© 1999 American Heart Association, Inc.
Original Contributions |
Low-Density Lipoprotein Particle Size Is Inversely Related to Plasminogen Activator Inhibitor-1 Levels
The Insulin Resistance Atherosclerosis Study
From the Department of Medicine, Division of Clinical Epidemiology, University of Texas Health Science Center at San Antonio, TX (A.F., L.M., S.M.H.); Department of Public Health Sciences, Bowman Gray School of Medicine, Winston Salem, NC (R.D'A.); Department of Pathology, University of Vermont School of Medicine, VT (R.T.); and Medlantic Research Institute, Washington, DC (B.V.H.).
Correspondence to Andreas Festa, MD, Department of Medicine, Division of Clinical Epidemiology, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78284-7873. E-mail festa{at}uthscsa.edu
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Abstract |
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Abstract—High levels of plasminogen activator inhibitor-1 (PAI-1) and preponderance of small dense low-density lipoproteins (LDL) have both been associated with atherosclerotic disease and with the insulin resistance syndrome (IRS). In vitro studies have shown a stimulatory effect of various lipoproteins on PAI-1 release from different cells, including endothelial cells and adipocytes. The authors sought to investigate the relation of PAI-1 to LDL particle size in a large tri-ethnic population (n=1549) across different states of glucose tolerance. LDL size was determined by gradient gel electrophoresis, and PAI-1 was measured by a 2-site immunoassay, sensitive to free PAI-1. PAI-1 was inversely related to LDL size in the overall population (r=-0.21, P<0.0001), independent of gender and ethnicity. However, the authors found a significant interaction with glucose tolerance status (P=0.035). In univariate analysis, the association between PAI-1 and LDL size was most pronounced in subjects with normal glucose tolerance (NGT, r=-0.22, P<0.0001) and weaker in impaired glucose tolerance (IGT, r=-0.12, P=0.03) and type-2 diabetes (r=-0.10, P=0.02). After adjustment for demographic variables and metabolic variables known to influence PAI-1 levels (triglyceride and insulin sensitivity), a significant inverse relation of LDL size to PAI-1 levels was only present in NGT (P=0.023). In subjects with IGT or overt diabetes, who usually have elevated PAI-1 levels, additional factors other than LDL size seem to contribute more importantly to PAI-1 levels. The demonstrated inverse relation of LDL size and PAI-1 levels provides one possible explanation for the atherogeneity of small dense LDL particles.
Key Words: plasminogen activator inhibitor-1 • low-density lipoprotein particle size • glucose tolerance • insulin resistance
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Introduction |
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Low-density lipoproteins (LDL) are heterogeneous in terms of size and density.1 2 Small dense LDL particles have been proved to be more atherogenic than larger LDL particles in cross-sectional3 4 and prospective5 studies and have been associated with most individual components of the insulin resistance syndrome (IRS), including hypertriglyceridemia,3 4 5 6 7 8 9 low serum high density lipoprotein (HDL) cholesterol levels,3 6 7 8 9 hypertension,7 8 and diabetes.7 9 10
PAI-1 is a potent inhibitor of fibrinolysis, and high levels of PAI-1 have been associated with myocardial infarction11 12 13 and coronary artery disease14 15 16 and with recurrence of myocardial infarction.17 High levels of PAI-1 have also been associated with the IRS,18 19 20 21 including increased insulin concentrations18 and decreased insulin sensitivity.19 20 21 Increased PAI-1 levels have been suggested as a possible link between insulin resistance and coronary heart disease.22
Recently, an independent inverse association of LDL size and impaired fibrinolysis, as expressed by elevated PAI-1 levels, was reported.23 Results of this study are in accordance with data from in vitro studies, demonstrating a stimulatory effect of various lipoproteins, namely very low-density lipoprotein (VLDL),24 25 Lp(a),26 native LDL,27 and oxidized LDL28 29 on PAI-1 release from various cells, such as endothelial cells,24 25 26 27 28 29 hepatocytes,30 and adipocytes.31 Small, dense LDL particles are particularly prone to oxidative modification.32 33 34 These data potentially provide one mechanism for the atherogeneity of small, dense LDL particles. However, no data are currently available on the association of LDL size and PAI-1 in a larger number of subjects and across different states of glucose tolerance. Moreover, it is not known how common factors that influence both LDL size and PAI-1 levels, such as insulin sensitivity, modify the association between LDL size and PAI-1 levels.
