Oxidative structural modifications of low density lipoprotein in homozygous familial hypercholesterolemia

Napoli, Claudio; Postiglione, Alfredo; Triggiani, Massimo; Corso, Gaetano; Palumbo, Giuseppe; Carbone, Virginia; Ruocco, Antonio; Ambrosio, Giuseppe; Montefusco, S; Malorni, Antonio; Condorelli, M; Chiariello, Massimo

doi:10.1016/0021-9150(95)05612-2

Cited by 56 publications

(55 citation statements)

References 50 publications

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“…To investigate the correlation of fetal cholesterol levels with maternal cholesterol levels and fetal age, only data from fetal blood samples obtained before death were used. Lipoperoxide levels in EDTA-containing plasma were evaluated spectrophotometrically using the LPO kit (Kamiya Biomedical Company, Thousand Oaks, CA) as previously described (31,32).…”

Section: Methodsmentioning

confidence: 99%

“…Because hypercholesterolemia is a well-recognized risk factor of atherogenesis and because it enhances LDL oxidation in humans (30)(31)(32), we used fetal aortas from hypercholesterolemic mothers and mothers with temporary hypercholesterolemia during pregnancy in addition to normocholesterolemic mothers. In doing so, this study also provides the first systematic morphometric assessment of fatty streak development in fetal aortas, and yields information on the role of maternal and fetal hypercholesterolemia in fetal fatty streak formation.…”

Section: Introductionmentioning

confidence: 99%

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Fatty streak formation occurs in human fetal aortas and is greatly enhanced by maternal hypercholesterolemia. Intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atherosclerotic lesions.

Napoli¹,

D’Armiento²,

Mancini³

et al. 1997

J. Clin. Invest.

864

584

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To determine whether oxidized LDL enhances atherogenesis by promoting monocyte recruitment into the vascular intima, we investigated whether LDL accumulation and oxidation precede intimal accumulation of monocytes in human fetal aortas (from spontaneous abortions and premature newborns who died within 12 h; fetal age 6.2 Ϯ 1.3 mo). For this purpose, a systematic assessment of fatty streak formation was carried out in fetal aortas from normocholesterolemic mothers ( n ϭ 22), hypercholesterolemic mothers ( n ϭ 33), and mothers who were hypercholesterolemic only during pregnancy ( n ϭ 27). Fetal plasma cholesterol levels showed a strong inverse correlation with fetal age ( R ϭ Ϫ 0.88, P Ͻ 0.0001). In fetuses younger than 6 mo, fetal plasma cholesterol levels correlated with maternal ones ( R ϭ 0.86, P ϭ 0.001), whereas in older fetuses no such correlation existed. Fetal aortas from hypercholesterolemic mothers and mothers with temporary hypercholesterolemia contained significantly more and larger lesions (758,651 Ϯ 87,449 and 451,255 Ϯ 37,448 m 2 per section, respectively; mean Ϯ SD) than aortas from normocholesterolemic mothers (61,862 Ϯ 9,555 m 2 ; P Ͻ 0.00005). Serial sections of the arch, thoracic, and abdominal aortas were immunostained for recognized markers of atherosclerosis: macrophages, apo B, and two different oxidation-specific epitopes (malondialdehyde-and 4-hydroxynonenal-lysine). Of the atherogenic sites that showed positive immunostaining for at least one of these markers, 58.6% were established lesions containing both macrophage/foam cells and oxidized LDL (OxLDL). 17.3% of all sites contained only native LDL, and 13.3% contained only OxLDL without monocyte/ macrophages. In contrast, only 4.3% of sites contained isolated monocytes in the absence of native or oxidized LDL. In addition, 6.3% of sites contained LDL and macrophages but few oxidation-specific epitopes. These results demonstrate that LDL oxidation and formation of fatty streaks occurs already during fetal development, and that both phenomena are greatly enhanced by maternal hypercholesterolemia. The fact that in very early lesions LDL and Ox-LDL are frequently found in the absence of monocyte/macrophages, whereas the opposite is rare, suggests that intimal LDL accumulation and oxidation contributes to monocyte recruitment in vivo. ( J. Clin. Invest. 1997. 100:2680-2690.)

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Fatty streak formation occurs in human fetal aortas and is greatly enhanced by maternal hypercholesterolemia. Intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atherosclerotic lesions.

Napoli¹,

D’Armiento²,

Mancini³

et al. 1997

J. Clin. Invest.

864

584

View full text Add to dashboard Cite

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“…13 Plasma malondialdehyde (MDA) content was measured as thiobarbituric acid reactive substances. 14 In maternal plasma, these parameters were measured at the 2nd and 3rd week of pregnancy; in their offspring, plasma and aortic measurements were performed at euthanasia.…”

Section: Peroxidative End-productsmentioning

confidence: 99%

Maternal Hypercholesterolemia and Treatment During Pregnancy Influence the Long-Term Progression of Atherosclerosis in Offspring of Rabbits

