IOX-1 suppresses metastasis of osteosarcoma by upregulating histone H3 lysine trimethylation.

New therapeutic approaches are needed for metastatic osteosarcoma (OS), as survival rates remain low despite surgery and chemotherapy. Epigenetic changes, such as histone H3 methylation, play key roles in many cancers including OS, although the underlying mechanisms are not clear. In this study, human OS tissue and OS cell lines displayed lower levels of histone H3 lysine trimethylation compared with normal bone tissue and osteoblast cells. Treating OS cells with the histone lysine demethylase inhibitor 5-carboxy-8-hydroxyquinoline (IOX-1) dose-dependently increased histone H3 methylation and inhibited cellular migratory and invasive capabilities, suppressed matrix metalloproteinase expression, reversed epithelial-to-mesenchymal transition by increasing levels of epithelial markers E-cadherin and ZO-1 and decreasing the expression of mesenchymal markers N-cadherin, vimentin, and TWIST, and also reduced stemness properties. An analysis of cultivated MG63 cisplatin-resistant (MG63-CR) cells revealed lower histone H3 lysine trimethylation levels compared with levels in MG63 cells. Exposing MG63-CR cells to IOX-1 increased histone H3 trimethylation and ATP-binding cassette transporter expression, potentially sensitizing MG63-CR cells to cisplatin. In conclusion, our study suggests that histone H3 lysine trimethylation is associated with metastatic OS and that IOX-1 or other epigenetic modulators present promising strategies to inhibit metastatic OS progression.

ANGPTL2 promotes VEGF-A synthesis in human lung cancer and facilitates lymphangiogenesis.

Lung cancer is an extremely common cancer and metastatic lung cancer has a greatly low survival rate. Lymphangiogenesis is essential for the development and metastasis of lung cancer. The adipokine angiopoietin-like protein 2 (ANGPTL2) regulates tumor progression and metastasis, although the functions of ANGPTL2 in lung cancer are unknown. Analysis of data from TCGA genomics program, the GEPIA web server and the Oncomine database revealed that higher levels of ANGPTL2 expression were correlated with progressive disease and lymph node metastasis. ANGPTL2 enhanced VEGF-A-dependent lymphatic endothelial cell (LEC) tube formation and migration. Integrin α5ß1, p38 and nuclear factor (NF)-κB signaling mediated ANGPTL2-regulated lymphangiogenesis. Importantly, overexpression ANGPTL2 facilitated tumor growth and lymphangiogenesis in vivo. Thus, ANGPTL2 is a promising therapeutic object for treating lung cancer.

HMGB1 Promotes In Vitro and In Vivo Skeletal Muscle Atrophy through an IL-18-Dependent Mechanism.

Skeletal muscle atrophy occurs due to muscle wasting or reductions in protein associated with aging, injury, and inflammatory processes. High-mobility group box-1 (HMGB1) protein is passively released from necrotic cells and actively secreted by inflammatory cells, and is implicated in the pathogenesis of various inflammatory and immune diseases. HMGB1 is upregulated in muscle inflammation, and circulating levels of the proinflammatory cytokine interleukin-18 (IL-18) are upregulated in patients with sarcopenia, a muscle-wasting disease. We examined whether an association exists between HMGB1 and IL-18 signaling in skeletal muscle atrophy. HMGB1-induced increases of IL-18 levels enhanced the expression of muscle atrophy markers and inhibited myogenic marker expression in C2C12 and G7 myoblast cell lines. HMGB1-induced increases of IL-18 production in C2C12 cells involved the RAGE/p85/Akt/mTOR/c-Jun signaling pathway. HMGB1 short hairpin RNA (shRNA) treatment rescued the expression of muscle-specific differentiation markers in murine C2C12 myotubes and in mice with glycerol-induced muscle atrophy. HMGB1 and IL-18 signaling was suppressed in the mice after HMGB1 shRNA treatment. These findings suggest that the HMGB1/IL-18 axis is worth targeting for the treatment of skeletal muscle atrophy.

