Lipoprotein immunogenetics and atherosclerosis

Rapacz, J.; Opitz, John M.

doi:10.1002/ajmg.1320010403

Cited by 47 publications

(24 citation statements)

References 84 publications

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“…The animals had been selected on the basis of apoB allotypes, 21 and those allotypes correlated with specific markers in apoB genomic DNA. by guest on May 10, 2018 http://atvb.ahajournals.org/ Downloaded from allele was responsible for the hypercholesterolemia of those pigs.…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein B and a second major gene locus contribute to phenotypic variation of spontaneous hypercholesterolemia in pigs.

Aiello

Nevin

Ebert

et al. 1994

Arterioscler Thromb

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The Lpb 5 apolipoprotein B (apoB) allele occurs in pigs with spontaneous hypercholesterolemia. Low-density lipoprotein (LDL) from these pigs binds to the LDL receptor with a lower affinity and is cleared from the circulation more slowly than control pig LDL. However, the severity of hypercholesterolemia in pigs with the mutant apoB allele is highly variable. This study aimed to determine the metabolic basis for the phenotypic heterogeneity among Lpb5 pigs. Lpb5 pigs were divided into two groups: those with plasma cholesterol greater than 180 mg/dL (Lpb5.1) and those with plasma cholesterol less than 180 mg/dL (Lpb5.2). LDL from both Lpb5.1 and Lpb5.2 pigs was catabolized in vivo and in vitro at a similarly reduced rate. The difference in plasma cholesterol between the two phenotypic groups was in part due to a higher buoyant LDL P opulation genetic studies have demonstrated that heredity contributes significantly to hyperlipidemia. In some instances, particular hyperlipidemic syndromes have been shown to be caused by single-gene mutations. However, the frequency of the known single-gene mutations is still far below the frequency of hyperlipidemia. The population studies therefore predict that multiple gene loci are involved and that in some instances there may be interactions between gene loci to produce a clinical syndrome.Apolipoprotein B (apoB) may be one such gene locus. ApoB is the primary protein component of low-density lipoprotein (LDL), which carries the bulk of cholesterol in human plasma, and is a ligand for the LDL receptor; thus, apoB functions in the assembly of the LDL particle and mediates its clearance from the blood. Given the central role of apoB in LDL metabolism, apoB mutations alone or in combination with other defects probably contribute significantly to hypercholesterolemia in the human population. One recently discovered apoB point mutation (Argjjoo->Gln) results in LDL particles with reduced LDL receptor binding activity and in some patients is associated with a reduced rate of LDL clearance from the plasma.1 This mutation is relatively common in the human population, Received July 19, 1993; revision accepted December 16, 1993. Hypercholesterolemia is also highly heritable in pigs. Rapacz et al 2 described a strain of pigs bearing an immunogenetically defined lipoprotein-associated marker, designated Lpb5, 3 and having marked hypercholesterolemia and premature atherosclerosis. The antiserum used to identify the Lpb5 pigs was shown to react only with apoB-100, 2 and the apoB gene from Lpb5 pigs has a unique 283-bp insertion at intron 28. 46In addition, Lpb5 pigs have LDL with defective binding to the LDL receptor 7 and delayed plasma clearance. 8These observations strongly suggest an association between apoB polymorphisms and hypercholesterolemia in pigs. However, pigs with the Lptr allele of apoB are phenotypically heterogeneous; the more severe phenotype (designated Lpb5.1) involves twofold to fourfold increases in plasma cholesterol, whereas a second phenotypic group (designa...

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Section: Discussionmentioning

confidence: 99%

Apolipoprotein B and a second major gene locus contribute to phenotypic variation of spontaneous hypercholesterolemia in pigs.

