Increased risk of coronary artery disease in Caucasians with extremely low HDL cholesterol due to mutations in ABCA1, APOA1, and LCAT

Mutations in ABCA1, APOA1, and LCAT reduce HDL cholesterol (HDLc) in humans. However, the prevalence of these mutations and their relative effects on HDLc reduction and risk of coronary artery disease (CAD) are less clear. Here we searched for ABCA1, APOA1, and LCAT mutations in 178 unrelated probands with HDLc < 10th percentile but no other major lipid abnormalities, including 89 with ≥ 1 first-degree relative with low HDLc (familial probands) and 89 where familial status of low HDLc is uncertain (unknown probands). Mutations were most frequent in LCAT (15.7%), followed by ABCA1 (9.0%) and APOA1 (4.5%), and were found in 42.7% of familial but only 14.6% of unknown probands (p = 2.44 ∗ 10^− 5). Interestingly, only 16 of 24 (66.7%) mutations assessed in families conferred an average HDLc < 10th percentile. Furthermore, only mutation carriers with HDLc < 5th percentile had elevated risk of CAD (odds ratio (OR) = 2.26 for 34 ABCA1 mutation carriers vs. 149 total first-degree relative controls, p = 0.05; OR = 2.50 for 26 APOA1 mutation carriers, p = 0.04; OR = 3.44 for 38 LCAT mutation carriers, p = 1.1 ∗ 10^− 3). These observations show that mutations in ABCA1, APOA1, and LCAT are sufficient to explain > 40% of familial hypoalphalipoproteinemia in this cohort. Moreover, individuals with mutations and large reductions in HDLc have increased risk of CAD. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010).     

The association of MDR1 C3435T and G2677T/A polymorphisms with plasma platelet-activating factor levels and coronary artery disease risk in Turkish population

Increased levels of peripheral proinflammatory mediators can contribute to the development of coronary artery disease (CAD). Platelet activating factor (PAF) is an important proinflammatory mediator and plasma levels of PAF correlate with transmembrane transporter multidrug resistant 1 P-glycoprotein (MDR1 Pgp) expression and activity. MDR1 polymorphisms can affect the expression and activity of Pgp and plasma PAF levels. Therefore, we investigated the possible relationship between MDR1 C3435T and G2677T/A polymorphisms and plasma PAF levels and the risk of CAD. The study population consisted of 198 patients angiographically documented CAD, including 113 cases with at least 1 coronary artery with ≥ 50% luminal diameter stenosis and 85 control subjects with strictly normal coronary angiograms. Genotypes of the MDR1 C3435T and G2677T/A polymorphisms were determined by polymerase chain reaction (PCR) followed by restriction fragment length polymorphism (RFLP). Plasma PAF levels were detected by enzyme-linked immunosorbent assay (ELISA). There were no significant differences among plasma PAF levels in regard to MDR1 C3435T and G2677T polymorphisms in CAD patients and controls. No statistically significant difference was found for the genotypic and allelic distributions of the polymorphisms in the MDR1 gene between the patients and the control subjects. Furthermore, analysis of MDR1 haplotypes did not show any associations with increased plasma PAF levels and risk of CAD. Our results suggest that plasma PAF levels are not associated with MDR1 gene polymorphisms. There is no association between MDR1 C3435T and G2677T/A polymorphisms and the risk of CAD in Turkish patients.     

Coronary artery anomalies detected by MSCT-coronary angiography in the adult

Background. Before coronary evaluation by modern imaging techniques was feasible, premorbid diagnoses of coronary artery anomalies (CAAs) were usually made fortuitously by invasive coronary angiography (ICA). However, this technique is limited by its invasive and projectional nature. Coronary magnetic resonance angiography (CMRA) and multi-slice computed tomography (MSCT) broadened clinical information by enabling visualisation of the coronary arteries in their anatomical environment. Methods. This case series visualises and reviews anomalous coronary artery from the opposite sinus (ACAOS) and coronary artery fistulae. All CAAs were detected by means of 64-slice dual source computed tomography after 1000 cardiac scans at the Erasmus MC, Rotterdam, the Netherlands. Results. Eight ACAOS cases, one anomalous left coronary artery from the pulmonary artery (ALCAPA) and one congenital aneurysm of an aortic sinus were found. Seven out often detected CAAs were considered malignant whereas three CAAs of the ACAOS type (retroaortic path) were considered benign. Significant coronary artery disease was found in three out of eight ACAOS cases. In one of the ACAOS cases complete evaluation of the anomalous coronary artery was limited by motion artifacts. All five cases of right ACAOS were referred for MSCT because the right coronary artery could not be located by invasive angiography. Conclusion. All CAAs were easy to diagnose because of 3D imaging and high temporal and spatial resolution. High resolution made it possible to not only depict coronary artery abnormalities, but also to quantify luminal and vessel properties such as stenosis grade, aspects of plaque, anomalous vessel length, luminal area ratio and the asymmetry ratio. Because of its comprehensiveness, MSCT can be an effective imaging modality in patients suspected of coronary artery abnormalities caused by coronary artery disease, CAAs, or a combination of both. (Neth Heart J 2008;16:369-75.)     

