Increased formation of distinct F-2 isoprostanes in hypercholesterolemia

Background-F-2 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 spectrome try for the F-2 isoprostanes iPF(2 alpha)-III and iPF(2 alpha)-VI and arach idonic acid (AA). Urinary excretion of the 2 F-2 isoprostanes was significa ntly increased in hypercholesterolemic patients, whereas substrate AA in ur ine did not differ between the groups. iPF(2a)-III (pmol/mmol creatinine) w as elevated (P<0.0005) in homozygous familial hypercholesterolemic (HFH) pa tients (85+/-5.5; n=38) compared with age- and sex-matched normocholesterol emic control subjects (58+/-4.2; n=38), as were levels of iPF(2 alpha)-VI ( 281+/-22 versus 175+/-13; P<0.0005). Serum cholesterol correlated with urin ary iPF(2 alpha)-III (r=0.41; P<0.02) and iPF(2 alpha)-VI (r=0.39; P<0.03) in HFH patients. Urinary excretion of iPF(2 alpha)-III (81+/-10 versus 59+/ -4; P<0.05) and iPF(2 alpha)-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(2 alpha)-III and iPF(2 alpha)-VI w as correlated (r=0.57; P<0.0001; n=106). LDL iPF(2 alpha)-III levels (ng/mg arachidonate) were elevated (P<0.01) in HFH patients (0.32+/-0.08) compare d with controls (0.09+/-0.02). The concentrations of iPF(2)-III in LDL and urine were significantly correlated (r=0.42; P<0.05) in HFH patients. Conclusions-Asymptomatic patients with moderate and severe hypercholesterol emia have evidence of oxidant stress in vivo.