Palinski

D’Armiento

Witztum

et al. 2001

Circulation Research

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137

116

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Abstract-Maternal hypercholesterolemia during pregnancy is associated with enhanced fatty streak formation in human fetuses and faster progression of atherosclerosis during childhood even under normocholesterolemic conditions. A causal role of maternal hypercholesterolemia in lesion formation during fetal development has previously been established in rabbits. The same experimental model is now used to establish that maternal hypercholesterolemia or ensuing pathogenic events in fetal arteries enhance atherogenesis later in life. Five groups of rabbit mothers were fed chow, cholesterol-enriched chow, or cholesterol-enriched chow plus 1000 IU vitamin E, 3% cholestyramine, or both during pregnancy. Offspring of all groups (nϭ136) were fed a mildly hypercholesterolemic diet for up to a year and had similar cholesterol levels. Aortic lesion sizes and lipid peroxidation products in plasma and lesions in offspring were determined at birth, 6 months, or 12 months. Lesion progression in offspring of hypercholesterolemic mothers was greater than in all other groups. At each time point, offspring of hypercholesterolemic mothers had 1.5-to 3-fold larger lesions than offspring of normocholesterolemic mothers (PϽ0.01), with the greatest absolute differences at 12 months. Maternal treatment reduced lesions by 19% to 53%, compared with offspring of untreated hypercholesterolemic mothers (PϽ0.01), with the greatest effect in the vitamin E groups. At 12 months, lesions in offspring of all vitamin E and cholestyramine-treated mothers were similar to those of normocholesterolemic mothers. Lipid peroxidation end-products in lesions and plasma showed analogous differences between groups as lesions (PϽ0.01). Thus, pathogenic programming in utero increases the susceptibility to atherogenic risk factors later in life and maternal intervention with cholesterol-lowering drugs or antioxidants reduce postnatal lipid peroxidation and atherosclerosis in their offspring.

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“…Plasma oxidation was assessed spectrophotometrically by measurements of LDL lag time (propensity of LDL for oxidation) and plasma levels of the endogenous antioxidant vitamins E (␣-tocopherol) and C (ascorbic acid) by high-performance liquid chromatography, as previously described. 18,19 Renal tissue activities of the oxygen radical scavengers catalase, glutathione peroxidase, copper-zinc (CuZn) superoxide dismutase (SOD), and manganese SOD (Mn-SOD) were determined spectrophotometrically and normalized for protein content by the Lowry method, as previously described. 19,20 …”

Section: Methodsmentioning

confidence: 99%

Combination of Hypercholesterolemia and Hypertension Augments Renal Function Abnormalities

et al. 2001

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Abstract-Hypercholesterolemia and hypertension are both risk factors for end-stage renal disease. This study was designed to examine whether their coexistence augmented impairment in renal function and redox status. Regional renal hemodynamics and function in response to vasoactive challenges with acetylcholine or sodium nitroprusside were quantified by using electron-beam computed tomography in pigs after 12 weeks of either a normal (nϭ10) or hypercholesterolemic (nϭ10) diet, renovascular hypertension (nϭ7), or combined hypercholesterolemiaϩhypertension (nϭ6). The hypercholesterolemic and hypercholesterolemicϩhypertensive groups had significantly increased serum cholesterol levels, whereas in the hypertensive and hypercholesterolemicϩhypertensive groups, mean arterial pressure was significantly elevated compared with the group fed a normal diet. Basal regional renal perfusion and glomerular filtration rates were similar among the groups. In response to acetylcholine, cortical perfusion increased in normal animals (15.6Ϯ4.7%, Pϭ0.002) but not in hypercholesterolemic or hypertensive animals (8.0Ϯ7.4% and 8.2Ϯ5.9%, respectively; PϾ0.05). Moreover, in the hypercholesterolemicϩhypertensive group, cortical perfusion response was further attenuated (2.5Ϯ4.8%, Pϭ0.02) and significantly different from the group fed a normal diet (PϽ0.05). The response to sodium nitroprusside followed a similar pattern, and the impairment was augmented in the hypercholesterolemicϩhypertensive group. The functional abnormalities in hypercholesterolemia or hypertension were associated with a decrease in systemic and/or renal tissue levels of oxygen radical scavengers that was again accentuated in hypercholesterolemiaϩhypertension. These results demonstrate that concurrent hypercholesterolemia and hypertension have a greater detrimental effect on renal perfusion responses compared with hypercholesterolemia or hypertension alone, associated with a marked pro-oxidant shift in redox status. These effects may potentially augment renal functional impairment and play a role in the initiation and progression of renal injury in hypertension and atherosclerosis. Clinical studies have shown that the coexistence of dyslipidemia and HT greatly increases the incidence of cardiovascular morbidity and mortality 4 and likely modulates the deterioration of renal function as well. 5 Indeed, both antihypertensive and lipid-lowering therapies can halt the progression of renovascular disease and contribute to the preservation of renal function. 6 The onset of renal injury is detectable after a relatively short exposure to cardiovascular risk factors, inasmuch as experimental HC and HT have each been linked to alterations of vascular and tubular function. We have previously shown that experimental HC was associated with alterations in the renal vascular response to challenge both in vivo 7 and in vitro 8 and abnormal tubular dynamics in vivo. 7 Similarly, HT has been shown to induce abnormalities of renal vascular 9 and tubular 10 function. One of the mechanisms...

show abstract

Oxidative structural modifications of low density lipoprotein in homozygous familial hypercholesterolemia

Cited by 56 publications

References 50 publications

Fatty streak formation occurs in human fetal aortas and is greatly enhanced by maternal hypercholesterolemia. Intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atherosclerotic lesions.

Fatty streak formation occurs in human fetal aortas and is greatly enhanced by maternal hypercholesterolemia. Intimal accumulation of low density lipoprotein and its oxidation precede monocyte recruitment into early atherosclerotic lesions.

Maternal Hypercholesterolemia and Treatment During Pregnancy Influence the Long-Term Progression of Atherosclerosis in Offspring of Rabbits

Combination of Hypercholesterolemia and Hypertension Augments Renal Function Abnormalities

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