Genome wide DNA methylation profiling for epigenetic alteration in coronary artery disease patients

Background

The alteration in the epigenome forms an interface between the genotype and the environment. Epigenetic alteration is expected to make a significant contribution to the development of cardiovascular disease where environmental interactions play a key role in disease progression. We had previously shown that global DNA hypermethylation per se is associated with coronary artery disease (CAD) and is further accentuated by high levels of homocysteine, a thiol amino acid which is an independent risk factor for cardiovascular disease and is also a key modulator of macromolecular methylation.

Results

We have identified 72 differentially methylated regions (DMRs) that were hypermethylated in CAD patients in the background of varying homocysteine levels. Following deep bisulfite sequencing of a few of the selected DMRs, we found significantly higher methylation in CAD cases. We get six CpG sites in three DMRs that included the intronic region of C1QL4 gene and upstream region of CCDC47 and TGFBR3 genes.

Conclusion

To the best of our knowledge, this is the first study to identify hypermethylated regions across the genome in patients with coronary artery disease. Further validation in different populations is necessary for this information to be used for disease risk assessment and management.     

Monocyte-to-albumin ratio as a novel predictor of long-term adverse outcomes in patients after percutaneous coronary intervention

Background: Monocyte count and serum albumin (Alb) have been proven to be involved in the process of systemic inflammation. Therefore, we investigated the prognostic value of monocyte-to-albumin ratio (MAR) in patients who underwent percutaneous coronary intervention (PCI).Methods: We enrolled a total of 3561 patients in the present study from January 2013 to December 2017. They were divided into two groups according to MAR cut-off value (MAR < 0.014, n=2220; MAR ≥ 0.014, n=1119) as evaluated by receiver operating characteristic (ROC) curve. The average follow-up time was 37.59 ± 22.24 months.Results: The two groups differed significantly in the incidences of all-cause mortality (ACM; P<0.001), cardiac mortality (CM; P<0.001), major adverse cardiovascular events (MACEs; P=0.038), and major adverse cardiovascular and cerebrovascular events (MACCEs; P=0.037). Multivariate Cox regression analyses revealed MAR as an independent prognostic factor for ACM and CM. The incidence of ACM increased by 56.5% (hazard ratio [HR] = 1.565; 95% confidence interval [CI], 1.086–2.256; P=0.016) and that of CM increased by 76.3% (HR = 1.763; 95% CI, 1.106–2.810; P=0.017) in patients in the higher-MAR group. Kaplan–Meier survival analysis suggested that patients with higher MAR tended to have an increased accumulated risk of ACM (Log-rank P<0.001) and CM (Log-rank P<0.001).Conclusion: The findings of the present study suggested that MAR was a novel independent predictor of long-term mortality in patients who underwent PCI.     

APOA1 gene polymorphisms in the South Asian immigrant population in the United States

BACKGROUND:

Coronary artery disease (CAD) is a leading cause of death in the United States. South Asian immigrants (SAIs) from the Indian subcontinent living in the US are disproportionately at higher risk of CAD than other immigrant populations. Unique genetic factors may predispose SAIs to increased risk of developing CAD when adopting a Western lifestyle including a higher-fat diet, more sedentary behavior and additional gene-environment interactions. SAIs are known to have low levels of the protective high density lipoprotein (HDL) and an altered function for Apo-lipoprotein A-1 (ApoA1), the main protein component of HDL cholesterol. One gene that may be genetically distinctive in this population is APOA1 which codes for ApoA-1 protein, a potentially important contributing factor in the development of CAD.

