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B Paigen

Publications and source records attributed to B Paigen.

At least 73 records · Page 4Linked to original sources
PubMed1994

The mouse as a model for human cardiovascular disease and hyperlipidemia.

The mouse has been used as an experimental model for atherosclerosis research for only a short time; however, the sophisticated genetics of this species has resulted in a number of innovative approaches that are not possible with other models. The availability of inbred, congenic, recombinant inbred, and mutant strains has resulted in the discovery of a number of genes affecting atherosclerosis susceptibility. More importantly, the newer genetic technologies such as quantitative trait-loci mapping, transgenic mice, and gene-targeted mice are producing important insights into atherosclerosis. This review, focusing on murine models of cardiovascular disease and hyperlipidemia, will be divided into two parts: naturally occurring models and genetically engineered models.

Animals↗
PubMed1994

Mouse apolipoprotein J: characterization of a gene implicated in atherosclerosis.

Apolipoprotein J (apoJ), a glycoprotein associated with subclasses of plasma high density lipoproteins (HDL), was found to accumulate in aortic lesions in a human subject with transplantation-associated arteriosclerosis and in mice fed a high-fat atherogenic diet. Foam cells present in mouse aortic valve lesions expressed apoJ mRNA, suggesting local synthesis contributes to apoJ's localization in atherosclerotic plaque. As a prerequisite for elucidating the physiological function of apoJ by using a mouse model, cDNA clones representing the mouse homolog of apoJ were isolated, characterized, and sequenced. The nucleotide sequence predicts a 448 amino acid, 50,260 dalton protein. There was 81% nucleotide sequence similarity between mouse and human apoJ, and 75% similarity at the amino acid level. Mouse apoJ contains six potential N-glycosylation sites, a potential Arg-Ser cleavage site to generate alpha and beta subunits, a cluster of five cysteine residues in each subunit, three putative amphipathic helices, and four potential heparin-binding domains. Southern blot analysis indicates that the gene encompasses approximately 23 kb of DNA. Recombinant inbred strains were used to map apoJ to mouse chromosome 14, tightly linked to Mtv-11. All of the transcribed portions of the gene were cloned and analyzed, and all intron-exon boundaries were defined. The first of the 9 exons is untranslated. Single exons encode the signal peptide, the cysteine-rich domain in the alpha subunit, two potential amphipathic helices flanking a heparin-binding consensus sequence, and a potential amphipathic helix overlapping a heparin-binding domain, supporting their potential functional significance in apoJ. A variety of mouse tissues constitutively express a 1.9 kb apoJ mRNA, with apparently identical transcriptional start sites utilized in all tissues tested. ApoJ mRNA was most abundant in stomach, liver, brain, and testis, with intermediate levels in heart, ovary, and kidney. The high degree of similarity between mouse and human apoJ, in structure and distribution of the gene product, gene structure, and deposition in atherosclerotic plaques, suggests that the mouse is an ideal model with which to elucidate the role of apoJ in HDL metabolism and atherogenesis.

Amino Acid Sequence↗
PubMed1993

Strain distribution pattern in AXB and BXA recombinant inbred strains for loci on murine chromosomes 10, 13, 17, and 18.

Strain distribution patterns (SDPs) of selected loci previously mapped to murine Chromosomes (Chrs) 10, 13, 17, and 18 are reported for the AXB, BXA recombinant inbred (RI) strain set derived from the progenitor strains A/J (A) and C57BL/6J (B). The loci included the simple sequence length polymorphisms (D10Nds1, D10Mit2, D10Mit10, D10Mit14, D13Mit3, D13Nds1, D13Mit10, D13Mit13, D13Mit7, D13Mit11, D17Mit18, D17Mit10, D17Mit20, D17Mit3, D17Mit2, D18Mit17, D18Mit9, and D18Mit4), the restriction fragment length polymorphisms Pdea and Csfmr, and the biochemical marker AS-1. These loci were chosen because they map to genomic regions that had few or no genetic markers in the AXB, BXA RI set. Several of these loci also were typed in backcross progeny of matings of the (AXB)F1 to strain A or B. The strain distribution patterns for chromosomes 10, 13, 17, and 18 are reported, and the gene order and map distances determined from the backcross data. The addition of these markers to the AXB, BXA RI strain set increases the genomic region over which linkage for new markers can be detected.

