2

Essalmani

Andréo

Evagelidis

et al. 2023

Viruses

View full text Add to dashboard Cite

Proprotein convertases activate various envelope glycoproteins and participate in cellular entry of many viruses. We recently showed that the convertase furin is critical for the infectivity of SARS-CoV-2, which requires cleavage of its spike protein (S) at two sites: S1/S2 and S2′. This study investigates the implication of the two cholesterol-regulating convertases SKI-1 and PCSK9 in SARS-CoV-2 entry. The assays used were cell-to-cell fusion in HeLa cells and pseudoparticle entry into Calu-3 cells. SKI-1 increased cell-to-cell fusion by enhancing the activation of SREBP-2, whereas PCSK9 reduced cell-to-cell fusion by promoting the cellular degradation of ACE2. SKI-1 activity led to enhanced S2′ formation, which was attributed to increased metalloprotease activity as a response to enhanced cholesterol levels via activated SREBP-2. However, high metalloprotease activity resulted in the shedding of S2′ into a new C-terminal fragment (S2”), leading to reduced cell-to-cell fusion. Indeed, S-mutants that increase S2′’ formation abolished S2′ and cell-to-cell fusion, as well as pseudoparticle entry, indicating that the formation of S2′’ prevents SARS-CoV-2 cell-to-cell fusion and entry. We next demonstrated that PCSK9 enhanced the cellular degradation of ACE2, thereby reducing cell-to-cell fusion. However, different from the LDLR, a canonical target of PCSK9, the C-terminal CHRD domain of PCSK9 is dispensable for the PCSK9-induced degradation of ACE2. Molecular modeling suggested the binding of ACE2 to the Pro/Catalytic domains of mature PCSK9. Thus, both cholesterol-regulating convertases SKI-1 and PCSK9 can modulate SARS-CoV-2 entry via two independent mechanisms.

show abstract

Section: Discussionmentioning

confidence: 99%

SKI-1/S1P Facilitates SARS-CoV-2 Spike Induced Cell-to-Cell Fusion via Activation of SREBP-2 and Metalloproteases, Whereas PCSK9 Enhances the Degradation of ACE2

Essalmani

Andréo

Evagelidis

et al. 2023

Viruses

View full text Add to dashboard Cite

show abstract

“…In the current study, although the LDL-cholesterol level was not different between patients with high and low PCAT attenuation (median 100 versus 106 mg/dL; P =0.390), statins and PCSK-9 not only have LDL-cholesterol lowering effects but also anti-inflammatory effects that may help prevent the development and progression of atherosclerosis. 23,24 Thus, detection of vulnerable plaque using high PCAT detected by the threshold of −70.1 HU around the culprit coronary artery might help identify patients who could benefit from more aggressive prevention using high-intensity statins, PCSK9 inhibitors, or anti-inflammatory therapies.…”

Section: Discussionmentioning

confidence: 99%

Coronary Inflammation and Plaque Vulnerability: A Coronary Computed Tomography and Optical Coherence Tomography Study

Jang

Sugiyama

Suzuki

et al. 2023

Circ: Cardiovascular Imaging

View full text Add to dashboard Cite

BACKGROUND: Vascular inflammation plays a key role in atherogenesis and in the development of acute coronary syndromes. Coronary inflammation can be measured by peri-coronary adipose tissue (PCAT) attenuation on computed tomography angiography. We examined the relationships between the level of coronary artery inflammation assessed by PCAT attenuation and coronary plaque characteristics by optical coherence tomography. METHODS: A total of 474 patients (198 acute coronary syndromes and 276 stable angina pectoris) who underwent preintervention coronary computed tomography angiography and optical coherence tomography were included. To compare the relationships between the level of coronary artery inflammation and detailed plaque characteristics, we divided the subjects into high (n=244) and low (n=230) PCAT attenuation groups using a threshold value of −70.1 Hounsfield units. RESULTS: The high PCAT attenuation group, compared with the low PCAT attenuation group, had more males (90.6% versus 69.6%; P <0.001), more non-ST-segment elevation myocardial infarction (38.5% versus 25.7%; P =0.003), and less stable angina pectoris (51.6% versus 65.2%; P =0.003). Aspirin, dual antiplatelet, and statins were less frequently used in the high PCAT attenuation group compared to the low PCAT attenuation group. Patients with high PCAT attenuation, compared with those with low PCAT attenuation, had lower ejection fraction (median 64% versus 65%; P =0.014) and lower levels of high-density lipoprotein cholesterol (median 45 versus 48 mg/dL; P =0.027). Optical coherence tomography features of plaque vulnerability were significantly more common in patients with high PCAT attenuation, compared to those with low PCAT attenuation, including lipid-rich plaque (87.3% versus 77.8%; P =0.006), macrophage (76.2% versus 67.8%; P =0.041), microchannels (61.9% versus 48.3%; P =0.003), plaque rupture (38.1% versus 23.9%; P <0.001), and layered plaque (60.2% versus 50.0%; P =0.025). CONCLUSIONS: Optical coherence tomography features of plaque vulnerability were significantly more common in patients with high PCAT attenuation, compared with those with low PCAT attenuation. Vascular inflammation and plaque vulnerability are intimately related in patients with coronary artery disease. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04523194.

show abstract

“… 45 The similar results were also observed by Barcena et al that PCSK9 could also suppress the anti-inflammatory action mediated by VLDL in human macrophages by inhibiting VLDLR, whilst PCSK9-iTs could reverse the pro-inflammatory function in the experimental studies. 165 , 166 LRP5 and LRP6, as two potential PCSK9’s coreceptors, could also exacerbate atherosclerosis through the activation of the Wnt/β-catenin pathway, leading to the promotion of vascular SMCs (vSMCs) while suppressing anti-inflammatory macrophages. 105 , 106 PCSK9-iTs could also act by decreasing the migration of monocytes into the plaques of atherosclerosis, which was linked to increased levels of the anti-inflammatory cytokine IL-10, resulting in a reduction in the expression of TNF-α and C-C chemokine receptor 2 (CCR2), both of which controlled the entrance of monocytes into those plaques.…”

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

View full text Add to dashboard Cite

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.

show abstract

The impact of the PCSK-9/VLDL-Receptor axis on inflammatory cell polarization

Cited by 7 publications

References 62 publications

SKI-1/S1P Facilitates SARS-CoV-2 Spike Induced Cell-to-Cell Fusion via Activation of SREBP-2 and Metalloproteases, Whereas PCSK9 Enhances the Degradation of ACE2

SKI-1/S1P Facilitates SARS-CoV-2 Spike Induced Cell-to-Cell Fusion via Activation of SREBP-2 and Metalloproteases, Whereas PCSK9 Enhances the Degradation of ACE2

Coronary Inflammation and Plaque Vulnerability: A Coronary Computed Tomography and Optical Coherence Tomography Study

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

Contact Info

Product

Resources

About