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Data-driven transcriptomics analysis identifies PCSK9 as a novel potential liver rejuvenation agent

ABSTRACT: Data-driven transcriptomics analysis identifies PCSK9 as a novel potential liver rejuvenation agent

PROVIDER: PRJNA865377 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR20773600_1.fastq.gz	Fastqsanger.gz
	SRR20773600_2.fastq.gz	Fastqsanger.gz
	SRR20773601_1.fastq.gz	Fastqsanger.gz
	SRR20773601_2.fastq.gz	Fastqsanger.gz
	SRR20773602_1.fastq.gz	Fastqsanger.gz

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Data-driven transcriptomics analysis identifies PCSK9 as a novel potential liver rejuvenation agent

Project description:Aging is an inevitable process in life that leads to numerous systemic effects on the human body. Here, we investigated systematically the effect of aging on the liver using a rat model of aging using data-driven approaches. We performed systems biology approaches to analyze genome-wide transcriptomics data from liver samples obtained from 3- and 19 months old rats. We observed significant alterations in multiple biological processes, including (1) disruption of mitochondrial functions and protein synthesis, and (2) activation of immune and inflammation pathways and lipid metabolism. We validated our results in two independent aging datasets. Finally, we demonstrated the power of the co-expression network to identify novel driver genes for liver aging and confirmed our findings in human aging subjects. Overall, we identified and validated a liver-specific gene, PCSK9, as a potential therapeutic target for attenuating the aging effect on the liver.

2023-09-08 | GSE210371 | GEO

Transcription profiling of human HepG2 cells expressing gain-of-function mutant D374Y-PCSK9

Project description:We have transfected Hep2G cells with the gain-of-function mutant D374Y-PCSK9.

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PCSK9, a promising novel target for age-related cardiovascular dysfunction

Project description:Cardiovascular diseases (CVD) are the leading cause of death among elderly people. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an important regulator of cholesterol metabolism. Herein, we investigated the role of PCSK9 in age-related CVD. Both in humans and rats, sPCSK9 correlated positively with increasing age and the development of cardiovascular dysfunction. Network analysis identified PCSK9 as an important factor in age-associated lipid alterations and it correlated positively with intima media thickness, a clinical parameter of CVD risk. PCSK9 inhibition with alirocumab effectively reduced the CVD progression in aging rats suggesting that PCSK9 plays an important role in cardiovascular aging.

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Microarray data for rejuvenation experiments through reprogramming

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Targeting myeloid-PCSK9 enhancing cardio-protection beyond LDL cholesterol-lowering

Project description:Circulating Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) levels, known for regulating plasma cholesterol by degrading LDL receptors, correlate with acute myocardial infarction (AMI) risk. Recent studies suggest that PCSK9 improves cardiac function beyond LDL cholesterol levels after cardiac ischemic injury, but the precise role of PCSK9 in this process is not clarified yet. Our study reveals that PCSK9 deficiency induces heterogeneous changes in myeloid cells and macrophages, potentially protecting the heart in AMI regardless of LDL cholesterol homeostasis. Single-cell RNA sequencing identifies PCSK9-dependent cardiac macrophages (PDCMs) as reparative macrophages enriched in activator protein-1 (AP-1) transcription factor (TF)-related pathways. PDCMs enhance VEGF-C secretion and activate Akt signalling in cardiac endothelial cells, improving cardiac remodelling. Indeed, PCSK9 inhibitor-treated coronary artery disease (CAD) patients show increased myeloid cells with PDCM-like features. In sum, targeting myeloid-PCSK9 may offer cardio-protective effects through increased AP-1 activity and VEGF-C expression, providing a novel approach to prevent cardiac dysfunction in AMI.

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PCSK9 knockdown in EndoC-bH1 cells at 72 hours

Project description:The aim of the study was to characterize the role of PCSK9 in human beta cells. We performed siRNA-mediated knockdown of PCSK9 in human beta cell line EndoC-bH1 and compared the expression profiles against control siRNA-treated cells.

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PCSK9 promotes vein graft lesion development

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Project description:Proprotein convertase subtilisin kexin type 9 (PCSK9) is a key regulator of LDL cholesterol metabolism and the target of lipid-lowering drugs. PCSK9 is mainly expressed in hepatocyte. Here, we show that PCSK9 is highly expressed in undifferentiated hiPSCs. PCSK9 inhibition in hiPSCs with the use of shRNA, CRISPR/cas9-mediated knockout or endogenous PCSK9 loss-of-function mutation R104C/V114A unveiled its new role as a potential cell cycle regulator through the NODAL signaling pathway. Indeed, PCSK9 inhibition leads to a decrease of SMAD2 phosphorylation and hiPSCs proliferation. Conversely, PCSK9 overexpression stimulates hiPSCs proliferation. PCSK9 can interfere with the NODAL pathway by regulating the expression of its endogenous inhibitor DACT2, which is involved in the TGFß-R1 lysosomal degradation. Using different PCSK9 constructs we show that PCSK9 interacts with DACT2 through its CHRD domain. Altogether these data highlight a new role of PCSK9 in cellular proliferation and development, beyond its canonical effect on lipid metabolism.

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Engineering chimeric PCSK9 for a vaccine against atherosclerosis

Project description:Cardiovascular diseases, especially atherosclerosis, are the major cause of death in the modern era. In most cases, amelioration is achieved by decreasing the concentration of LDL cholesterol in blood, using statins or monoclonal antibodies targeting PCSK9, which are highly efficient, but are costly and requires bimonthly administration. Vaccination against PCSK9 represents an attractive alternative with potentially long-lasting efficiency, but has to overcome the challenge of autoimmune reactivity against an endogenous protein to prevent healthy tissue damage. We developed an autologous chimeric vaccine against PCSK9, which triggers a B cell immune response to produce neutralizing antibodies but avoids induction of self antigen mediated T cell cytotoxicity. We demonstrated in atherosclerosis murine model that vaccination generated an adequate humoral immune response with the effect persistent over 24°weeks, observed in lower circulating PCSK9, lower cholesterol and reduced atherosclerotic disease burden in the aortas. This is a proof of concept study for a therapeutic amelioration of atherosclerosis, which also provides a perspective on the rational design of a vaccine against endogenous proteins.

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PCSK9 is involved in human induced pluripotent stem cell proliferation through the regulation of the NODAL signaling pathway II

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