Genetic Associations of Visfatin Polymorphisms with EGFR Status and Clinicopathologic Characteristics in Lung Adenocarcinoma.

Lung adenocarcinoma (LUAD) is the most common histologic type of lung cancer. Mutations of the epidermal growth factor receptor (EGFR) gene are among the most common genetic alterations in LUAD and are the targets of EGFR tyrosine kinase inhibitors. The enzyme visfatin is involved in the generation of the oxidized form of nicotinamide adenine dinucleotide (NAD+) and regulation of intracellular adenosine triphosphate (ATP), critical processes in cancer cell survival and growth. This study explored the relationship between visfatin single nucleotide polymorphisms (SNPs) with EGFR status and the clinicopathologic development of LUAD in a cohort of 277 Taiwanese men and women with LUAD. Allelic discrimination of four visfatin SNPs rs11977021, rs61330082, rs2110385 and rs4730153 was determined using a TaqMan Allelic Discrimination assay. We observed higher prevalence rates of advanced (T3/T4) tumors and distant metastases in EGFR wild-type patients carrying the rs11977021 CT + TT and rs61330082 GA + AA genotypes, respectively, compared with patients carrying the CC and GG genotypes. EGFR wild-type patients carrying the rs11977021 CT + TT genotypes were also more likely to develop severe (stage III/IV) malignancy compared with patients carrying the CC genotype. An analysis that included all patients found that the association persisted between the rs11977021 CT + TT and rs61330082 GA + AA genotypes and the development of T3/T4 tumors compared with patients carrying the rs11977021 CC and rs61330082 GG genotypes. In conclusion, these data indicate that visfatin SNPs may help to predict tumor staging in LUAD, especially in patients with EGFR wild-type status.

Visfatin-Induced Inhibition of miR-1264 Facilitates PDGF-C Synthesis in Chondrosarcoma Cells and Enhances Endothelial Progenitor Cell Angiogenesis.

New treatments for chondrosarcoma are extremely important. Chondrosarcoma is a primary malignant bone tumor with a very unfavorable prognosis. High-grade chondrosarcoma has a high potential to metastasize to any organ in the body. Platelet-derived growth factor (PDGF) is a potent angiogenic factor that promotes tumor angiogenesis and metastasis. The adipocytokine visfatin promotes metastatic potential of chondrosarcoma; however, the role of visfatin in angiogenesis in human chondrosarcoma is unclear. We report that the levels of PDGF-C expression were positively correlated with tumor stages, significantly higher than the levels of expression in normal cartilage. Visfatin increased PDGF-C expression and endothelial progenitor cell (EPC) angiogenesis through the PI3K/Akt/mTOR signaling pathway, and dose-dependently down-regulated the synthesis of miR-1264, which targets the 3'-UTR of PDGF-C. Additionally, we discovered inhibition of visfatin or PDGF-C in chondrosarcoma tumors significantly reduced tumor angiogenesis and size. Our results indicate that visfatin inhibits miR-1264 production through the PI3K/Akt/mTOR signaling cascade, and thereby promotes PDGF-C expression and chondrosarcoma angiogenesis. Visfatin may be worth targeting in the treatment of chondrosarcoma angiogenesis.

Apelin Promotes Prostate Cancer Metastasis by Downregulating TIMP2 via Increases in miR-106a-5p Expression.

Prostate cancer commonly affects the urinary tract of men and metastatic prostate cancer has a very low survival rate. Apelin belongs to the family of adipokines and is associated with cancer development and metastasis. However, the effects of apelin in prostate cancer metastasis is undetermined. Analysis of the database revealed a positive correlation between apelin level with the progression and metastasis of prostate cancer patients. Apelin treatment facilitates cell migration and invasion through inhibiting tissue inhibitor of metalloproteinase 2 (TIMP2) expression. The increasing miR-106a-5p synthesis via c-Src/PI3K/Akt signaling pathway is controlled in apelin-regulated TIMP2 production and cell motility. Importantly, apelin blockade inhibits prostate cancer metastasis in the orthotopic mouse model. Thus, apelin is a promising therapeutic target for curing metastatic prostate cancer.

