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Biomedical subjects

Kevin D O'Brien

Publications and source records attributed to Kevin D O'Brien.

At least 19 recordsLinked to original sources
PubMed2007

Tesaglitazar, a dual peroxisome proliferator-activated receptor alpha/gamma agonist, reduces atherosclerosis in female low density lipoprotein receptor deficient mice.

OBJECTIVE: The transcription factors, peroxisome proliferator-activated receptors (PPAR) alpha (alpha) and gamma (gamma), which are involved in lipid and glucose homeostasis, also exert modulatory actions on vascular cells where they exhibit anti-inflammatory and anti-proliferative properties. Hence, PPAR agonists potentially can affect atherogenesis both via metabolic effects and direct effects on the vessel wall. We tested whether the dual PPAR-alpha/gamma agonist, tesaglitazar (TZ), would reduce atherosclerosis in a non-diabetic, atherosclerosis-prone mouse model, independent of effects on plasma lipids. METHODS AND RESULTS: Low-density lipoprotein receptor deficient (LDLr-/-) mice were fed a Western type diet consisting of 21% butterfat and 0.15% cholesterol, with or without TZ 0.5 micromol/kg of diet, for 12 weeks. TZ reduced atherosclerosis in the female, but not male, LDLr-/- mice without affecting cholesterol and triglyceride levels, HDL binding to biglycan, or the inflammatory markers serum amyloid A (SAA) and serum amyloid P (SAP). TZ also decreased adiposity in both genders. CONCLUSIONS: TZ reduced atherosclerosis in the female LDLr-/- mice via lipid-independent mechanisms, probably at least in part by direct actions on the vessels. The body weight changes in these mice are different from the effects of dual PPAR agonists seen in humans.

Alkanesulfonates↗
PubMed2006

Inflammation in carotid atherosclerotic plaque: a dynamic contrast-enhanced MR imaging study.

PURPOSE: To prospectively evaluate if there is an association between plaque enhancement at magnetic resonance (MR) imaging and proinflammatory cardiovascular risk factors and plaque content. MATERIALS AND METHODS: This study was performed with informed consent, HIPAA compliance, and institutional review board approval. Contrast agent dynamics within carotid plaques were measured in 30 patients (29 men, one woman; mean age, 67.7 years +/- 10.7 [standard deviation]) who were scheduled to undergo carotid endarterectomy. Measurements were based on kinetic modeling of images obtained at 15-second intervals during which a gadolinium-based contrast agent was injected. The time-varying signal intensities within the plaques were used to estimate the fractional plasma volume (vp) and transfer constant (Ktrans) of contrast material into the extracellular space. Pearson correlation coefficients were computed between blinded MR measurements and histologic measurements of plaque composition, including macrophages, neovasculature, necrotic core, calcification, loose matrix, and dense fibrous tissue. Correlation coefficients or mean differences were computed regarding clinical markers of cardiovascular risk. RESULTS: Analyzable MR images and histologic results were obtained in 27 patients. Measurements of Ktrans correlated with macrophage (r = 0.75, P < .001), neovasculature (r = 0.71, P < .001), and loose matrix (r = 0.50, P = .01) content. Measurements of v(p) correlated with macrophage (r = 0.54, P = .004), neovasculature (r = 0.68, P < .001), and loose matrix (r = 0.42, P = .03) content. For clinical parameters, significant associations were correlated with Ktrans only, with decreased high-density lipoprotein levels (r = -0.66, P < .001) and elevated Ktrans measurements in smokers compared with nonsmokers (mean, 0.134 min(-1) vs 0.074 min(-1), respectively; P = .01). CONCLUSION: The correlations between Ktrans and histologic markers of inflammation suggest that Ktrans is a quantitative and noninvasive marker of plaque inflammation, which is further supported by the correlation of Ktrans with proinflammatory cardiovascular risk factors, decreased high-density lipoprotein levels, and smoking.