MATERIALS AND METHODS:

DNA sequencing was performed to determine the status of the seven single-nucleotide polymorphisms (SNPs) in the APOA1 gene from 94 unrelated SAI adults. Genotypes, allelic frequencies, and intragenic linkage disequilibrium of the APOA1 SNPs were calculated.

RESULTS:

Several polymorphisms and patterns were common among persons of south Asian ethnicity. Frequencies for SNPs T655C, T756C and T1001C were found to be different than those reported in European Caucasian individuals. Linkage disequilibrium was found to be present between most (13 of 15) SNP pairings indicating common inheritance patterns.

CONCLUSIONS:

SAIs showed variability in the sequence of the APOA1 gene and linkage disequilibrium for most SNPS. This pattern of APOA1 SNPs may contribute to decreased levels of HDL cholesterol reported in SAIs, leading to an increased risk for developing CAD in this population.     

Impact of DNA demethylation of the G0S2 gene on the transcription of G0S2 in squamous lung cancer cell lines with or without nuclear receptor agonists

We recently identified that DNA methylation of the G0S2 gene was significantly more frequent in squamous lung cancer than in non-squamous lung cancer. However, the significance of G0S2 methylation levels on cancer cells is not yet known. We investigated the effect of G0S2 methylation levels on cell growth, mRNA expression, and chromatin structure using squamous lung cancer cell lines and normal human bronchial epithelial cells. DNA methylation and mRNA expression of G0S2 were inversely correlated, and in one of the squamous lung cancer cell lines, LC-1 sq, G0S2 was completely methylated and suppressed. Overexpression of G0S2 in LC-1 sq did not show growth arrest or apoptosis. The G0S2 gene has been reported to be a target gene of all-trans retinoic acid and peroxisome proliferator-activated receptor agonists. We treated LC-1 sq with 5-Aza-2′-deoxycytidine, Trichostatin A, all-trans retinoic acid, Wy 14643, or Pioglitazone either alone or in combination. Only 5-Aza-2′-deoxycytidine restored mRNA expression of G0S2. Chromatin immunoprecipitation revealed that histone H3 lysine 9 was methylated regardless of DNA methylation or mRNA expression. In summary, mRNA expression of G0S2 was regulated mainly by DNA methylation in squamous lung cancer cell lines. When the G0S2 gene was methylated, nuclear receptor agonists could not restore mRNA expression of G0S2 and did not show any additive effect on mRNA expression of G0S2 even after the treatment with 5-Aza-2′-deoxycytidine.     

Common variant in FUT2 gene is associated with levels of vitamin B12 in Indian population

Vitamin B₁₂ is an essential micronutrient synthesized by microorganisms. Mammals including humans have evolved ways for transport and absorption of this vitamin. Deficiency of vitamin B₁₂ (either due to low intake or polymorphism in genes involved in absorption and intracellular transport of this vitamin) has been associated with various complex diseases. Genome-wide association studies have recently identified several common single nucleotide polymorphisms (SNPs) in fucosyl transferase 2 gene (FUT2) to be associated with levels of vitamin B₁₂—the strongest association was with a non-synonymous SNP rs602662 in this gene. In the present study, we attempted to replicate the association of this SNP (rs602662) in an Indian population since a significant proportion has been reported to have low levels of vitamin B₁₂ in this population. A total of 1146 individuals were genotyped for this SNP using a single base extension method and association with levels of vitamin B₁₂ was assessed in these individuals. Regression analysis was performed to analyze the association considering various confounding factors like for age, sex, diet, hypertension, diabetes mellitus and coronary artery disease status. We found that the SNP rs602662 was significantly associated with the levels of vitamin B₁₂ (p value < 0.0001). We also found that individuals adhering to a vegetarian diet with GG (homozygous major genotype) have significantly lower levels of vitamin B₁₂ in these individuals. Thus, our study reveals that vegetarian diet along with polymorphism in the FUT2 gene may contribute significantly to the high prevalence of vitamin B₁₂ deficiency in India.     