Therapeutic Effects of Live Lactobacillus plantarum GKD7 in a Rat Model of Knee Osteoarthritis.

Osteoarthritis (OA) is a painful, progressive chronic inflammatory disease marked by cartilage destruction. Certain synovial inflammatory cytokines, such as IL-1ß and TNF-α, promote OA inflammation and pain. Lactobacillus spp. is a well-known probiotic with anti-inflammatory, analgesic, antioxidant, and antiosteoporotic properties. This study evaluated the therapeutic effects of a live L. plantarum strain (GKD7) in the anterior cruciate ligament transection (ACLT)-induced OA rat model. The results show that oral administration of live L. plantarum GKD7 improved weight-bearing asymmetry after ACLT surgery. Moreover, micro-computed tomography images and histopathological analysis show that oral live L. plantarum GKD7 improved subchondral bone architecture, protected articular cartilage against ACLT-induced damage, and reduced synovial inflammation. L. plantarum GKD7 also reduced IL-1ß and TNF-α production in OA cartilage and synovium. Thus, orally administered live L. plantarum GKD7 appears to effectively slow the progression of OA.

Oral Administration of Clostridium butyricum GKB7 Ameliorates Signs of Osteoarthritis in Rats.

Osteoarthritis (OA) is a degenerative and painful inflammatory joint disease affecting the cartilage, bone, and synovial membranes, without any effective treatment that targets the underlying mechanisms of OA. Our study evaluated the therapeutic effects of a live probiotic strain, Clostridium butyricum GKB7, administered for 6 weeks to rats with knee OA (KOA) induced by anterior cruciate ligament transection (ACLT) of the right knee. All rats underwent weekly weight-bearing behavioral testing and body weight measurements. At 6 weeks, all rats were sacrificed, and the right hind knees were collected for micro-computed tomography imaging and histopathological and immunohistochemical analyses. Compared with rats in the ACLT-only group, ACLT rats administered the probiotic exhibited dramatic improvements in pain-related behavior from postoperative week 2, had significantly less osseous and cartilaginous damage at week 6, and significantly lower levels of the inflammatory markers interleukin 1 beta (IL-1ß) and tumor necrosis factor alpha (TNF-α) in cartilage and synovium sections. C. butyricum GKB7 appeared to slow or even reverse OA progression and is worth investigating as a novel therapeutic for OA.

CCN2 Facilitates IL-17 Production and Osteoclastogenesis in Human Osteoarthritis Synovial Fibroblasts by Inhibiting miR-655 Expression.

Osteoarthritis (OA) is associated with extensive upregulation of osteoclastogenesis and subsequent bone breakdown. The CCN family protein connective tissue growth factor (CCN2, also called CCN2) enhances inflammatory cytokine production in OA disease. The cytokine interleukin (IL)-17 is known to induce osteoclastogenesis and bone erosion in arthritic disease. Our retrieval of data from the Gene Expression Omnibus (GEO) data set and clinical tissues exhibited higher CCN2 and IL-17 expression in OA synovial sample than in normal healthy samples. We observed the same phenomenon in synovial tissue from rats with anterior cruciate ligament transaction (ACLT)-elicited OA compared with synovial tissue from control healthy rats. We also found that CCN2 facilitated increases in IL-17 synthesis in human OA synovial fibroblasts (OASFs) and promoted osteoclast formation. CCN2 affected IL-17 production by reducing miR-655 expression through the ILK and Syk signaling cascades. Our findings improve our understanding about the effect of CCN2 in OA pathogenesis and, in particular, IL-17 production and osteoclastogenesis, which may help with the design of more effective OA treatments. © 2022 American Society for Bone and Mineral Research (ASBMR).

Antcin K inhibits VCAM-1-dependent monocyte adhesion in human rheumatoid arthritis synovial fibroblasts.