Aged↗
PubMed2006

Pathogenesis of calcific aortic valve disease: a disease process comes of age (and a good deal more).

BACKGROUND: Over the past 10 to 15 years, calcific aortic valve disease, which includes aortic sclerosis and aortic stenosis, has come to be recognized as an active process, based on: (1) epidemiologic studies demonstrating associations of specific risk factors with increased prevalence or rate of progression of aortic valve disease; (2) identification, in valve lesions, of histopathologic features of chronic inflammation, lipoprotein deposition, renin-angiotensin system components, and molecular mediators of calcification; and (3) identification of cell-signaling pathways and genetic factors that may participate in valve disease pathogenesis. These studies will be reviewed and organized into a proposed global hypothesis for the pathogenesis of calcific aortic valve disease.

Animals↗
PubMed2006

Features of the metabolic syndrome and diabetes mellitus as predictors of aortic valve calcification in the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Calcific aortic valve disease is common in the elderly, is correlated with common cardiovascular risk factors, and is associated with increased cardiovascular event risk; however, whether metabolic syndrome is associated with an increased prevalence of aortic valve calcium (AVC) is not known. METHODS AND RESULTS: The prevalence of AVC, as assessed by computed tomography, was compared in 6780 Multi-Ethnic Study of Atherosclerosis (MESA) participants with metabolic syndrome (n=1550; National Cholesterol Education Program's Adult Treatment Panel III [ATP III] criteria), diabetes mellitus (n=1016), or neither condition (n=4024). The prevalence of AVC for those with neither condition, metabolic syndrome, or diabetes mellitus was, respectively, 8%, 12%, and 17% in women (P<0.001) and 14%, 22%, and 24% in men (P<0.001). Compared with those with neither condition, the adjusted relative risks for the presence of AVC were 1.45 (95% CI 1.11 to 1.90) for metabolic syndrome and 2.12 (95% CI 1.54 to 2.92) for diabetes mellitus in women and 1.70 (95% CI 1.32 to 2.19) for metabolic syndrome and 1.73 (95% CI 1.33 to 2.25) for diabetes mellitus in men. There was a graded, linear relationship between AVC prevalence and the number of metabolic syndrome components in both women and men (both P<0.001). Similar results were obtained when the International Diabetes Federation metabolic syndrome definition was used. CONCLUSIONS: In the MESA cohort, the metabolic syndrome and diabetes mellitus are associated with increased risk of AVC, and AVC prevalence is increased with increasing number of metabolic syndrome components.

Aged↗
PubMed2006

Validation of the severity index by cardiac catheterization and Doppler echocardiography in patients with aortic sclerosis and stenosis.

The severity index is a new echocardiographic measure that is thought to be an accurate indicator of aortic leaflet pathology in patients with AS. However, it has not been validated against cardiac catheterization or Doppler echocardiographic measures of AS severity nor has it been applied to patients with aortic sclerosis. The purposes of this study were to compare the severity index to invasive hemodynamics and Doppler echocardiography across the spectrum of calcific aortic valve disease, including aortic sclerosis and AS. 48 patients with aortic sclerosis and AS undergoing echocardiography and cardiac catheterization comprised the study population. The aortic valve leaflets were assessed for mobility (scale 1 to 6) and calcification (scale 1 to 4) and the severity index was calculated as the sum of the mobility and calcification scores according to the methods of Bahler et al. The severity index increased with increasing severity of aortic valve disease; the severity indices for patients with aortic sclerosis, mild to moderate AS and severe AS were 3.38 +/- 1.06, 6.45 +/- 2.16 and 8.38 +/- 1.41, respectively. The aortic jet velocity by echocardiography and the square root of the maximum aortic valve gradient by cardiac catheterization correlated well with the severity index (r = 0.84, p < 0.0001; r = 0.84, p < 0.0001, respectively). These results confirm that the severity index correlates with hemodynamic severity of aortic valve disease and may prove to be a useful measure in patients with aortic sclerosis and AS.