Identification of differentially expressed genes and the role of PDK4 in CD14+ monocytes of coronary artery disease

Background. Coronary artery disease (CAD) is a chronic inflammatory disease caused by development of atherosclerosis (AS), which is the leading cause of mortality and disability. Our study aimed to identify the differentially expressed genes (DEGs) in CD14⁺ monocytes from CAD patients compared with those from non-CAD controls, which might pave the way to diagnosis and treatment for CAD. Methods. The RNA-sequencing (RNA-seq) was performed by BGISEQ-500, followed by analyzing with R package to screening DEGs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed by R package. In addition, we validated the results of RNA-seq using real-time quantitative polymerase chain reaction (RT-qPCR). Furthermore, we explored the function of selected ten genes in LDL-treated CD14⁺ monocytes by RT-qPCR. Results. a total of 2897 DEGs were identified, including 753 up- and 2144 down-regulated genes in CD14⁺ monocytes from CAD patients. These DEGs were mainly enriched in plasma membrane and cell periphery of cell component, immune system process of biological process, NF-κB signaling pathway, cell adhesion molecules signaling pathway and cytokine–cytokine receptor interaction signaling pathway. In LDL-treated CD14⁺ monocytes, the mRNA expression of pyruvate dehydrogenase kinase 4 (PDK4) was significantly up-regulated. Conclusion. In the present study, we suggested that PDK4 might play a role in progression of CAD. The study will provide some pieces of evidence to investigate the role and mechanism of key genes in the pathogenesis of CAD.     

Association of m.5178C>A variant with serum lipid levels: a systematic review and meta-analysis

Background: Emerging evidence shows that m.5178C>A variant is associated with a lower risk of coronary artery disease (CAD). However, the specific mechanisms remain elusive. Since dyslipidemia is one of the most critical risk factors for CAD and accounts for at least 50% of the population-attributable risk, it is tempting to speculate that the reduced CAD risk caused by the m.5178C>A variant may stem from an improved lipid profile. In order to verify this hypothesis, we conducted the present study to clarify the association of m.5178C>A variant with lipid levels.Methods: By searching ten databases for studies published before 30 June 2021. Thirteen East Asian populations (7587 individuals) were included for the analysis.Results: The present study showed that m.5178C>A variant was associated with higher high-density lipoprotein cholesterol (HDL-C) [standardized mean difference (SMD) = 0.12, 95% confidence interval (CI) = 0.06–0.17, P<0.001] and total cholesterol (TC) (SMD = 0.08, 95% CI = 0.02–0.14, P=0.01) levels. In subgroup analysis, the association of m.5178C>A variant with higher HDL-C levels were observed in Japanese (SMD = 0.09, 95% CI = 0.01–0.17, P=0.03) and Chinese populations (SMD = 0.13, 95% CI = 0.07–0.20, P<0.001). However, the association of m.5178C>A variant with lower low-density lipoprotein cholesterol (LDL-C) levels were only observed in Japanese populations (SMD = −0.11, 95% CI = −0.22 to 0.00, P=0.04).Conclusions: The m.5178C>A variant was associated with higher HDL-C and lower LDL-C levels in Japanese populations, which may contribute to decreased CAD risk and longevity of Japanese.     

miRNA 206 and miRNA 574-5p are highly expression in coronary artery disease

Coronary artery disease (CAD) is the leading cause of human morbidity and mortality worldwide. Innovative diagnostic biomarkers are a pressing need for this disease. miRNAs profiling is an innovative method of identifying biomarkers for many diseases and could be proven as a powerful tool in the diagnosis and treatment of CAD. We performed miRNA microarray analysis from the plasma of three CAD patients and three healthy controls. Subsequently, we performed quantitative real-time PCR (qRT-PCR) analysis of miRNA expression in plasma of another 67 CAD patients and 67 healthy controls. We identified two miRNAs (miR-206 and miR-574-5p) that were significantly up-regulated in CAD patients as compared with healthy controls (P<0.05). The receiver operating characteristic (ROC) curves indicated these two miRNAs had great potential to provide sensitive and specific diagnostic value for CAD.     

