The Role of the Endothelium in Premature Atherosclerosis: Molecular Mechanisms

2020 ◽  
Vol 27 (7) ◽  
pp. 1041-1051 ◽  
Author(s):  
Michael Spartalis ◽  
Eleftherios Spartalis ◽  
Antonios Athanasiou ◽  
Stavroula A. Paschou ◽  
Christos Kontogiannis ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Low Density Lipoprotein ◽  
Critical Role ◽  
Density Lipoprotein ◽  
Number Of Genes ◽  
Causes Of Mortality ◽  
Artery Disease ◽  
Genetic And Environmental Factors ◽  
Made In

Atherosclerotic disease is still one of the leading causes of mortality. Atherosclerosis is a complex progressive and systematic artery disease that involves the intima of the large and middle artery vessels. The inflammation has a key role in the pathophysiological process of the disease and the infiltration of the intima from monocytes, macrophages and T-lymphocytes combined with endothelial dysfunction and accumulated oxidized low-density lipoprotein (LDL) are the main findings of atherogenesis. The development of atherosclerosis involves multiple genetic and environmental factors. Although a large number of genes, genetic polymorphisms, and susceptible loci have been identified in chromosomal regions associated with atherosclerosis, it is the epigenetic process that regulates the chromosomal organization and genetic expression that plays a critical role in the pathogenesis of atherosclerosis. Despite the positive progress made in understanding the pathogenesis of atherosclerosis, the knowledge about the disease remains scarce.

scholarly journals Prosaposin facilitates sortilin-independent lysosomal trafficking of progranulin

2015 ◽  
Vol 210 (6) ◽  
pp. 991-1002 ◽  
Author(s):  
Xiaolai Zhou ◽  
Lirong Sun ◽  
Francisco Bastos de Oliveira ◽  
Xiaoyang Qi ◽  
William J. Brown ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Low Density Lipoprotein ◽  
Critical Role ◽  
Density Lipoprotein ◽  
Lysosomal Trafficking ◽  
Density Lipoprotein Receptor ◽  
Drastic Increase ◽  
Trafficking Defects

Mutations in the progranulin (PGRN) gene have been linked to two distinct neurodegenerative diseases, frontotemporal lobar degeneration (FTLD) and neuronal ceroid lipofuscinosis (NCL). Accumulating evidence suggests a critical role of PGRN in lysosomes. However, how PGRN is trafficked to lysosomes is still not clear. Here we report a novel pathway for lysosomal delivery of PGRN. We found that prosaposin (PSAP) interacts with PGRN and facilitates its lysosomal targeting in both biosynthetic and endocytic pathways via the cation-independent mannose 6-phosphate receptor and low density lipoprotein receptor-related protein 1. PSAP deficiency in mice leads to severe PGRN trafficking defects and a drastic increase in serum PGRN levels. We further showed that this PSAP pathway is independent of, but complementary to, the previously identified PGRN lysosomal trafficking mediated by sortilin. Collectively, our results provide new understanding on PGRN trafficking and shed light on the molecular mechanisms behind FTLD and NCL caused by PGRN mutations.

Genome-wide identification of circulating-miRNA expression quantitative trait loci reveals the role of several miRNAs in the regulation of cardiometabolic phenotypes

2019 ◽  
Vol 115 (11) ◽  
pp. 1629-1645 ◽  
Author(s):  
Majid Nikpay ◽  
Kaitlyn Beehler ◽  
Armand Valsesia ◽  
Jorg Hager ◽  
Mary-Ellen Harper ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Mature Mirnas ◽  
European Ancestry ◽  
Blood Proteins ◽  
Circulating Mirnas ◽  
Genome Wide ◽  
Regulatory Impact ◽  
Artery Disease

Abstract Aims To identify genetic variants that have a regulatory impact on circulating microRNAs (miRNAs) and to connect genetic risk to blood traits/biomarkers through the circulating miRNAs. Methods and results Leveraging miRNA-Seq data and the 1000 Genomes imputed genotypes, we carried out genome-wide association analysis for SNPs that regulate the expression of circulating miRNAs in a sample of 710 unrelated subjects of European ancestry. Wherever possible, we used data from the Framingham and the Geuvadis studies to replicate our findings. We found at least one genome-wide significant (P < 5e−8) miRNA-eQTL (mirQTL) for 143 circulating miRNAs. Overall each mirQTL explained a small portion (<1%) of variation in miRNA levels; however, we identified a few mirQTLs that explained 4% to 20% of variation in miRNA levels in plasma. Unlike trans-mirQTLs (P = 0.7), cis-mirQTLs tend to be also associated with their counterpart mature miRNAs (P < 0.0001), this suggests trans-mirQTLs exert their effect through processes that affect the stability of mature miRNAs; whereas, cis-mirQTLs mainly regulate the expression of primary-miRNAs. Next, we used the identified mirQTLs to investigate the links between circulating miRNAs with blood traits/biomarkers through Mendelian randomization analysis. We found miR-1908-5p plays an important role in regulating low-density lipoprotein (LDL), total cholesterol (TC), fasting glucose, HbA1c, and several lipid-metabolites in blood, whereas, miR-10b-5p mediates the trans-regulatory effect of the ABO locus on several blood proteins, coronary artery disease, and TC. Moreover, we demonstrated that a higher plasma level of miR-199a is causally associated with lower levels of LDL and TC. Finally, we found miR-143-3p and miR-145-5p are functionally related and mediate the effect of ZFPM2 on a number of its protein targets in blood including VEGFA, SERPINE1, and PDGFs. Conclusions This study identifies SNPs that have a regulatory impact on circulating miRNAs, and underlines the role of several circulating miRNAs in mediating the effect of a number of GWAS loci on cardiometabolic phenotypes.