Aortic Valve Insufficiency↗
PubMed2006

Serum amyloid A: the "other" inflammatory protein.

Inflammation long has been recognized as a hallmark of atherosclerotic lesions, but more recently attention has focused on chronic low-level elevations of specific plasma inflammatory proteins such as C-reactive protein (CRP) and serum amyloid A (SAA), which may not only represent markers of atherosclerosis risk but also participate directly in atherogenesis. This article briefly reviews evidence for and against potential roles of CRP as an atherosclerosis risk marker and in athero-genesis. The remainder of the article focuses on SAA, an inflammatory protein that is carried on, and may fundamentally alter the function of, high-density lipoprotein. Data are reviewed regarding the regulation of SAA by dietary cholesterol, obesity, and insulin resistance, and its potential role as an atherosclerosis mediator. Lying at the intersection of inflammation, dyslipidemia, obesity, and insulin resistance, SAA may play a key role in regulating the contributions of these processes to atherogenesis.

Atherosclerosis↗
PubMed2006

Reproducibility of CT measurements of aortic valve calcification, mitral annulus calcification, and aortic wall calcification in the multi-ethnic study of atherosclerosis.

RATIONALE AND OBJECTIVES: Extracoronary calcifications may have clinical significance. The error in extracoronary calcification measurements is still unknown. Accurate quantification of calcifications of the aortic valve (AVC), mitral annulus (MAC), and aortic wall (AWC) may be possible by using cardiac computed tomography (CT). We sought to establish the interscan, interobserver, and intraobserver reproducibility of these measures in all cardiac CT scans in the Multi-Ethnic Study of Atherosclerosis. MATERIALS AND METHODS: We measured extracoronary calcifications in 100 randomly selected participants to assess interobserver, interscan, and intraobserver variability. Two scans were available for analysis in 99 of these participants, and we quantified thoracic aorta and valvular calcifications. RESULTS: Mean interscan variability of AVC was 9.7% +/- 11.4% and 8% +/- 10.3% for Agatston and volume scores, with variability of the median at 6.4% and 5.5%, respectively (P > .05). MAC inter-reader variability was 8.2% and 8.9%, with interscan variability of 28% and 33% and intrareader variability of 4% and 4.1%, respectively. For AWC, inter-reader variability was 3%-7.1%, interscan variability was 17%-18%, and intrareader variability was 0.4%-1.4%. CONCLUSION: AVC, MAC, and AWC measurements are sufficiently reproducible to allow serial investigations over a time suitable for clinical studies.

Aged↗
PubMed2005

Phospholipid transfer protein activity is associated with inflammatory markers in patients with cardiovascular disease.

Plasma phospholipid lipid transfer protein (PLTP) has several known key functions in lipoprotein metabolism. Recent studies suggest that it also may play a role in the inflammatory response. Inflammatory cell activity contributes to the development of atherosclerosis. To seek further evidence for the association of PLTP with inflammation, we studied the relationship between PLTP activity and five inflammatory markers [C-reactive protein (CRP), serum amyloid A (SAA), interleukin 6 (IL-6), white blood cells (WBC), and fibrinogen] in 93 patients with low HDL and cardiovascular disease (CVD). Plasma PLTP activity had the strongest correlation with CRP (r=0.332, P<0.001) followed by SAA (r=0.239, P=0.021). PLTP, CRP, and SAA were significantly associated with body mass index (BMI), insulin or glucose, apolipoprotein (apo) B, and/or apo E level (r=0.264-0.393, P<0.01). PLTP, SAA, and IL-6 also were associated with the concentration of HDL particles without apo A-II [Lp(A-I)](r=0.373-0.472, P<0.005, n=56), but not particles with apo A-II. Smoking was associated with increased PLTP activity, CRP, and WBC, and hypertension with increased PLTP activity. In linear models, CRP remained significantly associated with PLTP after adjustment of CVD risk factors and insulin resistance. Also, much of the variability of plasma PLTP activity was explained by CRP, BMI, Lp(A-I), smoking, glucose, and blood pressure. These findings show for the first time that plasma PLTP activity is associated positively with CRP in CVD, a state of chronic inflammation.

