PCSK9, a promising novel target for age-related cardiovascular dysfunction
Ontology highlight
ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE225859 | GEO | 2023/08/09
REPOSITORIES: GEO
Similar Datasets
Project description:Hypertension is a most important risk factor of cardiovascular diseases (CVD), and its incidence is greatest among older adults, which indicates that aging is an independent risk for both hypertension and CVD. To date, the studies on the proteomics and phosphoproteomics of the aged hypertensive hearts for studying their impacts on the pathogenesis of CVD are limited. Here we present a dataset by using proteomics and phosphor-proteomics analysis on young and aged healthy and spontaneous hypertensive (SHR) rats. The dataset has following features: 1) numerical description of average 4000 total proteins and 1500 phosphor-proteins of detectable proteins in each group; 2) proteomic and phosphoproteomic profiles of their expression patterns; 3) Pathways for individual factor (age or hypertension) and their interaction and association with CVDs. Therefore, the integrated analysis of the dataset revealed the underlying pathways of aging and/or hypertension and their interaction on cardiovascular remodelling. In summary, the dataset provides a searchable multi-omics for the researchers to explore the interaction of aging and hypertension on the pathogenesis of CVD.
2021-06-18 | PXD026773 | Pride
Project description:Hypertension is a most important risk factor of cardiovascular diseases (CVD), and its incidence is greatest among older adults, which indicates that aging is an independent risk for both hypertension and CVD. To date, the studies on the proteomics and phosphoproteomics of the aged hypertensive hearts for studying their impacts on the pathogenesis of CVD are limited. Here we present a dataset by using proteomics and phosphor-proteomics analysis on young and aged healthy and spontaneous hypertensive (SHR) rats. The dataset has following features: 1) numerical description of average 4000 total proteins and 1500 phosphor-proteins of detectable proteins in each group; 2) proteomic and phosphoproteomic profiles of their expression patterns; 3) Pathways for individual factor (age or hypertension) and their interaction and association with CVDs. Therefore, the integrated analysis of the dataset revealed the underlying pathways of aging and/or hypertension and their interaction on cardiovascular remodelling. In summary, the dataset provides a searchable multi-omics for the researchers to explore the interaction of aging and hypertension on the pathogenesis of CVD.
2021-06-18 | PXD026608 | Pride
Project description:Human genetics as well as pharmacological intervention reveal that Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) plays a key role in regulating the levels of plasma low density lipoprotein cholesterol (LDL-C). Here we demonstrate that the compound PF-06446846 inhibits translation of PCSK9 by stalling the ribosome near codon 34 of its messenger RNA. Inhibition by PF-06446846 is sensitive to the amino acid sequence of the PCSK9 nascent chain, and not the messenger RNA. PF-06446846 also reduces plasma PCSK9 and total cholesterol levels in rats following oral dosing. Using ribosome profiling to examine the proteome-wide effects of PF-06446846, we find that it is exceptionally specific for PCSK9 and has no measurable effect on 99.7% of the translatome at concentrations sufficient for 90% inhibition of PCSK9 expression. Together, PF-06446846 represents the first example of an orally administered small molecule directly targeting PCSK9 that functions by a mechanism inhibiting translation during elongation with a high degree of selectivity. Selective inhibition of translation in human may represent a new approach to target proteins with small molecules.
2017-03-27 | PXD005835 | Pride
Project description:Human genetics as well as pharmacological intervention reveal that Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) plays a key role in regulating the levels of plasma low density lipoprotein cholesterol (LDL-C). Here we demonstrate that the compound PF-06446846 inhibits translation of PCSK9 by stalling the ribosome near codon 34 of its messenger RNA. Inhibition by PF-06446846 is sensitive to the amino acid sequence of the PCSK9 nascent chain, and not the messenger RNA. PF-06446846 also reduces plasma PCSK9 and total cholesterol levels in rats following oral dosing. Using ribosome profiling to examine the proteome-wide effects of PF-06446846, we find that it is exceptionally specific for PCSK9 and has no measurable effect on 99.7% of the translatome at concentrations sufficient for 90% inhibition of PCSK9 expression. Together, PF-06446846 represents the first example of an orally administered small molecule directly targeting PCSK9 that functions by a mechanism inhibiting translation during elongation with a high degree of selectivity. Selective inhibition of translation in human may represent a new approach to target proteins with small molecules.
