PCSK9 promotes the secretion of pro-inflammatory cytokines by macrophages to aggravate H/R-induced cardiomyocyte injury via activating NF-κB signalling

Yang, Chenglong; Zeng, Yirong; Hu, Zhixi; Liang, Hao

doi:10.4149/gpb_2019057

Cited by 29 publications

(34 citation statements)

References 27 publications

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“…PCSK9 was found to induce an inflammatory response on macrophages by releasing pro‐inflammatory cytokines, such as tumor necrosis factor (TNF)‐α, interleukin (IL)‐1 and IL‐6 [35]. This has also been confirmed in hypoxia/reoxygenation (H/R) stress, where primary murine cardiomyocytes released TNF‐α, IL‐6 and IL‐1β and enhanced the production for these pro‐inflammatory cytokines by macrophages undergoing H/R [36]. Therefore, the positive relationship between PTX3 and PCSK9 should not be surprising and is similar to what reported by Rannikko et al, who observed a significant positive correlation between PCSK9 and CRP levels [17].…”

Section: Discussionmentioning

confidence: 99%

PCSK9 is associated with mortality in patients with septic shock: data from the ALBIOS study

et al. 2020

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Background Pro‐protein convertase subtilisin/kexin 9 (PCSK9) is a proenzyme primarily known to regulate low‐density lipoprotein receptor re‐uptake on hepatocytes. Whether PCSK9 can concurrently trigger inflammation or not remains unclear. Here, we investigated the potential association between circulating levels of PCSK9 and mortality in patients with severe sepsis or septic shock. Methods Plasma PCSK9 levels at days 1, 2 and 7 were measured in 958 patients with severe sepsis or septic shock previously enrolled in the Albumin Italian Outcome Sepsis (ALBIOS) trial. Correlations between levels of PCSK9 and pentraxin 3 (PTX3), a biomarker of disease severity, were evaluated with ranked Spearman’s coefficients. Cox proportional hazards models were used to assess the association of PCSK9 levels at day 1 with 28‐ and 90‐day mortality. Results Median plasma PCSK9 levels were 278 [182–452] ng mL−1 on day 1. PCSK9 correlated positively with PTX3 at the three time‐points, and patients with septic shock within the first quartile of PCSK9 showed higher levels of PTX3. Similar mortality rates were observed in patients with severe sepsis across PCSK9 quartiles. Patients with septic shock with lower PCSK9 levels on day 1 (within the first quartile) showed the highest 28‐ and 90‐day mortality rate as compared to other quartiles. Conclusion In our sub‐analysis of the ALBIOS trial, we found that patients with septic shock presenting with lower plasma PCSK9 levels experienced higher mortality rate. Further studies are warranted to better evaluate the pathophysiological role of PCSK9 in sepsis.

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Section: Discussionmentioning

confidence: 99%

PCSK9 is associated with mortality in patients with septic shock: data from the ALBIOS study

et al. 2020

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“…Yet, whereas CD36 decline might be beneficial in the short-term post-ischaemia because of improved myocardial efficiency rates, levels of CD36 need to be restored upon glucose and intracellular TG storage depletion in order to meet cardiac energy demands (Kim and Dyck, 2016). In this regard, taking into consideration that PCSK9, which is found to be enhanced by hypoxia/reoxygenation (Yang et al, 2020), has also shown to degrade CD36 beyond the LDL-R (Demers et al, 2015), PCSK9 inhibition might hold promise as a therapeutic strategy to modulate myocardial CD36 content and expression and consequently FA metabolism levels in the setting of MI.…”

Section: Fatty Acid Translocase Cd36 and Pcsk9 In Irimentioning

confidence: 99%

“…The up-regulation of PCSK9 is driven by sterol response element binding protein 2 (SREBP-2) and hepatocyte nuclear factor 1 α (HNF1α), both of which are the predominate transcription factors for PCSK9 (Zhang et al, 2014). PCSK9 is also expressed in the myocardium and is significantly up-regulated in hypoxia/reoxygenation-stimulated primary murine cardiomyocytes compared with cells grown in normoxic environments (Ding et al, 2018;Yang et al, 2020). Again, in MI the maximum expression of PCSK9 was found in the border zone 1 week after left coronary artery (LCA) ligation (Ding et al, 2018).…”

Section: Effects Of Pcsk9 Beyond Ldl Reduction: Impact On Irimentioning

confidence: 99%

“…The investigation on PCSK9 regulatory function in myocardial ischaemia revealed that PCSK9 activated NF-κB signaling resulting in a more pronounced secretion of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and IL-1β by macrophages worsening the hypoxiareoxygenation-induced injury in cardiomyocytes (Yang et al, 2020). PCSK9 has been shown to promote inflammation in atherosclerosis through TLR4/NF-κB pathway and increase macrophage release of pro-inflammatory cytokines, TNF-α, IL-6, IL-1β, interferon-γ (IFN-γ), C-X-C motif ligand 2, and Monocyte Chemoattractant Protein-1 (Tang et al, 2017;Ricci et al, 2018;Macchi et al, 2019).…”

