(Circulation. 1998;98:2822-2828.)
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports* |
Increased Formation of Distinct F2 Isoprostanes in Hypercholesterolemia
Presented in part at the 69th Scientific Sessions of the American Heart Association, New Orleans, La, November 10–13, 1996, and at the Winter Prostaglandin Meeting, Keystone, Colo, January 26–31, 1997, and published in abstract form (Circulation. 1997;96:I-2332).
From the Center for Experimental Therapeutics (M.P.R., D.P., N.D., J.L., G.A.F.), Clinical Research Center (S.K.), and Lipid Center (D.R.), University of Pennsylvania, Philadelphia, Pa; Department of Clinical and Experimental Medicine, University of Naples (G.D.), Naples, Italy; Enrica Grossi Paoletti Lipid Clinic, Institute of Pharmacological Sciences, University of Milan (E.T.), Milan, Italy; and Florida Institute of Technology (J.R.), Claude Pepper Institute for Aging & Therapeutic Research, Melbourne, Fla.
Correspondence to Dr G.A. FitzGerald, Center for Experimental Therapeutics, 905 Stellar-Chance Laboratories, University of Pennsylvania School of Medicine, Philadelphia, PA 19104-6100. E-mail garret{at}spirit.gcrc.upenn.edu
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Abstract |
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Background—F2 isoprostanes are stable, free radical–catalyzed products of arachidonic acid that reflect lipid peroxidation in vivo.
Methods and Results—Specific assays were developed by use of mass
spectrometry for the F2 isoprostanes
iPF2
-III and iPF2-VI and
arachidonic acid (AA). Urinary excretion of the 2
F2 isoprostanes was significantly increased in
hypercholesterolemic patients, whereas substrate AA in
urine did not differ between the groups. iPF2-III
(pmol/mmol creatinine) was elevated
(P<0.0005) in homozygous familial
hypercholesterolemic (HFH) patients (85±5.5; n=38)
compared with age- and sex-matched normocholesterolemic
control subjects (58±4.2; n=38), as were levels of
iPF2-VI (281±22 versus 175±13;
P<0.0005). Serum cholesterol correlated
with urinary iPF2-III (r=0.41;
P<0.02) and iPF2-VI
(r=0.39; P<0.03) in HFH patients.
Urinary excretion of iPF2-III (81±10 versus 59±4;
P<0.05) and iPF2-VI (195±18 versus
149±20; P<0.05) was also increased in moderately
hypercholesterolemic subjects (n=24) compared with
their controls. Urinary excretion of iPF2-III and
iPF2-VI was correlated (r=0.57;
P<0.0001; n=106). LDL iPF2-III levels
(ng/mg arachidonate) were elevated (P<0.01)
in HFH patients (0.32±0.08) compared with controls (0.09±0.02). The
concentrations of iPF2-III in LDL and urine were
significantly correlated (r=0.42;
P<0.05) in HFH patients.
Conclusions—Asymptomatic patients with moderate and severe hypercholesterolemia have evidence of oxidant stress in vivo.
Key Words: eicosanoids • cholesterol • atherosclerosis
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Introduction |
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Oxidation of LDL is thought to play a critical role in atherogenesis.1 2 However, evaluation of antioxidants in cardiovascular disease has yielded conflicting results.3 4 5 6 7 8 Insight into the role of excessive free radical generation in human disease has been constrained by the limitations of current indexes of oxidant stress in vivo.9 10
Isoprostanes are chemically stable, free radical–catalyzed
products of arachidonic acid (AA) that are
structural isomers of conventional
prostaglandins11 12 for which a novel
nomenclature13 has recently been proposed (Figure 1
). We have recently immunolocalized 1 of
these compounds, iPF2-III (formerly known as
8-iso-PGF2), to
monocyte/macrophages and vascular smooth muscle cells in human
atherosclerotic plaque.14 Furthermore, we and
others15 16 17 have demonstrated that this compound is
formed in LDL when it is oxidized in vitro. Given that isoeicosanoids
are formed initially in situ in membrane phospholipid and are then
susceptible to phospholipase-dependent cleavage, circulation, and
excretion in urine,18 we wished to investigate their
formation as indexes of oxidant stress in human
hypercholesterolemia and
atherosclerosis.
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Methods |
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Clinical Studies
Volunteers and patients were enrolled at the hospitals of the University of Pennsylvania, the Children's Hospital of Philadelphia, the University of Naples, and the University of Milan.
