ABSTRACT
Ritonavir is a protease inhibitor associated with metabolic abnormalities and cardiovascular disease. We have investigated the effects of low-dose ritonavir treatment on gene expression in peripheral blood mononuclear cells (PBMC) of 10 healthy donors. Results using whole genome Illumina microarrays show that ritonavir modulates a number of genes implicated in lipid metabolism, inflammation and atherosclerosis. These candidate genes are dual specificity phosphatase 1 DUSP1), Kelch domain containing 3 (KLHDC3), neutral cholesterol ester hydrolase 1 (NCEH1) and acyl-CoA synthetase short-chain family member 2 (ACSS2). Validation experiments using quantitative PCR showed that ritonavir (at 100 mg once daily and 100 mg twice daily significantly down-regulated these 4 selected candidate genes in 20 healthy individuals. Lower expression levels of these 4 candidate genes, known to play a critical role in inflammation, lipid metabolism and atherosclerosis, may explain ritonavir adverse effects in patients.
Subject(s)
Gene Expression Profiling , Gene Expression Regulation/drug effects , HIV Protease Inhibitors/pharmacology , Leukocytes, Mononuclear/drug effects , Ritonavir/pharmacology , Acetate-CoA Ligase/genetics , Adolescent , Adult , Biomarkers , Carboxylic Ester Hydrolases/genetics , Computational Biology , Down-Regulation/drug effects , Dual Specificity Phosphatase 1/genetics , Female , Humans , Leukocytes, Mononuclear/metabolism , Male , Middle Aged , Sterol EsteraseABSTRACT
Aicardi syndrome (AIC) is an uncommon neurodevelopmental disorder affecting almost exclusively females. Chief features include infantile spasms, corpus callosal agenesis, and chorioretinal abnormalities. AIC is a sporadic disorder and hypothesized to be caused by heterozygous mutations in an X-linked gene but up to now without any defined candidate region on the X chromosome. Array based comparative genomic hybridisation (array-CGH) has become the method of choice for the detection of microdeletions and microduplications at high resolution. In this study, for the first time, 18 AIC patients were analyzed with a full coverage X chromosomal BAC arrays at a theoretical resolution of 82 kb. Copy number changes were validated by real-time quantitation (qPCR). No disease associated aberrations were identified. For such conditions as AIC, in which there are no familial cases, additional patients should be studied in order to identify rare cases with submicroscopic abnormalities, and to pursue a positional candidate gene approach.
Subject(s)
Abnormalities, Multiple/genetics , Agenesis of Corpus Callosum , Choroid/abnormalities , Chromosomes, Human, X/genetics , Genetic Diseases, X-Linked/genetics , Retina/abnormalities , Spasms, Infantile/genetics , Adolescent , Adult , Base Sequence , Child , Contractile Proteins/genetics , DNA Primers/genetics , Developmental Disabilities/genetics , Female , Filamins , Gene Dosage , Humans , Infant , Microfilament Proteins/genetics , Nucleic Acid Hybridization , Oligonucleotide Array Sequence Analysis , SyndromeABSTRACT
CD36 is a multi-ligand scavenger receptor present on the surface of a number of cells such as platelets, monocytes/macrophages, endothelial and smooth muscle cells. Monocyte/macrophage CD36 has been shown to play a critical role in the development of atherosclerotic lesions by its capacity to bind and endocytose oxidized low density lipoproteins (OxLDL), and it is implicated in the formation of foam cells. However, the significance of CD36 in atherosclerosis has recently been called into question by different studies, and therefore its exact role still needs to be clarified. The aim of this article is to carefully review the importance of CD36 as an essential component in the pathogenesis of atherosclerosis.
Subject(s)
Atherosclerosis/immunology , CD36 Antigens/metabolism , Macrophages/metabolism , Animals , Atherosclerosis/pathology , Blood Vessels/immunology , Blood Vessels/pathology , Humans , Lipoproteins, LDL/metabolism , Mice , Mice, Transgenic , Models, Animal , Structure-Activity RelationshipABSTRACT
Primarily statin drugs inhibit hepatic 3-hydroxy 3-methylglutaryl coenzyme A (HMG-CoA) reductase, which is responsible for the reduction in circulating low-density lipoprotein (LDL) cholesterol. Several findings from recent research studies indicate that statins have multiple actions that favorably influence key factors involved in the atherogenic process. These so-called pleiotropic properties affect various aspects of cell function, inflammation, coagulation, and vasomotor activity. These effects are mediated either indirectly through LDL cholesterol reduction or via a direct effect on cellular functions. Such actions may contribute to the early cardiovascular benefit observed in several outcome trials with statin drugs therapy. Although many of the pleiotropic properties of statins may be a class effect, some may be unique to certain agents and account for differences in their pharmacological activity. This review summarise the results of the major outcome trials of statins and non-statins therapy and the possible mechanisms beyond lipid lowering contributing to plaque stability.