Multi-allelic haplotype association identifies novel information different from single-SNP analysis: A new protective haplotype in the LRP8 gene is against familial and early-onset CAD and MI

Our previous studies identified a functional SNP, R952Q in the LRP8 gene, that was associated with increased platelet activation and familial and early-onset coronary artery disease (CAD) and myocardial infarction (MI) in American and Italian Caucasian populations. In this study, we analyzed four additional SNPs near R952Q (rs7546246, rs2297660, rs3737983, rs5177) to identify a specific LRP8 SNP haplotype that is associated with familial and early-onset CAD and MI. We employed a case–control association design involving 381 premature CAD and MI probands and 560 controls in GeneQuest, 441 individuals from 22 large pedigrees in GeneQuest II, and 248 MI patients with family history and 308 controls in an Italian cohort. Like R952Q, LRP8 SNPs rs7546246, rs2297660, rs3737983, and rs5177 were significantly associated with early-onset CAD/MI in both population-based and family-based association studies in GeneQuest. The results were replicated in the GeneQuest II family-based population and the Italian population. We then carried out a haplotype analysis for all five SNPs including R952Q. One common haplotype (TCCGC) was significantly associated with CAD (P = 4.0 × 10^− 11) and MI (P = 6.5 × 10^− 12) in GeneQuest with odds ratios of 0.53 and 0.42, respectively. The results were replicated in the Italian cohort (P = 0.004, OR = 0.71). The sib-TDT analysis also showed significant association between the TCCGC haplotype and CAD in GeneQuest II (P = 0.001). These results suggest that a common LRP8 haplotype TCCGC confers a significant protective effect on the development of familial, early-onset CAD and/or MI.     

ω-ethyl, ω-ethenyl and ω-ethynyl-α-alkylidene-γ-lactones from Clinostemon mahuba

The trunk wood of Clinostemon mahuba contains eight (3R)-2-alkylidene-3-hydroxy-4-methylenebutanolides, seven (3R,4S)-2-alkylidene-3-hydroxy-4-methylbutanolides and seven (3S,4S)-2-alkylidene-3-hydroxy-4-methylbutanolides distinguished by the alkylidene side chains with respect to their E- or Z-geometry, ethenyl, ethynyl or ethyl terminals and lengths (C₁₆ or C₁₈).     

GSTM1, GSTT1, GSTP1, and GSTA1 genetic variants are not associated with coronary artery disease in Taiwan

Background and objective

The genetic variants of xenobiotic-metabolizing enzymes, such as those encoded by glutathione-S-transferase (GST) genes, may be associated with the risk of coronary artery disease (CAD). To investigate the genetic factors for CAD, we examined the GSTM1, GSTT1, GSTP1, and GSTA1 genotypes in a CAD cohort in Taiwan.

Methods

Our study included 458 CAD participants and 209 control participants who received coronary angiography to assess CAD. The severity of CAD was defined as the number of coronary vessels with 50% or greater stenosis. Sequence variation of the GSTM1 and GSTT1 genes was determined using a polymerase chain reaction (PCR). The GSTP1 (Ile105Val), and GSTA1 (-69C > T) genetic variants were identified using a combination of PCR and restriction fragment length polymorphism analysis. Logistic regression analysis was used to calculate the odds ratios (ORs) and 95% confidence intervals.

Results

Among the GST genetic variants examined, the GSTT1 null genotype was more prevalent in CAD participants with 3 stenosed vessels than in control participants (OR = 1.64, P = .02). This association was no longer observed after adjusting for age, sex, smoking, alcohol use, diabetes mellitus, and serum levels of total cholesterol and high-density lipoprotein cholesterol (OR = 1.28, P = .40). Both univariate and multivariate logistic regression analyses found no significant associations between CAD and the other genetic variants, either separately or in combination. In addition, no effects of interactions between the genotypes and environmental factors, such as cigarette smoking, were significantly associated with the risk of CAD.

Conclusion

The GST genetic variants examined were not associated with susceptibility to CAD in our Taiwanese cohort. This null association requires further confirmation with larger samples.     

Meta-analyses of HFE variants in coronary heart disease

Aim

HFE gene variants can cause hereditary hemochromatosis (HH) that often comes along with an increased risk of coronary heart disease (CHD). The goal of our study is to assess the contribution of four HFE gene variants to the risk of CHD.

Methods and results

We conducted four meta-analyses of the studies examining the association between four HFE gene variants and the risk of CHD. A systematic search was conducted using MEDLINE, EMBASE, Web of Science and China National Knowledge Infrastructure (CNKI), Wanfang Chinese Periodical.