Adult↗
PubMed2005

Acrolein impairs ATP binding cassette transporter A1-dependent cholesterol export from cells through site-specific modification of apolipoprotein A-I.

Acrolein is a highly reactive alpha,beta-unsaturated aldehyde, but the factors that control its reactions with nucleophilic groups on proteins remain poorly understood. Lipid peroxidation and threonine oxidation by myeloperoxidase are potential sources of acrolein during inflammation. Because both pathways are implicated in atherogenesis and high density lipoprotein (HDL) is anti-atherogenic, we investigated the possibility that acrolein might target the major protein of HDL, apolipoprotein A-I (apoA-I), for modification. Tandem mass spectrometric analysis demonstrated that lysine 226, located near the center of helix 10 in apoA-I, was the major site modified by acrolein. Importantly, this region plays a critical role in the cellular interactions and ability of apoA-I to transport lipid. Indeed, we found that conversion of Lys-226 to N(epsilon)-(3-methylpyridinium)lysine by acrolein associated quantitatively with decreased cholesterol efflux from cells via the ATP-binding cassette transporter A1 pathway. In the crystal structure of truncated apoA-I, Glu-234 lies adjacent to Lys-226, suggesting that negatively charged residues might direct the modification of specific lysine residues in proteins. Finally, immunohistochemical studies with a monoclonal antibody revealed co-localization of apoA-I with acrolein adducts in human atherosclerotic lesions. Our observations suggest that acrolein might interfere with normal reverse cholesterol transport by HDL by modifying specific sites in apoA-I. Thus, acrolein might contribute to atherogenesis by impairing cholesterol removal from the artery wall.

ATP Binding Cassette Transporter 1↗
PubMed2005

Cholesterol feeding increases C-reactive protein and serum amyloid A levels in lean insulin-sensitive subjects.

BACKGROUND: Inflammatory markers associated with elevated cardiovascular risk are increased by cholesterol feeding in animal models. However, whether dietary cholesterol increases inflammatory marker levels in humans is not known. METHODS AND RESULTS: C-reactive protein (CRP), serum amyloid A (SAA), and lipoprotein levels were compared in 201 healthy subjects on an American Heart Association-National Cholesterol Education Program step 1 diet at baseline and after addition of 4 eggs per day for 4 weeks. Subjects were classified a priori into 3 groups based on their body mass index (BMI) and insulin sensitivity index (SI): lean insulin sensitive (LIS), mean+/-SEM BMI, 23.2+/-0.3 kg/m2, and SI, 6.7+/-0.3x10(-4)min(-1)/(microU/mL), n=66; lean insulin resistant (LIR), BMI, 24.5+/-0.2 kg/m2 and SI, 2.9+/-0.1x10(-4)min(-1)/(microU/mL), n=76; or obese insulin resistant (OIR), BMI, 31.4+/-0.5 kg/m2 and SI, 2.1+/-0.1x10(-4)min(-1)/(microU/mL), n=59. Insulin resistance and obesity each were associated with increased baseline levels of both CRP (P for trend, <0.001) and SAA (P for trend=0.015). Egg feeding was associated with significant increases in both CRP and SAA in the LIS group (both P<0.01) but not in the LIR or OIR groups. Egg feeding also was associated with a significant increase in non-HDL cholesterol (P<0.001) in LIS subjects; however, there was no correlation between the change in non-HDL cholesterol or changes in either CRP or SAA in this group. CONCLUSIONS: A high-cholesterol diet leads to significant increases in both inflammatory markers and non-HDL cholesterol levels in insulin-sensitive individuals but not in lean or obese insulin-resistant subjects.