Aiello

Nevin

Ebert

et al. 1994

Arterioscler Thromb

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“…For more than three decades, the FH swine model has been developed by Drs. Rapacz and Hasler-Rapacz (8,18), for which they screened over 4,000 animals to find the original FH trait. Approximately 15 yr ago, the animals were bred for downsized characteristics to increase their manageability.…”

Section: Methodological Considerationsmentioning

confidence: 99%

Familial hypercholesterolemia impairs exercise-induced systemic vasodilation due to reduced NO bioavailability

Beer

Merkus

Bender

et al. 2013

Journal of Applied Physiology

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Hypercholesterolemia impairs endothelial function [e.g., the nitric oxide (NO)-cyclic GMP-phosphodiesterase 5 (PDE5) pathway], limits shear stress-induced vasodilation, and is therefore expected to reduce exercise-induced vasodilation. To assess the actual effects of hypercholesterolemia on endothelial function and exercise-induced vasodilation, we compared the effects of endothelial NO synthase (eNOS) and PDE5 inhibition in chronically instrumented Yucatan (Control) and Rapacz familial hypercholesterolemic (FH) swine, at rest and during treadmill exercise. The increases in systemic vascular conductance produced by ATP (relative to nitroprusside) and exercise were blunted in FH compared with Control swine. The vasoconstrictor response to eNOS inhibition, with nitro-l-arginine (NLA), was attenuated in FH compared with Control swine, both at rest and during exercise. Furthermore, whereas the vasodilator response to nitroprusside was enhanced slightly, the vasodilator response to PDE5 inhibition, with EMD360527, was reduced in FH compared with Control swine. Finally, in the pulmonary circulation, FH resulted in attenuated vasodilator responses to ATP, while maintaining the responses to both NLA and EMD360527. In conclusion, hypercholesterolemia reduces exercise-induced vasodilation in the systemic but not the pulmonary circulation. This reduction appears to be the principal result of a decrease in NO bioavailability, which is mitigated by a lower PDE5 activity.

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“…In contrast, anti-Lpb20 cross-reacted with each human serum exhibiting precipitation reaction of the partial immunological identity (Rapacz 1978;Rapacz et a1. None of the human sera exhibited reaction with anti-Lpbs, anti-Lpb10 or anti-Lpb101.…”

Section: Resultsmentioning

confidence: 97%

“…None of the human sera exhibited reaction with anti-Lpbs, anti-Lpb10 or anti-Lpb101. The common allotypes (Lpbll-Lpb18) are shared with other species, thus indicating the common ancestral origin preserved during the evolution of mammalian apoB (Rapacz 1978;Rapacz et aI. 1978).…”

Section: Resultsmentioning

confidence: 98%

Identification of new apolipoprotein B epitopes and haplotypes and their distribution in swine populations

Hasler‐Rapacz

Rapacz

et al. 1994

Animal Genetics

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Results from comparative immunogenetic studies on inheritance and identification of four new apolipoprotein B (apoB) allotypes and three additional apoB haplotypes and their distribution in miniature and domestic swine are presented. Immunological surveys on the four new and 16 previously described Lpb allotypes and genetic analysis of their segregation in progenies, of miniature and domestic swine and their crosses, indicate that three new allotypes designated Lpb9, Lpb10 and Lpb101 are individual (mutant) apoB epitopes, each representing a discriminating marker for one of the new apoB haplotypes specified by three new apoB alleles designated Lpb9, Lpb10 and Lpb101. The fourth allotype, Lpb20, is one of the common epitopes forming the alternative epitope pair with Lpb10, and is a constituent of each of the eight previously described and two new apoB haplotypes. The new apoB alleles have so far been found only in miniature swine, with Lpb10 being the most frequent in the Göttingen, Vietnamese Pot-belly and Japanese Miniature, Lpb9 was detected only in Minnesota Miniature and Lpb101 only in Vietnamese Potbelly. The common allotype, Lpb20, shares immunological similarities with human apoB indicating its ancestral origin, whereas none of the alloreagents detecting the three individual apoB variants, Lpb9, Lpb10 or Lpb101, showed cross-reactivity with human apoB, suggesting their exclusive swine origin and evolvement during speciation through mutations.

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Lipoprotein immunogenetics and atherosclerosis

Cited by 47 publications

References 84 publications

Apolipoprotein B and a second major gene locus contribute to phenotypic variation of spontaneous hypercholesterolemia in pigs.

Apolipoprotein B and a second major gene locus contribute to phenotypic variation of spontaneous hypercholesterolemia in pigs.

Familial hypercholesterolemia impairs exercise-induced systemic vasodilation due to reduced NO bioavailability

Identification of new apolipoprotein B epitopes and haplotypes and their distribution in swine populations

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