Results

Meta-analyses showed that HFE rs1799945-G allele was associated with a 6% increased risk of CHD (P = 0.02, odds ratio (OR) = 1.06, 95% confidence interval (CI) = 1.01–1.11). However, no association between the other three HFE gene variants (rs1800562, rs1800730, and rs9366637) and CHD risk was observed by the meta-analyses (all P values > 0.05). In addition, the results of our case–control study indicated that rs1800562 and rs1800730 were monomorphic, and that rs1799945 and rs9366637 were not associated with CHD in Han Chinese.

Conclusions

Our meta-analysis suggested that a significant association existed between rs1799945 mutation and CHD, although this mutation was rare in Han Chinese.     

Association of TLR and TREM-1 gene polymorphisms with risk of coronary artery disease in a Russian population

Atherosclerosis, manifesting itself as acute coronary syndrome, stroke, and peripheral arterial diseases, is a chronic progressive inflammatory disease which is driven by responses of both innate and adaptive immunity. Toll-like receptors (TLRs) and Triggering Receptor Expressed on Myeloid Cells-1 (TREM-1) are important effectors of the innate immune system, and polymorphisms within genes encoding them may increase risk of occurrence of various pathologies including cardiovascular disorders. Thus, we carried out a genetic association study on the sample of 702 consecutive Caucasian (Russian) patients with coronary artery disease (CAD) and 300 age-, sex-, and ethnicity-matched healthy controls. We revealed that the C/C genotype of the TLR1 rs5743551 polymorphism was significantly associated with a reduced risk of CAD according to the recessive model (OR = 0.41, 95% CI = 0.20–0.84, P = 0.017, adjusted by age and gender). Concerning TREM-1 gene polymorphisms, we found that A/A genotype of the rs2234237 polymorphism, the G/G genotype of the rs6910730 polymorphism, the C/C genotype of the rs9471535 polymorphism, and the T/T genotype of the rs4711668 polymorphism were significantly associated with elevated CAD risk according to the recessive model (OR = 5.52, 95% CI = 1.17–25.98, P = 0.011; OR = 4.28, 95% CI = 1.09–16.81, P = 0.021; OR = 5.55, 95% CI = 1.18–26.09, P = 0.011, and OR = 1.66, 95% CI = 1.10–2.52, P = 0.014, respectively, adjusted by age and gender). Conversely, the G allele of the rs1817537 polymorphism, the T allele of the rs2234246 polymorphism, and the T allele of the rs3804277 polymorphism significantly correlated with similarly decreased risk of CAD according to the dominant model (OR = 0.57, 95% CI = 0.40–0.81, P = 0.0013; OR = 0.59, 95% CI = 0.42–0.84, P = 0.003, and OR = 0.58, 95% CI = 0.41–0.81, P = 0.0014, respectively, adjusted by age and gender). We conclude that certain TLR and TREM-1 gene polymorphisms may be associated with CAD in Russian population; however, their significance as predictive and pathogenic markers of CAD should be interpreted with caution in other populations.     

Pathways of glutathione degradation in the yeast Saccharomyces cerevisiae

The degradation of glutathione (GSH) in the yeast Saccharomyces cerevisiae appears to be mediated only by γ-glutamyltranspeptidase and cysteinylglycine dipeptidase. Other enzymes of the γ-glutamyl cycle, γ-glutamyl cyclotransferase and 5-oxo-l-prolinase, are not present in the yeast. In vivo transpeptidation was shown in the presence of a high intracellular level of γ-glutamyltranspeptidase, but only when the de-repressing nitrogen source was a suitable acceptor of the transferase reaction. In contrast, when the de-repressing source was not an acceptor of the transferase reaction (e.g. urea), only glutamate was detected. Intracellular GSH is virtually inert when the level of γ-glutamyltranspeptidase is low. Possible roles for in vivo transpeptidation are discussed.     