We therefore investigated the relationship of LDL size and PAI-1 levels relative to various components of the IRS including insulin sensitivity in a large, tri-ethnic population (blacks, non-Hispanic whites, and Mexican Americans) with varying degrees of glucose tolerance in the Insulin Resistance Atherosclerosis Study (IRAS).
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Methods |
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The IRAS is a multicenter epidemiologic study which aims to explore the relations between insulin resistance, cardiovascular risk factors, and disease across different ethnic groups and varying states of glucose tolerance. A full description of the design and methods of the IRAS has been published.35 In brief, this study was conducted at 4 clinical centers. Clinical centers in Oakland and Los Angeles, California, studied non-Hispanic whites and blacks recruited from Kaiser Permanente, a nonprofit health maintenance organization. Clinical centers in San Antonio, Texas, and San Luis Valley, Colorado, studied non-Hispanic whites and Hispanics recruited from 2 ongoing population-based studies (the San Antonio Heart Study36 and the San Luis Valley Diabetes Study37 ). Recruitment was tailored to yield approximately equal numbers of participants by ethnicity, gender, and glucose tolerance categories (type-2 diabetes mellitus, impaired glucose tolerance [IGT], and normal glucose tolerance [NGT]). This report includes data on 1549 subjects (age range, 39 to 69 years) in whom LDL size and PAI-1 were assessed. The IRAS protocol was approved by local institutional review committees, and all subjects gave informed consent.
Race and ethnicity were assessed by self-report. Hispanic ethnicity was defined by the US census question: "Are you of Spanish or Hispanic descent?" Height, weight, and girths (minimum waist and hips) were measured following a standardized protocol. Body mass index (weight/height2 [kg/m2]) was used as an estimate of overall adiposity. The ratio of waist-to-hip circumferences (WHR) was used as an estimate of body fat distribution. The IRAS examination required 2 visits. Patients were asked before each visit to fast for 12 hours, to abstain from heavy exercise and alcohol for 24 hours, and to refrain from smoking on the morning of the examination.
For the OGTT, a 75-g glucose load (Orangedex, Customs Laboratories) was administered for <10 minutes. Blood was drawn immediately before ingestion and 2 hours after the glucose load. Glucose tolerance status was based on World Health Organization criteria.38 Glucose and insulin levels in all samples were measured at the central IRAS laboratory at University of Southern California, Los Angeles, CA. Plasma glucose was measured with the glucose oxidase technique on an automated autoanalyzer (Yellow Springs Equipment Co). Insulin was measured using the dextran-charcoal radioimmunoassay.39 This insulin assay cross-reacts with proinsulin. The split pair coefficient of variation (CV) of the insulin assay was 19% (n=163).
Insulin sensitivity was assessed by a frequently sampled intravenous glucose tolerance test (FSIGT)40 with minimal model analysis.41 Two modifications of the original protocol were used. An injection of regular insulin, rather than tolbutamide, was used to ensure adequate plasma insulin levels for the accurate computation of insulin sensitivity across a broad range of glucose tolerance42 including diabetic patients because of their blunted or absent insulin response. In addition, the reduced sampling protocol (which required 12 rather than 30 plasma samples and had results similar to the full protocol43 ) was used because of the large number of subjects. Glucose in the form of a 50% solution (0.3 g/kg body weight) and regular human insulin (0.03 U/kg body weight) were injected through an intravenous line at 0 and 20 minutes, respectively. Blood was collected at -5, 2, 4, 8, 19, 22, 30, 40, 50, 70, 100, and 180 minutes for plasma glucose and insulin concentrations. Insulin sensitivity, expressed as the insulin sensitivity index (SI), was calculated by mathematical modeling methods (MINMOD, version 3.0 [1994]). This modified version of the FSIGT protocol used in the IRAS was recently compared with the hyperinsulinemic euglycemic clamp and shown to be a valid measure of insulin resistance.44
Plasma lipoprotein measurements were obtained from fasting single fresh plasma samples using Lipid Research Clinic methods. Plasma lipoproteins were measured at the central IRAS laboratory at Medlantic Research Institute, Washington, DC. LDL and HDL were isolated by preparative ultracentrifugation, and VLDL (top) and bottom fractions were measured for cholesterol and triglyceride concentrations. HDL cholesterol was measured in the presence of MnCl2 and heparin in which non-HDL lipoproteins were precipitated, leaving HDL in the supernatant. The supernatant was removed after centrifugation, and cholesterol content measured on a separate autoanalyzer channel set to measure low cholesterol values. LDL was calculated as the difference between the HDL cholesterol and the bottom cholesterol. Triglycerides were measured enzymatically after correction for free glycerol.