Three studies were performed. In the first, urinary isoprostane
excretion was measured in 38 subjects (24 males and 14 females aged 3
to 43 years;) with homozygous familial
hypercholesterolemia (HFH), defined as patients
with childhood cutaneous or tendonous xanthomata, fasting total
cholesterol levels of >500 mg/dL, and normal
triglyceride levels (<200 mg/dL) (Table 1). These patients were enrolled
prospectively in a consecutive manner as they were admitted to the
clinical research centers of the respective hospitals over a 1-year
period. None of the subjects were cigarette smokers. Six patients gave
a history of antioxidant consumption. None were diabetic or
hypertensive, and most were white (2 blacks and 1 Asian). Patients who
were receiving plasmapheresis had not undergone this treatment for 
1
week before assessment. All patients underwent a history and physical
examination and were admitted to the clinical research center for a
48-hour period. Overnight 12-hour urine samples were collected before
fasting blood samples were taken for the assessment of lipoproteins,
and coronary angiography was performed. An age-, sex-,
smoking-, and center-matched sample of subjects (aged 3 to 54 years; 24
males and 14 females) was used as a control group (n=38). They
underwent similar collections and fasting lipoprotein assessment.
Urinary arachidonate was measured in a subset of HFH
patients (aged 4 to 43 years; 6 males and 6 females) and matched
control subjects (aged 5 to 43 years; 6 males and 6 females).
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In a second study, we measured iPF2-III
corrected for LDL protein in unstimulated LDL from a sample of HFH
subjects (aged 5 to 54 years; 10 males and 6 females) and matched
control subjects (aged 11 to 54 years; 10 males and 6 females). Blood
samples were drawn for LDL isolation on the same day as the urine
collection and lipoprotein determination described above. Given the
possible differences in substrate concentrations between the groups, we
also corrected LDL iPF2-III values for
cholesterol and for AA in a subgroup of these HFH subjects
(aged 20 to 54 years; 5 men and 2 women) and control subjects
(aged 28 to 54 years; 5 men and 2 women).
The third study involved recruitment of a group of adults
presenting consecutively at lipid clinics over a 2-week period with
moderate hypercholesterolemia (HC; patients
with fasting total cholesterol levels >240 mg/dL; n=24)
and an age-, sex-, and smoking-matched group of
normocholesterolemic controls (n=24) (Table 2). All patients were on lipid-lowering
diets. There were 4 smokers each in the HC and control groups. No
patient gave a history of antioxidant consumption. None of the patients
were hypertensive or diabetic, and all were white. Twelve-hour urine
samples were collected for the determination of urinary
F2 isoprostanes, and fasting blood samples were
drawn during this period for lipoprotein assessment.
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Isoprostane and AA Analysis
Urinary isoprostanes were measured as previously
described.19 20 Urinary levels of AA were also measured by
gas chromatography/mass spectrometry. Briefly,
after addition of
[2H8]-AA to urine, the pH
was lowered to <3.0, and the sample was extracted twice before
derivatization with pentafluorobenzyl bromide. The sample was then
subjected to thin-layer chromatography and
analyzed by gas chromatography/mass
spectrometry, monitoring ions at m/z 303 and 311 for 50 ms each.
The retention time of AA is 
6 minutes. Total AA levels (after
hydrolysis with 15% aqueous KOH solution) in LDL were assayed by use
of a similar approach.
LDL for iPF2-III and AA determination was
prepared as follows. After an overnight fast, blood from HFH subjects
(n=16) and healthy, normolipemic volunteers (n=16) was collected, and
LDL was prepared by sequential density gradient
ultracentrifugation by use of a previously described
method that minimizes oxidation.21 Antioxidants were not
included. LDL protein concentration was determined by the Lowry
method.22 LDL cholesterol levels were measured
by a colorimetric assay that is certified by the
Centers for Disease Control and Prevention (Sigma Chemical
Co).
Statistical Analysis
Data are expressed as mean±SEM. Data from HFH and HC groups
were compared with their respective controls by initial ANOVA and by
2-tailed, unpaired t tests for continuous variables and
the Fisher exact test for categorical data, as appropriate. Grouped
data were initially analyzed for covariance of slopes
before calculation of pooled correlation coefficients if
appropriate.
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Results |
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Pertinent clinical characteristics and lipid profiles of patients with both HFH and HC are described in Tables 1
and 2.
