Search

Abstract: Background: PCSK9 plays a key role in plasma cholesterol metabolism by modulating the expression of LDL receptors. Objective and methods: In this study we investigated the effects of two common polymorphism of the PCSK9 gene (E670G and I474V) on the intima media thickness of the common carotid artery and the possible relation with polymorphisms of apolipoprotein E in 1541 middle aged subjects selected from the general population enrolled in the PLIC study and confirmed the major findings in a second free-living population enrolled in the Ventimiglia study. Results: 670G carriers showed significantly increased plasma total cholesterol, LDL-cholesterol, and Apo levels B while no significant differences were observed between carriers of the I474V SNP. IMT was significantly increased in 670G carriers compared to individuals homozygous for the E allele (0.640±0.102mm vs. 0.652±0.092mm, P <0.05). The presence of the 670G allele was also significantly associated with a greater progression of IMT compared to 670EE subjects. Plasma total cholesterol, LDL-cholesterol, apolipoprotein B, and IMT significantly increased from ApoE2;PCSK9-670EE carriers to ApoE4–PCSK9-670G carriers, while no significant differences were observed when the presence of the ApoE alleles was combined with that of the PCSK9 I474V SNP. In silico analysis on wild type and 670G variant showed several structural differences on the interactions of the loops of the “V” domain. Conclusions: The E670G polymorphism of the PCSK9 gene is associated with increased IMT progression in the general population. When the presence of 670G allele is stratified according to the ApoE gene alleles, ApoE2;PCSK9-670EE carriers show a more favorable plasma lipid profile and decreased IMT compared to ApoE4–PCSK9-670G carriers. [Copyright &y& Elsevier]

Background and aims Monocytes are known to play a key role in the initiation and progression of atherosclerosis and contribute to plaque destabilization through the generation of signals that promote inflammation and neoangiogenesis. In humans, studies investigating the features of circulating monocytes in advanced atherosclerotic lesions are lacking. Methods Patients (mean age 69 years, 56% males) with intermediate asymptomatic carotid stenosis (40–70% in diameter) were evaluated for maximal stenosis in common carotid artery, carotid bulb and internal carotid artery, overall disease burden as estimated with total plaque area (TPA), greyscale and neovascularization in 244 advanced carotid plaques. Absolute counts of circulating CD14+ monocytes, of classical (CD14 high CD16−), intermediate (CD14 high CD16+) and non-classical (CD14 low CD16+) monocytes and HLA-DR+ median fluorescence intensity for each subset were evaluated with flow cytometry. Results No correlation was found between monocytes and overall atherosclerotic burden, nor with high sensitivity C-reactive protein (hsCRP) or interleukin-6 (IL-6). In contrast, plaque signs of neovascularization were associated with significantly lower counts of circulating CD14+ monocytes (297 versus 350 cells/mm 3 , p = 0.039) and of classical monocytes (255 versus 310 cells/mm 3 , p = 0.029). Conclusions Neovascularized atherosclerotic lesions selectively associate with lower blood levels of CD14+ and CD14 high CD16− monocytes independently of systemic inflammatory activity, as indicated by normal hsCRP levels. Whether the reduction of circulating CD14+ and CD14 high CD16− monocytes is due to a potential redistribution of these cell types into active lesions remains to be explored. [ABSTRACT FROM AUTHOR]

Objective Familial hypobetalipoproteinemia (FHBL) is autosomal codominant disorder of lipoprotein metabolism characterized by low plasma levels of total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C) and apolipoprotein B (apoB) below the 5 th percentile of the distribution in the population. Patients with the clinical diagnosis of homozygous FHBL (Ho-FHBL) are extremely rare and few patients have been characterized at the molecular level. Here we report the medical history and the molecular characterization of one paediatric patient with clinical features of Ho-FHBL. Methods A one month old infant with failure to thrive, severe hypocholesterolemia and acanthocytosis was clinically and genetically characterized. Molecular characterization of the proband and her parents was performed by direct sequencing of the APOB gene and functional role of the identified mutations was assessed by the minigene methodology. Results The proband was found carrying two novel splicing mutations of the APOB gene (c.3696+1G > C and c.3697-1G > A). CHOK1H8 cells expressing minigenes harbouring the mutations showed that these two mutations were associated with the retention of intron 23 and skipping of exon 24, resulting in two truncated apoB fragments of approximate size of 26–28 % of ApoB-100 and the total absence of apoB. Conclusion We describe the first case of Ho-FHBL due to two splicing mutations affecting both the donor and the acceptor splice sites of the same intron of the APOB gene occurring in the same patient. The clinical management of the proband is discussed and a review of the clinical and genetic features of the published Ho-FHBL cases is reported. [ABSTRACT FROM AUTHOR]

Abstract: Objective: The presence of small dense LDL has been associated with increased cardiovascular risk and with the progression of coronary and carotid atherosclerosis in case-control and prospective studies. The aim of this study was to investigate the relation between different lipoprotein subfractions with intima-media thickness of the common carotid artery in a free-living, healthy population, and to evaluate whether in patients with comparable LDL-C, the different lipoprotein subclasses differently affected the expression of chemokines, cytokines and adhesion molecules in peripheral blood mononuclear and endothelial cells. Methods and results: The lipoprotein cholesterol profile and the LDL buoyancy (LDL-RF) were evaluated in a cohort of 156 healthy subjects randomly selected from the PLIC (Progressione Lesione Intimale Carotidea) study. The LDL-RF was directly and significantly correlated to weight, body mass index, waist, hip, waist/hip ratio, triglycerides, fasting glycemia and intima media thickness (IMT) of the common carotid artery and inversely related to HDL-C. After multivariate statistical analysis, IMT was independently associated with age, LDL-RF and HDL-C and among the lipoprotein subclasses, only those corresponding to triglyceride-rich lipoproteins (TGRL) and small dense LDL (sdLDL) independently predicted IMT variance. Peripheral blood mononuclear cells (PBMC) isolated from patients with the predominance of sdLDL (pattern B) had an increased mRNA expression of pro-inflammatory molecules compared to PBMC from patients with the predominance of large LDL (pattern A); in endothelial cells TGRL from pattern B subjects and much less those from pattern A induced the expression of pro-inflammatory genes while sdLDL from either pattern A or B subjects were less effective and showed comparable effects. Conclusion: LDL-relative flotation rate significantly correlates with several cardiometabolic parameters. Furthermore cholesterol levels lipoprotein subfractions within the TGRL and sdLDL density range are independent predictors of IMT variance and are associated with a pro-inflammatory activation of PBMC and endothelial cells. [Copyright &y& Elsevier]