scholarly journals The role of oxidation of low-density lipids in pathogenesis of osteoarthritis: A narrative review

2020 ◽  
Vol 48 (6) ◽  
pp. 030006052093160
Author(s):  
Kazuhiko Hashimoto ◽  
Masao Akagi
Keyword(s):  
Molecular Mechanisms ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Narrative Review ◽  
Molecular Pathways ◽  
Low Density ◽  
Lipoprotein Receptor ◽  
Density Lipoprotein Receptor ◽  
Joint Disorder

Osteoarthritis (OA) is a chronic joint disorder that causes degeneration of cartilage, synovial inflammation, and formation of osteophytes. Aging, obesity, and sex are considered the main risk factors of OA. Recent studies have suggested that metabolic syndrome (MetS) disorders, such as hypertension, hyperlipidemia, diabetes mellitus, and obesity, may be involved in the pathogenesis and progression of OA. MetS disorders are common diseases that also result in atherosclerosis. Researchers believe that OA and atherosclerosis have underlying similar molecular mechanisms because the prevalence of both diseases increases with age. Oxidation of low-density lipoprotein (ox-LDL) is believed to play a role in the pathogenesis of atherosclerosis. Recent reports have shown that ox-LDL and low-density lipoprotein receptor 1 (LOX-1) are involved in the pathogenesis of OA. The purpose of this narrative review is to summarize the current understanding of the role of the LOX-1/ox-LDL system in the pathogenesis of OA and to reveal common underlying molecular pathways that are shared by MetS in OA and the LOX-1/ox-LDL system.

scholarly journals Diabetes and Colorectal Cancer Risk: A New Look at Molecular Mechanisms and Potential Role of Novel Antidiabetic Agents

2021 ◽  
Vol 22 (22) ◽  
pp. 12409
Author(s):  
Jelena Vekic ◽  
Aleksandra Zeljkovic ◽  
Aleksandra Stefanovic ◽  
Rosaria Vincenza Giglio ◽  
Marcello Ciaccio ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Molecular Mechanisms ◽  
Potential Role ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Epidemiological Data ◽  
Beneficial Effects ◽  
Ldl Particles ◽  
Chronic Hyperglycemia

Epidemiological data have demonstrated a significant association between the presence of type 2 diabetes mellitus (T2DM) and the development of colorectal cancer (CRC). Chronic hyperglycemia, insulin resistance, oxidative stress, and inflammation, the processes inherent to T2DM, also play active roles in the onset and progression of CRC. Recently, small dense low-density lipoprotein (LDL) particles, a typical characteristic of diabetic dyslipidemia, emerged as another possible underlying link between T2DM and CRC. Growing evidence suggests that antidiabetic medications may have beneficial effects in CRC prevention. According to findings from a limited number of preclinical and clinical studies, glucagon-like peptide-1 receptor agonists (GLP-1RAs) could be a promising strategy in reducing the incidence of CRC in patients with diabetes. However, available findings are inconclusive, and further studies are required. In this review, novel evidence on molecular mechanisms linking T2DM with CRC development, progression, and survival will be discussed. In addition, the potential role of GLP-1RAs therapies in CRC prevention will also be evaluated.

ROLE OF HS CRP AND LIPID ABNORMALITIES AS RISK FACTOR IN CORONARY ARTERY DISEASE

2021 ◽  
pp. 37-39
Author(s):  
Dipankar Kundu ◽  
Aniket Paul ◽  
Sourish Ghosh
Keyword(s):  
Coronary Artery Disease ◽  
Risk Factor ◽  
Coronary Artery ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Study Results ◽  
Hs Crp ◽  
Artery Disease ◽  
Lipid Abnormalities