Background: Antcin K, an extract of Antrodia cinnamomea (a medicinal mushroom endemic to Taiwan commonly used in Chinese medicine preparations), inhibits proinflammatory cytokine production and angiogenesis in human rheumatoid arthritis synovial fibroblasts (RASFs), major players in RA disease. Antcin K also inhibits disease activity in mice with collagen-induced arthritis (CIA). Up until now, the effects of Antcin K upon cell adhesion molecules (CAMs) were unknown. Methods: RA and healthy synovial tissue samples (n = 10 in each group) were retrieved from the Gene Expression Omnibus (GEO) database (accession code: GDS5401) to compare CAM and monocyte marker expressions. In addition, synovial tissue samples from six RA patients and six patients undergoing arthroscopy for trauma/joint derangement (healthy controls) were subjected to immunohistochemical (IHC) analysis. mRNA and protein expression levels were analyzed in RASFs using RT-qPCR (Reverse transcription-quantitative polymerase chain reaction) and Western blot. RASFs were incubated with Antcin K and examined for monocyte adherence by fluorescence microscopy. Ankle joint tissue specimens from a CIA mouse model and healthy controls were stained with hematoxylin and eosin (H&E) and Safranin-O/Fast Green to examine histological changes and evidence of bone loss. IHC analysis determined levels of vascular cell adhesion molecule 1 (VCAM-1) and CD11b in CIA ankle tissue and clinical synovial tissue. Results: Levels of VCAM-1 expression were higher in the GEO database specimens and the study's clinical samples of RA synovial tissue compared with the healthy specimens. Antcin K dose-dependently inhibited VCAM-1 expression and monocyte adhesion in RASFs. Antcin K also significantly inhibited levels of VCAM-1 and monocyte CD11b expression in CIA tissue. These effects appeared to be mediated by MEK1/2-ERK, p38, and AP-1 signaling. Conclusions: Antcin K seems promising for the treatment of RA and deserves further investigations.

IL-17 Facilitates VCAM-1 Production and Monocyte Adhesion in Osteoarthritis Synovial Fibroblasts by Suppressing miR-5701 Synthesis.

Osteoarthritis (OA) is characterized by the infiltration and adhesion of monocytes into the inflamed joint synovium. Interleukin (IL)-17 is a critical inflammatory mediator that participates in the progression of OA, although the mechanisms linking IL-17 and monocyte infiltration are not well understood. Our analysis of synovial tissue samples retrieved from the Gene Expression Omnibus (GEO) dataset exhibited higher monocyte marker (CD11b) and vascular cell adhesion molecule 1 (VCAM-1) levels in OA samples than in normal, healthy samples. The stimulation of human OA synovial fibroblasts (OASFs) with IL-17 increased VCAM-1 production and subsequently enhanced monocyte adhesion. IL-17 affected VCAM-1-dependent monocyte adhesion by reducing miR-5701 expression through the protein kinase C (PKC)-α and c-Jun N-terminal kinase (JNK) signaling cascades. Our findings improve our understanding about the effect of IL-17 on OA progression and, in particular, VCAM-1 production and monocyte adhesion, which may help with the design of more effective OA treatments.

Recognition of a Novel Gene Signature for Human Glioblastoma.