Animals↗
PubMed1993

Atherosclerosis and plasma and liver lipids in nine inbred strains of mice.

Nine inbred strains of mice, which are progenitors of recombinant inbred sets, were evaluated for aortic lesion formation and plasma and liver lipid levels. This survey was done to determine if a semi-synthetic high-fat diet could elicit the same extent of diet-induced atherosclerosis as that observed in mice fed a natural ingredient high-fat diet and to discover strain-specific plasma and liver lipid variants for future genetic characterization. Evaluation of aortic lesions after 18 wk of diet consumption showed that strains C57BL/6J, C57L/J, SWR/J and SM/J were susceptible to atherosclerosis and that A/J, AKR/J, C3H/HeJ, DBA/2J and SJL/J were relatively resistant. High-density lipoprotein cholesterol (HDL-C) levels were negatively correlated to lesion formation. Susceptible strains had decreased HDL-C levels when switched from chow to the semi-synthetic high-fat, high cholesterol diet, whereas resistant strains either showed no change or a slight increase in HDL-C levels. The exception to this pattern was found in SM mice, which were susceptible to aortic lesion formation but maintained the same HDL-C level on both chow and high-fat diets. HDL size differed among the strains, and levels of plasma apolipoprotein A-I and A-II correlated with HDL-C levels. Liver damage was not correlated to HDL-C levels or to susceptibility to atherosclerosis. Mice from strain A, which are resistant to atherosclerosis, had evidence of liver damage as observed by elevated levels of plasma alanine aminotransferase activity, by liver histology, by increased liver weight and by exceptionally high hepatic cholesterol content.(ABSTRACT TRUNCATED AT 250 WORDS)

Alanine Transaminase↗
PubMed1993

Effects of dietary fats from animal and plant sources on diet-induced fatty streak lesions in C57BL/6J mice.

This study was designed to determine the effects of a variety of naturally occurring saturated fats on aortic lesion formation in C57BL/6J mice that are susceptible to diet-induced fatty streak lesions. Groups of female mice were randomly assigned to one of seven treatment groups and were fed diets containing 15% (w/w) hydrogenated coconut oil, hydrogenated soy oil, hydrogenated palm oil, cocoa butter, lard, tallow, or dairy butter, 1% cholesterol, and 0.5% cholic acid. Plasma lipid levels were measured to determine whether lesion formation was related to specific changes in these parameters. Lesions, which were observed in all groups of mice, ranged from 420 to 3220 microns2/aortic cross section. Lesion area was positively correlated to the percentage of saturated fatty acids contained in the fat sources and the ratio of combined VLDL plus LDL-cholesterol to HDL-cholesterol and inversely correlated to monounsaturated fatty acids content and to HDL-cholesterol levels. Results from this study demonstrate that inbred mice may provide a good model for dissecting the genetic basis for the differential atherogenic responses to diet-induction and for studying the effects of dietary factors on aortic lesion development.

Animals↗
PubMed1992

Multilocus markers for mouse genome analysis: PCR amplification based on single primers of arbitrary nucleotide sequence.

Polymerase chain reaction (PCR) based on single primers of arbitrary nucleotide sequence provides a powerful marker system for genome analysis because each primer amplifies multiple products, and cloning, sequencing, and hybridization are not required. We have evaluated this typing system for the mouse by identifying optimal PCR conditions; characterizing effects of GC content, primer length, and multiplexed primers; demonstrating considerable variation among a panel of inbred strains; and establishing linkage for several products. Mg2+, primer, template, and annealing conditions were identified that optimized the number and resolution of amplified products. Primers with 40% GC content failed to amplify products readily, primers with 50% GC content resulted in reasonable amplification, and primers with 60% GC content gave the largest number of well-resolved products. Longer primers did not necessarily amplify more products than shorter primers of the same proportional GC content. Multiplexed primers yielded more products than either primer alone and usually revealed novel variants. A strain survey showed that most strains could be readily distinguished with a modest number of primers. Finally, linkage for seven products was established on five chromosomes. These characteristics establish single primer PCR as a powerful method for mouse genome analysis.

Animals↗
PubMed1992

The AXB and BXA set of recombinant inbred mouse strains.