Acute-Phase Proteins↗
PubMed2005

Angiotensin-converting enzyme inhibitors and change in aortic valve calcium.

BACKGROUND: Calcium accumulation in the aortic valve is a hallmark of aortic sclerosis and aortic stenosis. Because lipoproteins, angiotensin-converting enzyme, and angiotensin II colocalize with calcium in aortic valve lesions, we hypothesized an association between angiotensin-converting enzyme inhibitor (ACEI) use and lowered aortic valve calcium (AVC) accumulation, as measured by electron beam computed tomography. METHODS: Rates of change in volumetric AVC scores were determined retrospectively for 123 patients who had undergone 2 serial electron beam computed tomographic scans. The mean (+/-SD) interscan interval was 2.5 (+/-1.7) years; 80 patients did not receive ACEIs and 43 received ACEIs. The relationship of ACEI use to median rates of AVC score change (both unadjusted and adjusted for baseline AVC scores and coronary heart disease risk factors) was determined. We also examined the relationship of ACEI use to the likelihood of and adjusted odds ratio for definite progression (AVC change >2 times the median interscan variability). RESULTS: Unadjusted and adjusted median rates of AVC score change were significantly higher in the no-ACEI group than in the ACEI group (adjusted median AVC changes [95% confidence interval]: relative, 28.7%/y [18.9%-38.5%/y] vs 11.0%/y [-1.9% to 24.0%/y], P = .04; absolute: 25.1/y [19.7-30.5/y] vs 12.2/y [4.5-19.9/y], P = .02). The adjusted odds ratio (95% confidence interval) for definite AVC progression was significantly lower for patients who received ACEIs (0.29 [0.11-0.75], P = .01). CONCLUSIONS: This retrospective study finds a significant association between ACEI use and a lower rate of AVC accumulation. The results support the need for prospective, randomized trials of ACEIs in calcific aortic valve disease.

Aged↗
PubMed2005

Serum amyloid A and lipoprotein retention in murine models of atherosclerosis.

OBJECTIVE: Elevated serum amyloid A (SAA) levels are associated with increased cardiovascular risk in humans. Because SAA associates primarily with lipoproteins in plasma and has proteoglycan binding domains, we postulated that SAA might mediate lipoprotein retention on atherosclerotic extracellular matrix. METHODS AND RESULTS: Immunohistochemistry was performed for SAA, apolipoprotein A-I (apoA-I), apolipoprotein B (apoB), and perlecan on proximal aortic lesions from chow-fed low-density lipoprotein receptor (LDLR)-/- and apoE-/- mice euthanized at 10, 50, and 70 weeks. SAA was detected on atherosclerotic lesion extracellular matrix at all time points in both strains. SAA area correlated highly with lesion areas (apoE-/-, r=0.76; LDLR-/-, r=0.86), apoA-I areas (apoE-/-, r=0.88; LDLR-/-, r=0.80), apoB areas (apoE-/-, r=0.74; LDLR-/-, r=0.89), and perlecan areas (apoE-/-, r=0.83; LDLR-/-, r=0.79) (all P<0.0001). In vitro, SAA enrichment increased high-density lipoprotein (HDL) binding to heparan sulfate proteoglycans, and immunoprecipitation experiments using plasma from apoE-/- and LDLR-/- mice demonstrated that SAA was present on both apoA-I-containing and apoB-containing lipoproteins. CONCLUSIONS: In chow-fed apoE-/- and LDLR-/- mice, SAA is deposited in murine atherosclerosis at all stages of lesion development, and SAA immunoreactive area correlates highly with lesion area, apoA-I area, apoB area, and perlecan area. These findings are consistent with a possible role for SAA-mediated lipoprotein retention in atherosclerosis.

Animals↗
PubMed2005

Statin use and risks of death or fatal rejection in the Heart Transplant Lipid Registry.