LDL size distribution (ie, distribution of diameter of the major LDL peak for each participant) was determined with use of the method of Krauss and Burke.45 Gradient gels were obtained from Isolab. Measurement of the size of the predominant peak was calibrated using LDL subfractions whose molecular diameter was determined by analytical ultracentrifugation (courtesy of Dr R. Krauss, Donner Laboratories). The LDL size of the predominant peak for an individual was defined as that person's LDL size.10 The CV for LDL size from 133 blind split duplicates was 2%.
PAI-1 was measured in citrated plasma,46 using a 2-site immunoassay that is sensitive to free PAI-1, but not to PAI-1 complexed with t-PA.47 The citrate sample was centrifuged for a minimum of 30 000g minutes to make certain that there was no contamination from platelet PAI-1; the CV was 14%. To minimize circadian variability of PAI-1 levels, participants were brought into the clinics in the morning and fasting samples were drawn no later than 10:00 AM. To minimize acute-phase responses, subjects with a current acute illness (including clinically significant infectious disease) were excluded from the study. Venipuncture methods were standardized and optimized for minimal trauma. The sample handling protocol, including centrifugation, was also optimized to provide the smallest possible analytical variance.46
Statistical Analysis
Statistical analyses were performed using the SAS
statistical software system (SAS, Inc.). Unadjusted Spearman rank
correlations of PAI-1 and LDL size with measures of body fat and
metabolic variables stratified by glucose tolerance
status were performed (Table 1
).
Additionally, correlations of LDL size with PAI-1 were stratified by
ethnicity and gender (Table 2). We tested
for interactions between LDL size and gender, ethnicity, and glucose
tolerance status on the association with PAI-1 by calculating the
significance of interaction terms (LDL sizexglucose tolerance status,
LDL sizexgender, and LDL sizexethnicity). The interaction models were
performed on ranked data analogous to the correlation analyses.
Furthermore, in these models adjustment for age, clinic and/or gender,
and/or ethnicity and/or glucose tolerance status was performed.
Subjects with SI calculated as 0 were included in
the present analysis. Despite the skewed distribution of
SI we decided not to transform the variable
because SI was analyzed as an independent
rather than a dependent variable of primary interest. In
correlation analysis Spearman rank correlations were used as a
nonparametric method accounting for the skewed distribution
of this variable. Stepwise multiple linear regression models were
then fit with the log of PAI-1 as the dependent variable. Log of
PAI-1 was used because the distribution of the residuals from the
fitted models became normally distributed after the log transformation.
Age, gender, ethnicity, and clinic were forced into the model and BMI,
triglyceride, insulin sensitivity, fasting glucose and LDL
size entered as independent variables (Tables 3 and 4).
Furthermore, we fit stepwise models including fasting insulin or HDL
cholesterol as independent variables in addition to
BMI, triglyceride, insulin sensitivity, fasting glucose,
and LDL size. Finally, the same models were used for analysis
by glucose tolerance status for subjects with NGT (Table 4A),
IGT (Table 4B), and type-2 diabetes (Table 4C).
