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

Abstract

The upregulation of proprotein convertase subtilisin/kexin type 9 (PCSK9) was reported to be involved in regulating the levels of inflammatory markers and apoptosis in macrophages. This study aims to investigate the function and regulation of PCSK9 in myocardial ischaemia. The results of our study showed dramatically increased expression of PCSK9 induced by hypoxia/reoxygenation (H/R) stress rather than by apoptosis in primary murine cardiomyocytes and HL-1 cells. Moreover, PCSK9 promoted H/R-induced pro-inflammatory cytokine release from macrophages, while silencing of PCSK9 inhibited the expression of the pro-inflammatory cytokines TNF-α, IL-6 and IL-1β. Additionally, PCSK9 facilitated the release of pro-inflammatory cytokines from macrophages under H/R conditions, which decreased cardiomyocyte viability and promoted apoptosis of cardiomyocytes. For the underlying mechanisms, we identified PCSK9-induced NF-κB activation as being involved in the cardiomyocyte apoptosis, which was blocked by the NF-κB inhibitor BAY 11-7082. Collectively, this study provides new insights into the therapeutic possibility of regulating PCSK9 in cardiomyocytes for the treatment of ischaemic cardiomyopathy.

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

“…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].…”

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

“…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.…”

“…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).…”

“…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).…”

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

“…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.…”