Increased formation of distinct F2 isoprostanes in hypercholesterolemia

Abstract

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 iPF(2α)-III and iPF(2α)-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. iPF(2α)-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 iPF(2α)-VI (281±22 versus 175±13; P<0.0005). Serum cholesterol correlated with urinary iPF(2α)-III (r=0.41; P<0.02) and iPF(2α)-VI (r=0.39; P<0.03) in HFH patients. Urinary excretion of iPF(2α)-III (81±10 versus 59±4; P<0.05) and iPF(2α)-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 iPF(2α)-III and iPF(2α)-VI was correlated (r=0.57; P<0.0001; n= 106). LDL iPF(2α)-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.