The pleiotropic effects of PCSK9 in cardiovascular diseases beyond cholesterol metabolism

Acta Physiologica, Journal Year: 2025, Volume and Issue: 241(2)

Published: Jan. 10, 2025

Abstract Cardiovascular diseases (CVD) are the leading cause of morbidity and mortality globally, with elevated low‐density lipoprotein cholesterol (LDL‐C) levels being a major risk factor. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays critical role in regulating LDL‐C by promoting degradation hepatic receptors (LDLR) responsible for clearing from circulation. PCSK9 inhibitors novel lipid‐modifying agents that have demonstrated remarkable efficacy reducing plasma decreasing incidence CVD. However, broader clinical impacts functions beyond metabolism, including both desired undesired effects therapeutic inhibition, underscore urgent necessity to elucidate underlying mechanisms. Recent studies shown local vascular system can interact other such as CD36, LRP‐1, ABCA1. This provides new evidence supporting potential contribution CVD through LDLR‐independent signaling pathways. Therefore, this review aimed outline diverse on discuss mechanisms non‐cholesterol‐related processes, which will provide rational basis its long‐term pharmacological inhibition clinic.

Language: Английский

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Research Progress and Clinical Translation Potential of Coronary Atherosclerosis Diagnostic Markers from a Genomic Perspective

Genes, Journal Year: 2025, Volume and Issue: 16(1), P. 98 - 98

Published: Jan. 18, 2025

Objective: Coronary atherosclerosis (CAD) is characterized by arterial intima lipid deposition, chronic inflammation, and fibrous tissue proliferation, leading to wall thickening lumen narrowing. As the primary cause of coronary heart disease acute syndrome, CAD significantly impacts global health. Recent genetic studies have demonstrated CAD’s polygenic multifactorial nature, providing molecular insights for early diagnosis risk assessment. This review analyzes recent advances in CAD-related markers evaluates their diagnostic potential, focusing on applications stratification within precision medicine. Methods: We conducted a systematic genomic from PubMed Web Science databases, analyzing findings genome-wide association (GWASs), gene sequencing, transcriptomics, epigenomics research. Results: GWASs sequencing identified key variations associated with CAD, including JCAD/KIAA1462, GUCY1A3, PCSK9, SORT1, which regulate metabolism, vascular function. Transcriptomic epigenomic analyses revealed disease-specific expression patterns, DNA methylation signatures, regulatory non-coding RNAs (miRNAs lncRNAs), new approaches detection. Conclusions: While marker research has advanced significantly, clinical implementation faces challenges dynamics, lack standardization, integration conventional diagnostics. Future should prioritize developing standardized guidelines, conducting large-scale prospective studies, enhancing multi-omics data advance diagnostics ultimately improving patient outcomes through

Language: Английский

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PCSK9 in metabolism and diseases

Metabolism, Journal Year: 2024, Volume and Issue: 163, P. 156064 - 156064

Published: Nov. 14, 2024

Language: Английский

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PCSK9 Expression in Vascular Smooth Muscle Cells: Role of Insulin Resistance and High Glucose

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(3), P. 1003 - 1003

Published: Jan. 24, 2025

Beyond the regulation of cholesterol metabolism, a number extrahepatic functions proprotein convertase subtilisin/kexin type 9 (PCSK9) have been increasingly identified. The main purpose this study was to verify whether PCSK9 expression in vascular smooth muscle cells (VSMC) is influenced by insulin resistance and high glucose (HG). In cultured rat aortic VSMC from lean insulin-sensitive Zucker rats (LZRs) obese insulin-resistant (OZRs), classical animal model resistance, we evaluated with or without monoclonal antibodies against Alirocumab Evolocumab synthetic PCSK9-binding peptide PEP 2-8. Effects molecular mechanisms underlying altered were proliferation migration assay, reactive oxygen species (ROS) production, involvement PKC, NADPH-oxidase, MAPK/ERK-1/2 pathway activation. As result, found that, comparison LZR, OZR showed basal overexpression mitigated Alirocumab, Evolocumab, 2-8, inhibitors MAPK. finding upregulation paralleled increased ROS proliferation, migration. HG but not OZR, via oxidative stress effects reduced inhibitors. These findings suggest that dysregulation could be involved damage metabolic disorders, such as obesity diabetes.

Language: Английский

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Metabolomics and Microbiomics Perspectives Reveal the Regulatory Pathways of Monaphilone B Derived From Red Yeast Rice on Alcoholic Liver Injury in Mice

eFood, Journal Year: 2025, Volume and Issue: 6(2)