PLTP activity inversely correlates with CAAD: effects of PON1 enzyme activity and genetic variants on PLTP activity

Recent studies have failed to demonstrate a causal cardioprotective effect of HDL cholesterol levels, shifting focus to the functional aspects of HDL. Phospholipid transfer protein (PLTP) is an HDL-associated protein involved in reverse cholesterol transport. This study sought to determine the genetic and nongenetic predictors of plasma PLTP activity (PLTPa), and separately, to determine whether PLTPa predicted carotid artery disease (CAAD). PLTPa was measured in 1,115 European ancestry participants from a case-control study of CAAD. A multivariate logistic regression model was used to elucidate the relationship between PLTPa and CAAD. Separately, a stepwise linear regression determined the nongenetic clinical and laboratory characteristics that best predicted PLTPa. A final stepwise regression considering both nongenetic and genetic variables identified the combination of covariates that explained maximal PLTPa variance. PLTPa was significantly associated with CAAD (7.90 × 10⁻⁹), with a 9% decrease in odds of CAAD per 1 unit increase in PLTPa (odds ratio = 0.91). Triglyceride levels (P = 0.0042), diabetes (P = 7.28 × 10⁻⁵), paraoxonase 1 (PON1) activity (P = 0.019), statin use (P = 0.026), PLTP SNP rs4810479 (P = 6.38 × 10⁻⁷), and PCIF1 SNP rs181914932 (P = 0.041) were all significantly associated with PLTPa. PLTPa is significantly inversely correlated with CAAD. Furthermore, we report a novel association between PLTPa and PON1 activity, a known predictor of CAAD.     

Biochemical characterization of the apicoplast-targeted AAA+ ATPase ClpB from Plasmodium falciparum

ClpB is a molecular chaperone from the AAA+ superfamily of ATPases, which reactivates aggregated proteins in cooperation with the DnaK chaperone system. ClpB is essential for infectivity and in-host survival of a number of pathogenic microorganisms, but systematic studies on ClpB from pathogens have not been reported yet. We purified and characterized one of the two ClpB isoforms from the malaria parasite Plasmodium falciparum, PfClpB1. PfClpB1 is targeted to the apicoplast, an essential plastid organelle that is a promising anti-malaria drug target. PfClpB1 contains all characteristic AAA+ sequence motifs, but the middle domain of PfClpB1 includes a 52-residue long non-conserved insert. Like in most AAA+ ATPases, ATP induces self-association of PfClpB1 into hexamers. PfClpB1 catalyzes the hydrolysis of ATP and its ATPase activity is activated in the presence of casein and poly-lysine. Similar to Escherichia coli ClpB, PfClpB1 reactivates aggregated firefly luciferase, but the PfClpB1-mediated aggregate reactivation is inhibited in the presence of E. coli DnaK, DnaJ, and GrpE. The lack of effective cooperation between PfClpB1 and the bacterial DnaK system may arise from the Plasmodium-specific sequence of the ClpB middle domain. Our results indicate that the chaperone activity of PfClpB1 may support survival of Plasmodium falciparum by maintaining the folding status and activity of apicoplast proteins.     

CLA isomers inhibit TNFα-induced eicosanoid release from human vascular smooth muscle cells via a PPARγ ligand-like action

Conjugated linoleic acids (CLAs) were reported to have anti-atherogenic properties in animal feeding experiments. In an attempt to elucidate the molecular mechanisms of these anti-atherogenic effects, the modulatory potential of CLA on cytokine-induced eicosanoid production from smooth muscle cells (SMCs), which contributes to the chronic inflammatory response associated with atherosclerosis, has been investigated in the present study. cis-9, trans-11 CLA and trans-10, cis-12 CLA were shown to reduce proportions of the eicosanoid precursor arachidonic acid in SMC total lipids and to inhibit cytokine-induced NF-κB DNA-binding activity, mRNA levels of inducible enzymes involved in eicosanoid formation (cPLA₂, COX-2, mPGES), and the production of the prostaglandins PGE₂ and PGI₂ by TNFα-stimulated SMCs in a dose-dependent manner. The effect of 50 μmol/L of either CLA isomer was as effective as 10 μmol/L of the PPARγ agonist troglitazone in terms of inhibiting the TNFα-stimulated eicosanoid production by SMCs. PPARγ DNA-binding activity was increased by both CLA isomers compared to control cells. Moreover, it was shown that the PPARγ antagonist T0070907 partially abrogated the inhibitory action of CLA isomers on cytokine-induced eicosanoid production and NF-κB DNA-binding activity by vascular SMCs suggesting that PPARγ signalling is at least partially involved in the action of CLA in human vascular SMCs. With respect to the effects of CLA on experimental atherosclerosis, our findings suggest that the anti-inflammatory effect of CLA is at least partially responsible for the anti-atherogenic effects of CLA observed in vivo.