Although small, randomized trials have shown that statin use is associated with decreased risks of mortality and severe rejection, no study has examined statin therapy as used in actual practice in large numbers of heart transplant recipients. We analyzed data from the Heart Transplant Lipid Registry (n = 12 centers). Patients were included if they underwent transplantation between 1995 and 1999, survived >/=30 days after transplantation, and had >/=30 days of Registry follow-up. Multivariable Cox regression models, with propensity scoring performed to adjust for nonrandom allocation of statin therapy, were performed to determine the association of statin therapy with death and fatal rejection. The study included 1,186 patients, with a mean follow-up of 580 +/- 469 days; 937 patients (79%) received statin therapy. Overall, 71 patients (6%) died and 40 (3.4%) had fatal rejection. The statin group had a lower frequency of death (4% vs 13.7%, p <0.0001) and fatal rejection (2.4% vs 7.2%, p = 0.0001). Using multivariable Cox regression, with propensity scoring included to adjust for likelihood of receiving statin therapy, statin use was the only factor associated with lower risk of death (hazard ratio 0.29, 95% confidence interval 0.13 to 0.67) and fatal rejection (hazard ratio 0.27, 95% confidence interval 0.09 to 0.78). This study represents the largest population of heart transplant recipients analyzed for the relation between statin therapy and clinical outcomes in actual practice. Statin therapy was significantly associated with lower risk of death and fatal rejection, benefits that were independent of lipid values.

Chi-Square Distribution↗
PubMed2005

Diet-induced weight loss is associated with decreases in plasma serum amyloid a and C-reactive protein independent of dietary macronutrient composition in obese subjects.

Elevated levels of serum amyloid A (SAA) and C-reactive protein (CRP) have been associated with increased cardiovascular risk. Although levels of CRP decrease with weight loss, it is not known whether SAA decreases with weight loss or whether dietary macronutrient composition affects levels of either SAA or CRP. SAA and CRP levels were measured retrospectively on baseline and 3-month plasma samples from 41 obese (mean body mass index 33.63 +/- 1.86 kg/m2) women completing a randomized trial comparing a low-fat diet (n = 19) and a very low-carbohydrate diet (n = 22). For the 41 participants, there were significant decreases from baseline to 3 months in both LogSAA (P = 0.049) and LogCRP (P = 0.035). The very low-carbohydrate dieters had a significantly greater decrease in LogSAA (P = 0.04), but their weight loss also was significantly greater (-7.6 +/- 3.2 vs. -4.3 +/- 3.5 kg, P < 0.01). In this study, the decreases in inflammatory markers correlated significantly with weight loss (r = 0.44, P = 0.004 vs. LogSAA and r = 0.35, P = 0.03 vs. LogCRP). Also, change in LogSAA correlated with change in insulin resistance (r = 0.35, P = 0.03). Thus, in otherwise healthy, obese women, weight loss was associated with significant decreases in both SAA and CRP. These effects were proportional to the amount of weight lost but independent of dietary macronutrient composition.

Blood Pressure↗
PubMed2005

Association between progression of aortic valve calcification and coronary calcification: assessment by electron beam tomography.