Urinary iPF2-III (pmol/mmol
creatinine) was elevated in patients with HFH (85±5.5;
P<0.0005) compared with age- and sex-matched
normocholesterolemic controls (58±4.2) (Table 3). Serum cholesterol levels
were 548±30 and 180±8.0 mg/dL in the HFH and control groups,
respectively (P<0.0001). There was a significant
correlation (r=0.41; P<0.02) between urinary
iPF2-III excretion and serum
cholesterol for HFH patients but not for control subjects
(Figure 2A). Urinary levels (pmol/mmol
creatinine) of iPF2-VI were also
elevated in HFH patients (281±22; P<0.0001) compared with
controls (175±13) (Table 3). Similarly, urinary excretion of
iPF2-VI correlated (r=0.39;
P<0.03) with serum cholesterol levels in the
HFH patients but not among controls (Figure 2B). There was no
difference (P=NS) in urinary AA (nmol/mmol
creatinine) between HFH (2.04±0.69; n=12) and control
(2.5±0.66; n=12) subjects. Adjustment of
iPF2-VI excretion (487±71 versus 248±56
pmol/nmol arachidonate; P<0.05) for AA levels
in urine maintained the distinction previously observed between the
groups.
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In addition to the changes observed in urinary F2
isoprostanes, the levels (mean±SEM ng/mg protein) of
iPF2-III esterified in the LDL sampled from
HFH subjects (n=16) were significantly higher (1.09±0.08) than in
control subjects (0.40±0.03; n=16; P<0.0001) (Table 4). Notably,
iPF2-III levels in LDL and urine were
correlated in HFH patients (r=0.42; P<0.03) and
among controls (r=0.44; P<0.01) (Figure 3). Furthermore,
iPF2-III levels were elevated in HFH subjects
(n=7) compared with controls (n=7) when corrected for LDL
cholesterol (0.68±0.17 versus 0.25±0.04 ng/mg
cholesterol; P<0.05) or LDL AA (0.32±0.08
versus 0.09±0.02 ng/mg arachidonate; P<0.01)
(Table 4). Total (free and phospholipid-bound) LDL levels (ng/mg
protein) of AA were similar (P=NS) in HFH patients
(4.36±0.51) and in control subjects (4.76±0.53) (Table 4).
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There was no significant relationship between urinary
F2 isoprostane excretion and age, sex, or a
history of the use of lipid-lowering agents in HFH patients. Similarly,
a history of aspirin use (n=28/38) was not associated with lower levels
of urinary iPF2-III (86±6.4 versus
79±11; P=NS) or iPF2-VI (279±27
versus 285±38; P=NS). There were no significant differences
in urinary levels of either iPF2-III (95±19.3
versus 77±9.2) or iPF2-VI (295±32 versus
283±38) in the 6 patients who gave a history of antioxidant use in
HFH. Neither serum cholesterol nor urinary isoprostane
levels were significantly different between HFH patients with and
without angiographic evidence of coronary disease.
Urinary levels of iPF2-III (81±10 versus
59±4; P<0.05) and iPF2-VI
(195±18 versus 149±20; P<0.05) were also elevated in
patients with moderate hypercholesterolemia
compared with age- and sex-matched controls (Table 5). Serum cholesterol levels
correlated with urinary iPF2-III
(r=0.42; P<0.03) in HC patients but not in
controls.
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ANCOVA failed to identify a significant difference in the slopes
relating urinary levels of the 2 isoprostanes among the groups.
Therefore, correlation between these variables is reported for
patients and controls. Urinary excretion of
iPF2-III and iPF2-VI
was significantly correlated (0.57; P<0.0001) for all
hypercholesterolemic patients and control subjects
(Figure 4). A similar relationship was
seen within individual study groups for HFH (r=0.62;
P<0.0001; n=38), HC (r=0.59;
P<0.005; n=24), and control subjects (r=0.53;
P<0.0005; n=44).
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Discussion |
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Isoeicosanoids are formed by direct free radical attack on AA, a natural constituent of the phospholipid domain of cell membranes. Unlike the conventional enzymatic products of this fatty acid (the eicosanoids), these isomers are formed initially in situ in cell membranes, from which they are cleaved by phospholipases.18 These properties have raised the possibility of their use as markers of free radical generation that can be measured both at the cellular site of oxidant stress and in biological fluids, such as plasma and urine.23 24
In the present study, we applied specific assays, using mass
spectrometry, for 2 structurally distinct isomers of
F2 isoprostanes,
iPF2-III and iPF2-VI.