Glioblastoma (GBM) is one of the most common malignant and incurable brain tumors. The identification of a gene signature for GBM may be helpful for its diagnosis, treatment, prediction of prognosis and even the development of treatments. In this study, we used the GSE108474 database to perform GSEA and machine learning analysis, and identified a 33-gene signature of GBM by examining astrocytoma or non-GBM glioma differential gene expression. The 33 identified signature genes included the overexpressed genes COL6A2, ABCC3, COL8A1, FAM20A, ADM, CTHRC1, PDPN, IBSP, MIR210HG, GPX8, MYL9 and PDLIM4, as well as the underexpressed genes CHST9, CSDC2, ENHO, FERMT1, IGFN1, LINC00836, MGAT4C, SHANK2 and VIPR2. Protein functional analysis by CELLO2GO implied that these signature genes might be involved in regulating various aspects of biological function, including anatomical structure development, cell proliferation and adhesion, signaling transduction and many of the genes were annotated in response to stress. Of these 33 signature genes, 23 have previously been reported to be functionally correlated with GBM; the roles of the remaining 10 genes in glioma development remain unknown. Our results were the first to reveal that GBM exhibited the overexpressed GPX8 gene and underexpressed signature genes including CHST9, CSDC2, ENHO, FERMT1, IGFN1, LINC00836, MGAT4C and SHANK2, which might play crucial roles in the tumorigenesis of different gliomas.

Challenges of Diagnosing Viral Myocarditis in Adolescents in the Era of COVID-19 and MIS-C.

Myocarditis has a wide array of clinical presentations ranging from asymptomatic to sudden cardiac death. Pediatric myocarditis is a rare disease, with an estimated annual incidence of 1 to 2 per 100,000 children though its true prevalence remains unknown due to its variable and often subclinical presentation. The diagnosis of myocarditis is challenging in the era of COVID-19 and Multisystem Inflammatory Syndrome in Children (MIS-C), which can have overlapping clinical conundrum. Here, we present a case of a 17-year-old male presenting with chest tightness, shortness of breath, and electrocardiogram (EKG) findings concerning for myocardial injury along with elevated inflammatory markers such as D-dimer, ESR (Erythrocyte Sedimentation Rate), and CRP (C-Reactive Protein). We discuss the key elements of our clinical experience with this case and review the literature for pediatric myocarditis, with a focus on differentiating it from MIS-C in the current COVID-19 pandemic era.

Parcellation of the striatal complex into dorsal and ventral districts.

The striatal complex of basal ganglia comprises two functionally distinct districts. The dorsal district controls motor and cognitive functions. The ventral district regulates the limbic function of motivation, reward, and emotion. The dorsoventral parcellation of the striatum also is of clinical importance as differential striatal pathophysiologies occur in Huntington's disease, Parkinson's disease, and drug addiction disorders. Despite these striking neurobiologic contrasts, it is largely unknown how the dorsal and ventral divisions of the striatum are set up. Here, we demonstrate that interactions between the two key transcription factors Nolz-1 and Dlx1/2 control the migratory paths of striatal neurons to the dorsal or ventral striatum. Moreover, these same transcription factors control the cell identity of striatal projection neurons in both the dorsal and the ventral striata including the D1-direct and D2-indirect pathways. We show that Nolz-1, through the I12b enhancer, represses Dlx1/2, allowing normal migration of striatal neurons to dorsal and ventral locations. We demonstrate that deletion, up-regulation, and down-regulation of Nolz-1 and Dlx1/2 can produce a striatal phenotype characterized by a withered dorsal striatum and an enlarged ventral striatum and that we can rescue this phenotype by manipulating the interactions between Nolz-1 and Dlx1/2 transcription factors. Our study indicates that the two-tier system of striatal complex is built by coupling of cell-type identity and migration and suggests that the fundamental basis for divisions of the striatum known to be differentially vulnerable at maturity is already encoded by the time embryonic striatal neurons begin their migrations into developing striata.

Implantation of an Isoproterenol Mini-Pump to Induce Heart Failure in Mice.

Isoproterenol (ISO), is a non-selective beta-adrenergic agonist, that is used widely to induce cardiac injury in mice. While the acute model mimics stress-induced cardiomyopathy, the chronic model, administered through an osmotic pump, mimics advanced heart failure in humans. The purpose of the described protocol is to create the chronic ISO-induced heart failure model in mice using an implanted mini-pump. This protocol has been used to induce heart failure in 100+ strains of inbred mice. Techniques on surgical pump implantation are described in detail and may be relevant to anyone interested in creating a heart failure model in mice. In addition, the weekly cardiac remodeling changes based on echocardiographic parameters for each strain and expected time to model development are presented. In summary, the method is simple and reproducible. Continuous ISO administered via the implanted mini-pump over 3 to 4 weeks is sufficient to induce cardiac remodeling. Finally, the success for ISO model creation may be assessed in vivo by serial echocardiography demonstrating hypertrophy, ventricular dilation, and dysfunction.

