(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
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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