2017-03-27 | PXD005822 | Pride
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.
2021-08-05 | GSE181481 | GEO
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.
2021-08-07 | GSE181610 | GEO
Project description:Cardiovascular disease (CVD) is the leading cause of mortality, with sex and age being strong risk factors. Mitochondria are vital for normal cardiac function, and regulation of mitochondrial structure and function may impact susceptibility to CVD. We analyzed the basal expression levels of mitochondria-related genes in the hearts of male and female untreated control rats at different ages to identify potential role of mitochondria in differential susceptibility to CVD between the sexes.
2014-09-30 | GSE58204 | GEO
Project description:Cardiovascular disease (CVD) is the leading cause of mortality, with sex and age being strong risk factors. Mitochondria are vital for normal cardiac function, and regulation of mitochondrial structure and function may impact susceptibility to CVD. We analyzed the basal expression levels of mitochondria-related genes in the hearts of male and female untreated control rats at different ages to identify potential role of mitochondria in differential susceptibility to CVD between the sexes. Hearts from 5 male and 5 female rats at three different ages (young (8-week), adult (21-week), and old (78-week)) were used for investigation of sex-related differences in expression levels of genes. At each age, rats were humanely euthanized by CO2 asphyxiation and whole hearts were removed quickly, flash frozen in liquid nitrogen, and stored at -80ËC until further investigation. The frozen hearts were individually ground into powder in liquid nitrogen using a mortar and pestle chilled on dry ice. Total RNAs were extracted from heart tissue powder and gene expression was measured using Agilent Rat Whole Genome Microarrays (4 x 44k format; Agilent Technologies, Inc.).
2014-09-30 | E-GEOD-58204 | biostudies-arrayexpress
Project description:In this study, mice with different genotypes and fed diets with different lipid content were enrolled, aiming to set up an atlas of miRNA expression levels in different organs with a relevant role in lipid/lipoprotein metabolism. Specifically, three genotypes were investigated: C57Bl/6 mice as controls, together with mice knock-out (KO) for LDLr (low-density lipoprotein receptor) and for PCSK9 (proprotein convertase subtilisin/kexin type 9). LDLr and PCSK9 are both involved in LDL turnover, the former mediating LDL clearance [PMID: 19299327], the latter causing the degradation of the LDLr protein [PMID: 17080197]. As a result, LDLrKO mice, because of their impaired LDL catabolism, are hypercholesterolemic and prone to atherosclerosis development, particularly when fed high-fat, cholesterol-containing diets [PMID: 8349823; PMID: 8182121]. On the contrary, PCSK9KO mice, characterized by an accelerated LDL catabolism, are hypocholesterolemic and atherosclerosis resistant [PMID: 15805190]. miRNA expression was investigated in liver, intestine, aorta, white adipose tissue and brain of mice on both standard and Western diet.
2023-09-06 | GSE227578 | GEO
Project description:Sea spray aerosols (SSAs) have profound effects on our climate and ecosystems. They also contain microbiota and biogenic molecules which could affect human health. Yet the exposure and effects of SSAs on human health remain poorly studied. Here, we exposed human lung cancer cells to extracts of a natural sea spray aerosol collected at the seashore in Belgium, a laboratory-generated SSA, the marine algal toxin homoyessotoxin and a chemical inhibitor of the mammalian target of rapamycin (mTOR) pathway. We observed significant increased expression of genes related to the mTOR pathway and Proprotein convertase subtilisin/kexin type 9 (PCSK9) after exposure to homoyessotoxin and the laboratory-generated SSA. In contrast, we observed a significant decrease in gene expression in the mTOR pathway and of PCSK9 after exposure to the natural SSA and the mTOR inhibitor, suggesting induction of apoptosis. Our results indicate that marine biogenics in SSAs interact with PCSK9 and the mTOR pathway and can be used in new potential pharmaceutical applications. Overall, our results provide a substantial molecular evidence base for potential beneficial health effects at environmentally relevant concentrations of natural SSAs.
2018-12-27 | GSE113144 | GEO