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Results |
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In the overall population, LDL size was significantly inversely related to PAI-1 levels (r=-0.21, P<0.0001). The relation of PAI-1 to LDL size was significantly associated with glucose tolerance status (P=0.035 for interaction). The relation of PAI-1 and LDL size to various variables included in the insulin resistance syndrome are shown in Table 1
stratified by glucose
tolerance status. Compared with LDL size, the association of PAI-1 was
somewhat stronger with measures of body fat (BMI), body fat
distribution (WHR, waist circumference), and fasting glucose, fasting
insulin as well as insulin sensitivity, but equally strong with respect
to serum lipids (triglyceride, total
cholesterol, HDL-cholesterol,
LDL-cholesterol) (Table 1). No significant
interaction of ethnicity or gender on the relation of PAI-1 to LDL size
could be detected (Table 2A and 2B).
Multivariate analysis for log PAI-1 as a
dependent variable showed that LDL size was related to serum PAI-1
levels in the overall population and, if analyzed by glucose
tolerance status, in subjects with normal glucose tolerance (Tables 3 and 4A). Regression models shown on Tables 3 and 4 include as independent variables demographic variables
(age, gender, ethnicity, clinic) and metabolic
variables known to be closely associated with PAI-1 levels (BMI,
triglyceride, insulin sensitivity, fasting glucose). When
fasting insulin was additionally entered, R2 increased to
37.3% for the overall population and, by glucose tolerance status, to
39.6%, 34.8%, and 26.2% for subjects with NGT, IGT, and type-2
diabetes, respectively. In the latter models, fasting insulin was
significantly associated to log of PAI-1 in NGT (P=0.0001),
IGT (P=0.01), and type-2 diabetes (P=0.0002).
Entering HDL cholesterol into the model in addition to the
independent variables shown on Tables 3 and 4 (BMI,
triglyceride, fasting glucose, insulin sensitivity, and LDL
size) resulted in an R2 of 35.9% in the overall
population. HDL was significantly related to log of PAI-1
(P=0.0008) as were BMI, triglyceride, fasting
glucose, and insulin sensitivity (P=0.0001, respectively),
whereas the relation of LDL size to log of PAI-1 was weakened
(P=0.11). In NGT, however, LDL size was still significantly
related to log of PAI-1 in this regression model including HDL
cholesterol (P=0.023 in a stepwise model and
P=0.049 if HDL cholesterol was forced into the
model). |
Discussion |
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In this study, we showed an independent inverse relation of LDL size to serum PAI-1 levels, consistently among women and men and across all 3 ethnic groups studied. This relation was associated with the glucose tolerance status.
Both high levels of PAI-1 and small LDL particle size have been associated with cardiovascular disease3 4 5 11 12 13 14 15 16 17 as well as components of the insulin resistance syndrome.3 4 5 6 7 8 9 10 18 19 20 21 22 Consequently, both variables have been discussed as possible links between insulin resistance and cardiovascular disease.22 48 In one prospective study, the presence of small dense LDL particles was related to an increased risk of ischemic heart disease, independently of BMI, systolic blood pressure, diabetes, and plasma lipids, such as LDL, HDL, triglyceride, and apolipoprotein B.5 However, no data on PAI-1 antigen levels and/or activity has been reported from this study yet. Two other prospective case-control studies verified that decreased LDL size is a predictor of coronary heart disease in middle-aged subjects.49 50
Clinical and epidemiological studies addressing the relation of PAI-1 to LDL size are scarce. In 150 nondiabetic, middle-aged men, ApoB concentration in dense LDL particles, corresponding to the number of circulating dense LDL particles, was associated to PAI-1 activity.23 As in the present study, the association was independent of plasma triglyceride, fasting insulin, and BMI.23 In addition, we demonstrated that this relation was independent of insulin resistance, at least in subjects with NGT.