We favored urine as a target matrix over plasma; it may be obtained
noninvasively, and given the minor amount of AA substrate present
in urine compared with plasma, it is likely to be less susceptible to
isoprostane formation ex vivo. Our prior experience using both plasma
and urine to estimate eicosanoid biosynthesis suggests that
qualitatively distinct information is unlikely to be provided by a
plasma-based assay.25 26
Initially, we focused on iPF2-III. This
compound is a vasoconstrictor and a mitogen and may modulate
platelet function in vitro.27 28 However, the
relevance of these properties to its role in vivo remains unclear.
Urinary iPF2-III is elevated in several
syndromes putatively associated with oxidant stress, including
cigarette smoking29 and vascular
reperfusion.17 30 Controlled evaluation indicates that it
is suppressed by antioxidant vitamins.29 31 32 The
concentration of iPF2-III is elevated in human
atherectomy specimens compared with levels in normal
arterial segments, and we have immunolocalized the compound
to monocyte/macrophages and vascular smooth muscle cells in
such tissue.14 Given these observations, we wished to
address the hypothesis that formation of
iPF2-III, as reflected by its urinary
excretion, might be elevated in hyperlipidemia.
Urinary levels were increased in young patients with HFH compared
with age- and sex-matched controls. There was no difference in urinary
arachidonate between the 2 groups, which indicates that
this was not merely a difference in substrate availability. We have
also demonstrated that F2 isoprostanes are not
generated by auto-oxidation of lipid ex vivo when urine is stored under
the conditions described in the present study.19
Participants in the present study were not placed on controlled
diets. Thus, the precise role of dietary lipids in isoprostane
generation remains to be addressed definitively. The magnitude of the
increment in iPF2-III excretion over control
values in these patients, all of whom were nonsmokers, was similar to
that observed in apparently healthy individuals who were moderate (>15
cigarettes/d) cigarette smokers.29 Given the potentially
distinct mechanisms that might result in free radical generation in
smokers,33 one might anticipate an even greater increment
in dyslipidemic individuals who smoke cigarettes.
We extended the study to address this hypothesis in a sample of
patients with a more common form of dyslipidemia. Excretion
of iPF2-III was also elevated, although to a
lesser extent, in HC patients compared with a control group. It is
noteworthy that the HFH and HC groups in these studies were distinct
from each other, not only in terms of cholesterol levels
but also by virtue of age, gender distribution, cigarette smoking, and
presence of coronary disease. Thus, the relatively small
differences in urinary F2 isoprostanes between
the groups, despite major differences in serum cholesterol
levels, may reflect the confounding influence of variables such as
age, diet, or smoking. Although a history of supplementary intake of a
variety of antioxidant drugs and doses did not detectably influence the
levels of urinary F2 isoprostanes, such a history
was not assessed in a controlled manner in the present study. By
contrast, we have previously shown that antioxidants do suppress
elevated isoprostanes both in vitro and in
vivo.19 29 31 32 34 The quantitative relationship between
isoprostane generation and variables such as the extent of
coronary disease, age, sex, ethnicity, nutritional status, and
drug consumption in hypercholesterolemic patients
requires larger studies designed and controlled specifically to address
these issues. Interestingly, despite the lack of control for diet and
medications and the small sample sizes, urinary excretion of
iPF2-III exhibited a weak but statistically
significant correlation with fasting serum cholesterol in
both groups of hypercholesterolemic patients, albeit
not in controls, further facilitating its applicability to the
detection of oxidant stress in large samples.
In the present study, iPF2-III,
esterified in LDL, was elevated in a subset of the homozygotes compared
with matched controls. This was true whether
iPF2-III levels were corrected for LDL protein
or cholesterol, which suggests that elevated levels are not
dependent on differences in LDL cholesterol. More
importantly, HFH LDL iPF2-III levels remained
elevated compared with controls when corrected for LDL AA. Although it
is unknown if circulating LDL might represent a source of
augmented urinary F2 isoprostanes in such
patients, the levels of iPF2-III in LDL and
urine were significantly correlated in the HFH patients.