Systems Genetics Approach to Biomarker Discovery: GPNMB and Heart Failure in Mice and Humans.

We describe a simple bioinformatics method for biomarker discovery that is based on the analysis of global transcript levels in a population of inbred mouse strains showing variation for disease-related traits. This method has advantages such as controlled environment and accessibility to heart and plasma tissue in the preclinical selection stage. We illustrate the approach by identifying candidate heart failure (HF) biomarkers by overlaying mouse transcriptome and clinical traits from 91 Hybrid Mouse Diversity Panel (HMDP) inbred strains and human HF transcriptome from the Myocardial Applied Genomics Network (MAGNet) consortium. We found that some of the top differentially expressed genes correlated with known human HF biomarkers, such as galectin-3 and tissue inhibitor of metalloproteinase 1. Using ELISA assays, we investigated one novel candidate, Glycoprotein NMB, in a mouse model of chronic ß-adrenergic stimulation by isoproterenol (ISO) induced HF. We observed significantly lower GPNMB plasma levels in the ISO model compared to the control group (p-value = 0.007). In addition, we assessed GPNMB plasma levels among 389 HF cases and controls from the METabolic Syndrome In Men (METSIM) study. Lower levels of GPNMB were also observed in patients with HF from the METSIM study compared to non-HF controls (p-value < 0.0001). In summary, we have identified several candidate biomarkers for HF using the cardiac transcriptome data in a population of mice that may be directly relevant and applicable to human populations.

Isoproterenol-Induced Heart Failure Mouse Model Using Osmotic Pump Implantation.

Isoproterenol is used widely for inducing heart failure in mice. Isoproterenol is a nonselective beta-adrenergic agonist. The acute model mimics stress-induced cardiomyopathy. The chronic model mimics advanced heart failure in humans. In this chapter, we describe a protocol that we used to induce heart failure in 100+ strains of inbred mice. Techniques on surgical pump implantation and echocardiography are described in detail. We also discuss the impact of drug dosage, duration, mortality, age, gender, and strain on cardiac remodeling responses. The success of model creation may be assessed by echocardiogram or molecular markers. This chapter may be relevant to those who are interested in using this heart failure model.

Critical involvement of atypical chemokine receptor CXCR7 in allergic airway inflammation.

Trafficking and recruitment of immune cells to the site of inflammation with spatial and temporal synchronization is crucial for the development of allergic airway inflammation. Particularly, chemokines are known to be key players in these processes. Previous studies revealed that the CXCL12/CXCR4 axis plays an important role in regulating allergic airway inflammation. However, the role of CXCR7, a recently discovered second receptor for CXCL12, in regulating airway inflammation has not been explored. Initially, CXCR7 was considered as a decoy receptor; however, numerous subsequent studies revealed that engagement of CXCR7 triggered its own signalling or modulated CXCR4-mediated signalling. In the present study, we detected the expression of CXCR7 in airway epithelial cells. Use of a lentiviral delivery system to knock down the expression of CXCR7 in the lung of sensitized mice abrogated the cardinal features of asthma, indicating that CXCR7 plays a role in regulating allergic airway inflammation. The activation of mitogen-activated protein kinase and Akt signalling in response to CXCL12 in the mouse epithelial cell line MLE-12 was reduced when CXCR7 expression was knocked down. However, either knockdown or overexpression of CXCR7 in MLE-12 did not affect CXCL12-mediated calcium influx, indicating that CXCR7 does not modulate CXCR4-mediated signalling, and that it functions as a signalling receptor rather than a decoy receptor. Finally, we found that the expression of chemokine CCL2 is regulated by CXCR7/CXCL12-mediated signalling through ß-arrestin in airway epithelial cells. Hence, regulating the expression of CCL2 in airway epithelial cells may be one mechanism by which CXCR7 participates in regulating allergic airway inflammation.