Sound experimental evidence links lipidemia and hypofibrinolyis, as defined by increased PAI-1 levels. VLDL induced PAI-1 expression in endothelial cells,24 25 and, in a concentration range comparable with that found in normotriglyceridemic subjects, also in HepG2 cells, a hepatoma cell line comparable with human hepatocytes.30 Native LDL stimulated PAI-1 release from endothelial cells in one study,27 but failed to do so in 2 others.29 51 By contrast, chemically modified LDL, such as acetylated27 and oxidized LDL28 29 showed a clear-cut and dose-dependent stimulation of PAI-1 release from endothelial cells. More recently, triglyceride and free fatty acids stimulated PAI-1 expression in adipocytes.31 Oxidized LDL, in contrast to native LDL52 are cytotoxic and exert various interactions with endothelial cells,53 54 eventually leading to the initiation and/or progression of atherosclerosis.55 Modification of LDL, namely LDL-oxidation, is therefore considered a crucial, initial step in atherogenesis.56 57 Small, dense LDL particles are particularly susceptible to oxidation, and this enhanced susceptibility has been proposed as a possible explanation for the association of LDL particle size to atherogenesis.32 33 34
Summarizing the available experimental and clinical data, it is conceivable that a preponderance of small, dense LDL leads to enhanced PAI-1 expression, presumably via enhanced LDL oxidation. However, because the relation of LDL size to PAI-1 levels was relatively weak statistically in the present study, and specific in vitro data on small dense LDL are still scarce, the biologic significance of our findings remain speculative.
Of further interest is the origin of the enhanced PAI-1 expression. PAI-1 expression has been demonstrated in different cell types, such as endothelial cells, smooth muscle cells, liver cells, and, most recently, adipocytes.58 The independence of the association of PAI-1 and LDL particle size of measures of body fat,23 confirmed by the present study, points to tissues other than adipose tissue, ie, the endothelium, as a possible source of LDL-induced PAI-1 release. Although there is evidence that lipid peroxidation may also occur in the circulation,59 60 the endothelium is the primary and, in terms of atherogenesis, crucial site of LDL oxidation and accumulation.55
We found a significant interaction of glucose tolerance status on the relation of LDL particle size and PAI-1 levels. LDL size was statistically independently associated with PAI-1 levels only in subjects with NGT, but not in subjects with IGT or overt type-2 diabetes. Furthermore, we demonstrated a strong relation of variables included in the IRS to PAI-1 levels that was most pronounced in subjects with NGT. Impaired glucose tolerance and type-2 diabetes may represent states of increased insulin resistance. Therefore, because of the different distribution of SI among the different glucose tolerance categories, the association of SI to PAI-1 levels and other variables of the IRS may be altered, ie, weakened, in IGT and diabetes. In subjects with NGT, BMI, SI, triglyceride, fasting glucose, and fasting insulin were significantly related to PAI-1 levels, as opposed to BMI, fasting glucose and fasting insulin in IGT and BMI, fasting glucose, fasting insulin, and triglyceride in type-2 diabetes. These findings prompt us to speculate that in subjects with IGT and more importantly in type-2 diabetes, factors directly associated with chronic hyperglycemia, in addition to other IRS-associated variables, may have an effect on PAI-1 levels. The infusion of insulin alone failed to increase circulating PAI-1 levels,61 62 further stressing the concept of a combined effect of IRS variables on PAI-1 release. Accordingly, it has been shown recently in healthy subjects that the combined induction of hyperglycemia, hyperinsulinemia, and hypertriglyceridemia increased circulating PAI-1 levels, in contrast to hyperinsulinemia alone.63 A potentiating effect of various IRS-associated components (fatty acids and insulin) on PAI-1 expression has also been shown in vitro.64
In summary, we have shown a strong correlation of 2 potentially atherogenic factors, PAI-1 level, and LDL particle size, previously shown to be closely associated with clinically significant vascular disease as well as the IRS. The demonstrated relation was independent of the individual components of the IRS in the presence of normal glucose tolerance.
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Acknowledgments |
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This work was supported by the National Heart, Lung and Blood Institute (grants HL47887, HL47889, HL47890, HL47892, HL47902, and HL55208) and the General Clinic Research Centers Program (grants NCRR GCRC, M01 RR431 and M01 RR01346).
Received June 15, 1998; accepted August 18, 1998.
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