Despite evidence consistent with the value of urinary
iPF2-III as an index of oxidant stress, a
potential caveat is its capacity for formation as a minor product
of both cyclooxygenase (COX)
enzymes.20 34 We have previously shown that COX-1 in
platelets exhibits the potential to form
iPF2-III but not other
F2 isoprostanes in this manner.20
Similarly, monocyte COX-2 may be a source of the
compound.34 It seems likely that these pathways contribute
trivially to actual generation of iPF2-III in
vivo, as reflected by its excretion in urine. Thus, we have reported
that treatment of cigarette smokers with aspirin, a nonspecific COX
inhibitor,35 will depress excretion of
thromboxane metabolites but not of
iPF2-III in urine.29 Aspirin and
indomethacin both fail to depress urinary
iPF2-III in healthy
volunteers.19
Despite these observations, it seemed prudent to develop methods
to measure another F2 isoprostane that was not
susceptible to enzymatic formation. iPF2-VI is
a member of a distinct class of F2
isoprostanes.36 37 It is not formed by COX, and its
excretion in volunteers is not suppressed by aspirin. Urinary levels of
iPF2-VI are higher than those of
iPF2-III.19
Urinary iPF2-VI was also increased in
both groups of dyslipidemic patients. Urinary levels of the
2 F2 isoprostanes were highly correlated. This
observation is consistent with the hypothesis that excretion of
both compounds in urine reflects formation by a common mechanism: free
radical–catalyzed generation of prostaglandin isomers.
Recently, we have observed a similar relationship in urinary levels of
patients undergoing coronary reperfusion.30 This
correlation and the absence of any relationship between aspirin use and
urinary levels of both F2 isoprostanes in HFH
patients argue against COX-dependent formation of
iPF2-III in vivo in HFH. Given that
immunoassays are currently available only for
iPF2-III,38 this observation is
relevant to clinical investigation. This is especially so because COX
activation may coincide with oxidant stress in clinical settings such
as ischemia-reperfusion syndromes39 and in
cigarette smoking.40 Recently, Davi et al41
reported that urinary levels of immunoreactive
iPF2-III are elevated in
hypercholesterolemia. Given that chemically
synthesized standards for most of the 64 F2
isoprostanes and none of their potential metabolites have been checked
for cross-reactivity with this material, our results not only extend
these observations but provide important support for their findings. We
demonstrate that authentic iPF2-III is
elevated in both moderate and severe
hypercholesterolemia. Furthermore, our data
indicate that this does not reflect auto-oxidation of increased amounts
of substrate ex vivo in the urine of
hypercholesterolemic patients but rather its increased
generation in vivo. Finally, the concomitant increase in urinary
iPF2-VI is consistent with formation
of iPF2-III by a free radical–dependent
pathway rather than as a product of COX turnover.
In summary, we report that urinary excretion of 2 F2 isoprostanes is elevated in patients with hypercholesterolemia. Attempts to establish the efficacy of aspirin through clinical trials in cardiovascular disease were frustrated for more than a decade because populations were diluted with respect to likely benefit from the drug.42 The development of methods to estimate thromboxane biosynthesis using urinary metabolites not only aided in the selection of low doses of aspirin for cardiovascular indications42 but also identified unstable angina43 and therapeutic thrombolysis44 as biochemically rational targets for aspirin therapy, a contention borne out by the results of randomized clinical trials.45 46 Clinical trials of antioxidants have been performed in the past without a clear in vivo biochemical rationale, either for the choice of clinical targets or for the selection of antioxidant doses of such compounds. Given their formation in LDL oxidized in vitro, their presence in human atherosclerotic plaque, and now their augmented formation in circulating LDL and in urine of patients with dyslipidemias, it is likely that measurement of F2 isoprostanes may prove useful in the exploration of the importance of oxidant stress and its modulation in human atherosclerotic disease.
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Acknowledgments |
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This work was supported by grants from the National Institutes of Health (HL-54500, MO1-RR 0040, and DK-44730); NSF for an AMX-360 NMR Instrument (CHE-901345) and the American Heart Association (Grant-in-Aid). Dr FitzGerald is the Robinette Foundation Professor of Cardiovascular Medicine.
Received July 31, 1998; revision received September 8, 1998; accepted September 25, 1998.
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J. A. Lawson, J. Rokach, and G. A. FitzGerald Isoprostanes: Formation, Analysis and Use As Indices of Lipid Peroxidation in Vivo J. Biol. Chem., August 27, 1999; 274(35): 24441 - 24444. [Full Text] [PDF]
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M. A. Forgione, N. Weiss, S. Heydrick, A. Cap, E. S. Klings, C. Bierl, R. T. Eberhardt, H. W. Farber, and J. Loscalzo Cellular glutathione peroxidase deficiency and endothelial dysfunction Am J Physiol Heart Circ Physiol, April 1, 2002; 282(4): H1255 - H1261. [Abstract] [Full Text] [PDF]
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