Content analysis of homeless smokers' perspectives on established and alternative smoking interventions.

BACKGROUND: Cigarette smoking is 5 times more prevalent among homeless individuals than in the general population, and homeless individuals are disproportionately affected by smoking-related morbidity and mortality. Homeless smokers report interest in changing their smoking behavior; however, established smoking cessation interventions are neither desirable to nor highly effective for most members of this population. The aim of this study was to document homeless smokers' perceptions of established smoking interventions as well as self-generated, alternative smoking interventions to elucidate points for intervention enhancement. METHODS: Participants (N=25) were homeless smokers who responded to semistructured interviews regarding smoking and nicotine use as well as experiences with established and alternative smoking interventions. Conventional content analysis was used to organize data and identify themes. RESULTS: Participants appreciated providers' initiation of conversations about smoking. They did not, however, feel simple advice to quit was a helpful approach. Instead, they suggested providers use a nonjudgmental, compassionate style, offer more support, and discuss a broader menu of options, including nonabstinence-based ways to reduce smoking-related harm and improve health-related quality of life. Most participants preferred engaging in their own self-defined, alternative smoking interventions, including obtaining nicotine more safely (e.g., vaping, using smokeless tobacco) and using behavioral (e.g., engaging in creative activities and hobbies) and cognitive strategies (e.g., reminding themselves about the positive aspects of not smoking and the negative consequences of smoking). Abrupt, unaided quit attempts were largely unsuccessful. CONCLUSIONS: The vast majority of participants with the lived experience of homelessness and smoking were uninterested in established smoking cessation approaches. They did, however, have creative ideas about alternative smoking interventions that providers may support to reduce smoking-related harm and enhance quality of life. These ideas included providing information about the relative risks of smoking and the relative benefits of alternative strategies to obtaining nicotine and avoiding smoking.

Moderate statin treatment reduces prebeta-1 high-density lipoprotein levels in dyslipidemic patients.

BACKGROUND: Elevated plasma levels of prebeta-1 high-density lipoprotein (HDL), the principal acceptor of cholesterol effluxed from macrophages, are associated with increased risk of atherosclerotic coronary heart disease and myocardial infarction. OBJECTIVE: The objective of the study was to assess the effects on prebeta-1 HDL levels of 6-week moderate-dose statin treatment. METHODS: We studied 101 patients (mean age 52.7 years; 53.5% female; 63 with primary hypercholesterolemia; 38 with combined hyperlipidemia) before and after treatment with statins. Mean atorvastatin potency equivalence was 23.6 mg/d. Prebeta-1 HDL plasma levels were measured by immunofixation of agarose gels using anti-apolipoprotein A-1 antibody. RESULTS: We observed a 42.0% reduction of low-density lipoprotein cholesterol (181 ± 56 vs 105 mg/dL, P < .001). Triglyceride (TG) levels decreased by 22.3% (157 vs 122 mg/dL, P < .001), HDL cholesterol levels remained similar (56.0 vs 57.1, P = NS). Levels of prebeta-1 HDL were significantly reduced by 17.9% after statin treatment (mean 11.4 vs 9.4 mg apoA-1/dL, P < .001). The magnitude of this decrease was similar with each of 3 statins (atorvastatin, simvastatin, and rosuvastatin). The decrease in prebeta-1 HDL was strongly associated with the decline in TG, but not with the decline in low-density lipoprotein cholesterol. CONCLUSIONS: The association of high prebeta-1 HDL with coronary heart disease identifies it as an inferential measure of the rate of cholesterol efflux from the artery wall. Our observations demonstrate a reduction of prebeta-1 HDL with statin therapy, partially reflecting the reduced TGs, and probably reflecting a direct beneficial impact on cholesterol efflux.