Published: March 12, 2025

ABSTRACT Red yeast rice (RYR) has been extensively used as a natural food for thousands of years and still plays an important role in the world industry. In this study, protective effect mechanism monaphilone B (MB) from RYR on alcoholic liver injury were investigated mice. The results showed that MB effectively ameliorated alcohol‐induced lipid metabolism (decreasing serum total cholesterol [TC], triglyceride [TG], low‐density lipoprotein [LDL‐C], increasing high‐density [HDL‐C]), oxidative stress hepatic maleic dialdehyde [MDA] level, catalase [CAT], superoxide dismutase [SOD], alcohol dehydrogenase [ADH] glutathione [GSH] activities), inflammatory response lipopolysaccharide [LPS], tumor necrosis factor‐α [TNF‐α], Interferon‐γ [IFN‐γ] interleukin 6 [IL‐6]), repaired function (reducing alanine aminotransferase [ALT], aspartate [AST], lactate [LDH] activity). 16S amplicon sequencing administration modulated intestinal flora its metabolism, which highly correlated with improvement barrier function. Liver metabolomics analysis indicated regulated 69 potential biomarkers involved glycerophospholipid nicotinate nicotinamide tryptophan so on. Reverse transcription‐quantitative polymerase chain reaction (RT‐qPCR) Western blot (WB) revealed gene transcription protein expression related to stress. These findings provide scientific evidence biological activity ameliorate disorders, stress, enterobacterial dysbiosis.

Language: Английский

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Unraveling the Impact of Micro- and Nano-sized Polymethyl methacrylate on Gut Microbiota and Liver Lipid Metabolism: Insights from Oral Exposure Studies

Environmental Pollution, Journal Year: 2025, Volume and Issue: unknown, P. 126157 - 126157

Published: March 1, 2025

Language: Английский

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Deciphering Oxidative Stress in Cardiovascular Disease Progression: A Blueprint for Mechanistic Understanding and Therapeutic Innovation

Antioxidants, Journal Year: 2024, Volume and Issue: 14(1), P. 38 - 38

Published: Dec. 31, 2024

Oxidative stress plays a pivotal role in the pathogenesis and progression of cardiovascular diseases (CVDs). This review focuses on signaling pathways oxidative during development CVDs, delving into molecular regulatory networks underlying various disease stages, particularly apoptosis, inflammation, fibrosis, metabolic imbalance. By examining dual roles influences sex differences levels susceptibility, this study offers comprehensive understanding diseases. The integrates key findings from current research three ways. First, it outlines major CVDs associated with their respective pathways, emphasizing stress’s central pathology. Second, summarizes protective effects, mechanisms action, animal models antioxidants, offering insights future drug development. Third, discusses applications, advantages, limitations, potential targets gene therapy providing foundation for novel therapeutic strategies. These tables underscore systematic integrative nature while theoretical basis precision treatment CVDs. A contribution is differential effects across different stages addition to proposal innovative, multi-level intervention strategies, which open new avenues system.

Language: Английский

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The functions of apolipoproteins and lipoproteins in health and disease

Molecular Biomedicine, Journal Year: 2024, Volume and Issue: 5(1)

Published: Oct. 28, 2024

Lipoproteins and apolipoproteins are crucial in lipid metabolism, functioning as essential mediators the transport of cholesterol triglycerides being closely related to pathogenesis multiple systems, including cardiovascular. a (Lp(a)), unique subclass lipoproteins, is low-density lipoprotein(LDL)-like particle with pro-atherosclerotic pro-inflammatory properties, displaying high heritability. More more strong evidence points possible link between amounts Lp(a) cardiac conditions like atherosclerotic cardiovascular disease (ASCVD) aortic stenosis (AS), making it risk factor for heart diseases. In recent years, Lp(a)'s role other diseases, neurological disorders cancer, has been increasingly recognized. Although therapies aimed at lipoprotein (LDL-C) high-density (HDL-C) have achieved significant success, elevated levels remain clinical management problem. Despite limited efficacy current lipid-lowering therapies, major advances new Lp(a)-lowering significantly advanced field. This review, grounded pathophysiology seeks summarize wide-ranging connections lipoproteins (such LDL-C HDL-C) various alongside latest developments, special emphasis placed on pivotal disease, while also examining its future potential mechanisms conditions. Furthermore, this review discusses highlights emerging treatments, advocates further exploration into pathogenic therapeutic target, proposing secondary prevention strategies high-risk individuals.

Language: Английский

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Connecting intermediate phenotypes to disease using multi-omics in heart failure

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 7, 2024

Heart failure (HF) is one of the most common, complex, heterogeneous diseases in world, with over 1-3% global population living condition. Progression HF can be tracked via MRI measures structural and functional changes to heart, namely left ventricle (LV), including ejection fraction, mass, end-diastolic volume, LV end-systolic volume. Moreover, while genome-wide association studies (GWAS) have been a useful tool identify candidate variants involved risk, they lack crucial tissue-specific mechanistic information which gained from incorporating additional data modalities. This study addresses this gap by transcriptome-wide proteome-wide (TWAS PWAS) gain insights into genetically-regulated gene expression protein abundance precursors measured using MRI-derived cardiac as well full-stage all-cause HF. We identified several overlaps between fraction volume measures. Many measurements through TWAS PWAS appear shared implicate many putative pathways relevant associated these genes proteins gene-set enrichment protein-protein interaction network approaches. The results (1) highlight benefit multi-omics better understand genetics (2) provide novel how heart structure function may relate

Language: Английский

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