BACKGROUND: In recent years, data suggesting that certain markers of inammation play a key role in the development and progression of atherosclerosis. hsCRP has shown promising results as a predictor of Coronary Artery Disease(CAD). OBJECTIVES: To evaluate the signicance of CRP as one of the most reliable markers in coronary artery disease and to study the role of lipid abnormalities as a risk factor in coronary artery disease. MATERIALS AND METHODS: Study was conducted at MedicalCollege, Kolkata.30 cases and 30 controls were studied. Angiographically proven cases of CAD aged between 40- 60 years of both sexes were included in the study as cases. Age and sex matched individuals without CAD weSre considered as cases. Patients with recent myocardial infarction, unstable angina (<6months).and with other inammatory conditions were excluded from the study. RESULTS: hsCRP was signicantly higher in CAD cases2.0±1.4 compared with controls0.8±0.7 and this was statistically signicant <0.001.Lipid parameters such as Total Cholesteol,Triglycerides and Low density lipoprotein were elevated in cases compared with controls and was found to be statistically signicant. Blood glucose parameters both in fasting and post-prandial conditions were found to be elevated in cases compared with controls. CONCLUSION: The study thus suggests that hsCRP level appears to be a dependable marker of CAD.Thus, hsCRP can be used as a sensitive predictor of CAD.

scholarly journals Role of the APOB Gene Polymorphism (c.12669G>A, p. Gln4154Lys) in Coronary Artery Disease in the Indian Punjabi Population

2011 ◽  
Vol 14 (2) ◽  
pp. 35-40 ◽  
Author(s):  
R Sharma ◽  
M Mahajan ◽  
B Singh ◽  
G Singh ◽  
P Singh
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Gene Polymorphism ◽  
Low Density Lipoprotein ◽  
Elevated Serum ◽  
Density Lipoprotein ◽  
Low Density ◽  
High Concentration ◽  
Artery Disease

Role of theAPOBGene Polymorphism (c.12669G>A, p. Gln4154Lys) in Coronary Artery Disease in the Indian Punjabi PopulationHigh concentration of apolipoprotein B (apoB) is a risk factor for coronary artery disease (CAD). The association of theAPOBgene polymorphism c.12669G>A, p. Gln4154Lys with the risk of CAD varies considerably in different populations. The present study represents the first investigation regarding the role of thisAPOBgene polymorphism with CAD in the Indian Punjabi population. We have studied theAPOBgene polymorphism c.12669G>A, p. Gln4154Lys and its relationship with lipid, apoB, low-density lipoprotein (LDL) heterogeneity and oxidation in subjects suffering from CAD. The study was conducted on 87 patients with CAD; 75 healthy subjects served as controls. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to determine the DNA polymorphism in theAPOBgene. Frequency of R-(mutant) allele was significantly high (p<0.05) in CAD patients when compared to controls. Variations in serum lipid levels in the R+R+ and R+R-APOBgenotypes were insignificant (p>0.05). However, serum apoB levels were significantly raised (p<0.05) in CAD patients with the R+R- genotype as compared to those with the R+R+APOBgenotype. Coronary artery disease patients had raised significantly raised (p<0.01) Log triglyceride/high density lipoprotein-cholesterol (HDL-C) ratio, apoB carbonyl content and increased malondialdehyde-low density lipoprotein (MDA-LDL levels, irrespective ofAPOBgenotype as compared to controls. Carriers of the R- allele are at higher risk of CAD, probably because of elevated serum apoB levels in the Indian Punjabi population. Overall, it may be concluded that the R- allele might be associated with increased susceptibility towards CAD development in the Indian Punjabi population, and one of the linking factor is the elevation in serum apoB levels. However, this association needs further evaluation in a larger population. Secondly, the robust mechanism behind the positive association of the R- allele with raised serum apoB levels needs to be explored, which might be helpful in the strengthening the observed results.

scholarly journals Understanding hyperlipidemia and atherosclerosis: lessons from genetically modified apoe and ldlr mice

2005 ◽  
Vol 43 (5) ◽  
Author(s):  
Kristiaan Wouters ◽  
Ronit Shiri-Sverdlov ◽  
Patrick J. van Gorp ◽  
Marc van Bilsen ◽  
Marten H. Hofker
Keyword(s):  
Mouse Models ◽  
Molecular Mechanisms ◽  
Genetically Modified ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Lipid Lowering ◽  
Density Lipoprotein Receptor ◽  
Mutant Forms ◽  
Deficient Mice

AbstractHyperlipidemia is the most important risk factor for atherosclerosis, which is the major cause of cardiovascular disease. The etiology of hyperlipidemia and atherosclerosis is complex and governed by multiple interacting genes. However, mutations in two genes have been shown to be directly involved, i.e., the low-density lipoprotein receptor (LDLR) and apolipoprotein E (ApoE). Genetically modified mouse models have been instrumental in elucidating the underlying molecular mechanisms in lipid metabolism. In this review, we focus on the use of two of the most widely used mouse models, ApoE- and LDLR-deficient mice. After almost a decade of applications, it is clear that each model has unique strengths and drawbacks when carrying out studies of the role of additional genes and environmental factors such as nutrition and lipid-lowering drugs. Importantly, we elaborate on mice expressing mutant forms of APOE, including the

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