Section: Effects Of Pcsk9 Beyond Ldl Reduction: Impact On Irimentioning

confidence: 99%

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PCSK9 in Myocardial Infarction and Cardioprotection: Importance of Lipid Metabolism and Inflammation

et al. 2020

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Extensive evidence from epidemiologic, genetic, and clinical intervention studies has indisputably shown that elevated low-density lipoprotein cholesterol (LDL-C) concentrations play a central role in the pathophysiology of atherosclerotic cardiovascular disease. Apart from LDL-C, also triglycerides independently modulate cardiovascular risk. Reduction of proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a therapeutic target for reducing plasma LDL-C, but it is also associated with a reduction in triglyceride levels potentially through modulation of the expression of free fatty acid transporters. Preclinical data indicate that PCSK9 is up-regulated in the ischaemic heart and decreasing PCSK9 expression impacts on infarct size, post infarct inflammation and remodeling as well as cardiac dysfunction following ischaemia/reperfusion. Clinical data support that notion in that PCSK9 inhibition is associated with reductions in the incidence of myocardial infarction, stroke, and coronary revascularization and an improvement of endothelial function in subjects with increased cardiovascular risk. The aim of the current review is to summarize the current knowledge on the importance of free fatty acid metabolism on myocardial ischaemia/reperfusion injury and to provide an update on recent evidence on the role of hyperlipidemia and PCSK9 in myocardial infarction and cardioprotection.

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“…Moreover, recent experimental data suggest that PCSK-9 could be involved in the release of pro-inflammatory cytokines by macrophages after hypoxia and reperfusion injury. The authors even suggest that PCSK-9 could alleviate the activation of the nuclear factor "kappa-light-chain-enhancer" of activated B-cells (NFKB) pathway after experimental myocardial ischemia [20]. Furthermore, PCSK-9 also interacts with the oxidized-LDL-receptor (LOX-1), which is a central regulator of inflammation, atherogenesis and apoptosis of endothelial cells.…”

Section: Introductionmentioning

confidence: 99%

Low PCSK-9 levels Are Associated with Favorable Neurologic Function after Resuscitation from out of Hospital Cardiac Arrest

Merrelaar

Buchtele

Schriefl

et al. 2020

JCM

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Endotoxemia after cardiopulmonary resuscitation (CPR) is associated with unfavorable outcome. Proprotein convertase subtilisin/kexin type-9 (PCSK–9) regulates low-density lipoprotein receptors, which mediate the hepatic uptake of endotoxins. We hypothesized that PCSK–9 concentrations are associated with neurological outcome in patients after CPR. Successfully resuscitated out-of-hospital cardiac arrest patients were included prospectively (n = 79). PCSK–9 levels were measured on admission, 12 h and 24 h thereafter, and after rewarming. The primary outcome was favorable neurologic function at day 30, defined by cerebral performance categories (CPC 1–2 = favorable vs. CPC 3–5 = unfavorable). Receiver operating characteristic curve analysis was used to identify the PCSK–9 level cut-off for optimal discrimination between favorable and unfavorable 30-day neurologic function. Logistic regression models were calculated to estimate the effect of PCSK–9 levels on the primary outcome, given as odds ratio (OR) and 95% confidence interval (95%CI). PCSK–9 levels on admission were significantly lower in patients with favorable 30-day neurologic function (median 158 ng/mL, (quartiles: 124–225) vs. 207 ng/mL (174–259); p = 0.019). The optimally discriminating PCSK–9 level cut-off was 165ng/mL. In patients with PCSK–9 levels ≥ 165 ng/mL, the odds of unfavorable neurological outcome were 4.7-fold higher compared to those with PCSK–9 levels < 165 ng/mL. In conclusion, low PCSK–9 levels were associated with favorable neurologic function.

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PCSK9 promotes the secretion of pro-inflammatory cytokines by macrophages to aggravate H/R-induced cardiomyocyte injury via activating NF-κB signalling

Cited by 29 publications

References 27 publications

PCSK9 is associated with mortality in patients with septic shock: data from the ALBIOS study

PCSK9 is associated with mortality in patients with septic shock: data from the ALBIOS study

PCSK9 in Myocardial Infarction and Cardioprotection: Importance of Lipid Metabolism and Inflammation

Low PCSK-9 levels Are Associated with Favorable Neurologic Function after Resuscitation from out of Hospital Cardiac Arrest

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