RATIONALE AND OBJECTIVES: It has been demonstrated that aortic valve calcification (AVC) shares many similarities with coronary atherosclerosis, including risk factors and pathologic characteristics. We sought to examine the relationship of AVC to coronary artery calcification (CC), to assess whether similar risk factors affect the process in a similar way. MATERIALS AND METHODS: The study included 620 asymptomatic persons (513 men and 107 women, mean age 59 years range [30-82]) who underwent two consecutive electron beam tomography (EBT) scans at least 1 year apart (mean 3.3 years). Calcification scores were obtained by summation of Agatston and volumetric scores. Stabilization of calcium was defined as no increase in score per year or positive percent change in score </=1%/year. Progression was defined as a positive percent change in score >1%/year. Of 106 with AVC, 105 (99%) had CC. Sixty-five patients had an AVC >10 on initial scan, and 50 (77%) demonstrated progression on the follow-up scan. Of 394 participants with CC >10 on initial scan, follow-up scans showed CC stabilization in 64 (16.2%) and CC progression in 330 (83.8%). Patients with AVC were significantly older than those with only CC (64.5 versus 56.5 years, P < .0001). The average age of the patient with AVC was 7 years older than the average age with CC. AVC (by volumetric score) progressed more rapidly in patients with diabetes (P = .036) and smoking (P = .042) than those without. RESULTS: We found no difference in the degree of change in the CC scores (by Agatston or volumetric methods) over time between men and women, or in any baseline cardiac risk factor (P > .05 for all measures). In 65 patients with both AVC and CC >10, there was a significant association between progression of AVC and CC (P = .047); the absolute rate of change of AVC was 24.5 +/- 43.2 %/year, and CC was 28.0 +/- 49.1 %/year. CONCLUSION: Virtually all patients with AVC had CC, potentially explaining the coronary risk associated with AVC. There is substantially parallel development between rates of progression of EBT-assessed AVC and CC.

Adult↗
PubMed2005

Index of orthodontic treatment need as a predictor of orthodontic treatment uptake.

INTRODUCTION: The aim of this study was to evaluate whether the index of orthodontic treatment need (IOTN) could be weighted by using consumer-based sociodental measures to predict the uptake of orthodontic services. METHODS: The sample consisted of 525 schoolchildren, 11 to 12 years old, from Greater Manchester, United Kingdom. Child-perceived IOTN aesthetic component (AC), examiner IOTN AC and dental health component, and child socioeconomic status (Townsend score) were recorded. Two consumer sociodental measures (utility and oral aesthetic subjective impact scale values) were recorded. Three years later, the proportion of the subjects who had received orthodontic treatment or were on a waiting list for orthodontic treatment was recorded, and the rate of service uptake was determined. RESULTS: Sociodental indicators did not predict uptake of orthodontic services. A child with higher normative clinical treatment need was 3 times more likely to receive orthodontic treatment than a child with low clinical need (P < .05). CONCLUSIONS: Consumer-based sociodental information does not predict future use of orthodontic services. Factors such as clinical IOTN and child-perceived IOTN AC will adequately predict use of orthodontic services.

Adolescent↗
PubMed2005

Advanced glycation end product precursors impair ABCA1-dependent cholesterol removal from cells.

Abnormal HDL metabolism may contribute to the increased atherosclerosis associated with diabetes. The ATP-binding cassette transporter A1 (ABCA1) is an atheroprotective cell protein that mediates cholesterol transport from cells to apolipoprotein (apo) A-I, the major protein in HDL. Because formation of advanced glycation end products (AGEs) is associated with diabetic vascular complications, we examined the effects of carbonyls implicated in AGE formation on the ABCA1 pathway in cultured fibroblasts and macrophages. Treating cells with glycolaldehyde (GA) and glyoxal (GO) strongly inhibited ABCA1-dependent transport of cholesterol from cells to apoA-I, while methylglyoxal had little effect. This occurred under conditions where other lipoprotein receptors or lipid metabolic pathways were little affected, indicating that ABCA1 was uniquely sensitive to these carbonyls. GA and GO destabilized ABCA1 and nearly abolished its binding of apoA-I, indicating that these carbonyls directly modified ABCA1. Immunohistology of coronary arteries from hyperlipidemic swine revealed that inducing diabetes with streptozotocin increased atherosclerotic lesion area and dramatically reduced the fraction of macrophages that expressed detectable ABCA1. These results raise the possibility that reactive carbonyl-mediated damage to ABCA1 promotes accumulation of cholesterol in arterial macrophages and thus contribute to the increased cardiovascular disease associated with diabetes, insulin resistance, and other inflammatory conditions.

ATP Binding Cassette Transporter 1↗