The recombinant inbred (RI) set of strains, AXB and BXA, derived from C57BL/6J and A/J, originally constructed and maintained at the University of California/San Diego, have been imported into The Jackson Laboratory and are now in the 29th to 59th generation of brother-sister matings. Genetic quality control testing with 45 proviral and 11 biochemical markers previously typed in this RI set indicated that five strains had been genetically contaminated sometime in the past, so these strains have been discarded. The correct and complete strain distribution patterns for 56 genetic markers are reported for the remaining RI strain set, which consists of 31 living strains and 8 extinct strains for which DNA is available. Two additional strains, AXB 12 and BXA 17, are living and may be added to the set pending further tests of genetic purity. The progenitors of this RI set differ in susceptibility to 27 infectious diseases as well as atherosclerosis, obesity, diabetes, cancer, cleft palate, and hydrocephalus. Thus, the AXB and BXA set of RI strains will be useful in the genetic analysis of several complex diseases.

Animals↗
PubMed1992

Silver-enhanced radial immunodiffusion assay of plasma apolipoproteins.

Silver-staining of immunoprecipitates extends the sensitivity of the radial immunodiffusion assay by tenfold. This modification permits the quantification of apolipoproteins A-I, A-II, C, and E at levels of 0.2-1.0 mg/dl in plasma samples at a sensitivity threshold of 10 ng. The silver-enhanced radial immunodiffusion method is readily adapted from the standard method, simple and inexpensive to perform, and does not require costly instrumentation. These advantages make the modified RID assay an attractive alternative to other forms of immunoassay.

Animals↗
PubMed1991

Effects of atherogenic diet consumption on lipoproteins in mouse strains C57BL/6 and C3H.

Inbred mouse strains C57BL/6J (B6) (susceptible) and C3H/HeJ (C3H) (resistant) differ in atherosclerosis susceptibility due to a single gene, Ath-1. Plasma lipoproteins from female mice fed chow or an atherogenic diet displayed strain differences in lipoprotein particle sizes and apolipoprotein (apo) composition. High density lipoprotein (HDL) particle sizes were 9.5 +/- 0.1 nm for B6 and 10.2 +/- 0.1 nm for C3H. No major HDL particle size subclasses were observed. Plasma HDL level in the B6 strain was reduced by the atherogenic diet consumption while the HDL level in the resistant C3H mice was unaffected. The reduction in HDL in the B6 strain was associated with decreases in HDL apolipoproteins A-I(-34%) and A-II(-60%). The HDL apoC content in mice fed chow was two-fold higher in C3H than B6. Lipoproteins containing apolipoprotein B (VLDL, IDL, LDL) shifted from a preponderance of the B-100 (chow diet) to a preponderance of the B-48 (atherogenic diet). The LDL-particle size distribution was strain-specific with the chow diet but not genetically associated with the Ath-1 gene. In both strains on each diet, apolipoprotein E was largely distributed in the VLDL, LDL, and HDL fractions. The B6 strain became sixfold elevated in total lipoprotein E content which in the C3H strain was not significantly affected by diet. However, the C3H LDL apoE content was reduced. On both diets, the C3H strain exhibited apolipoprotein E levels comparable to the atherogenic diet-induced levels of the B6 mice.

Animals↗
PubMed1990

Interconversion of prebeta-migrating lipoproteins containing apolipoprotein A-I and HDL.

Mouse plasma from strains C57BL/6J and C3H/HeJ includes a high density lipoprotein (HDL) fraction containing apolipoprotein A-I which migrates in the prebeta region upon agarose gel electrophoresis, similar to the prebeta HDL previously reported in humans. This prebeta A-I lipoprotein species has a buoyant density of 1.080-1.210 g/ml and has two molecular weight species, 65,000 and 71,000. It is lipid-poor and deficient in apolipoprotein E. When mice are fed a high fat and high cholesterol diet, the quantity of prebeta A-I increases in both strains as determined by quantitative densitometry of agarose gel immunoblots. Prebeta A-I species are highly unstable in plasma at 37 degrees C. Initially (0-1 h) levels decreased and with further incubation (1-8 h) levels increased. Nondenaturing polyacrylamide gel electrophoresis (PAGE) demonstrated that the prebeta HDL formed during prolonged incubation (1-8 h) was identical in size to HDL in unincubated samples. The initial decrease of prebeta HDL observed during the first hour of incubation, phase I, was inhibited by DTNB, suggesting that phase I is dependent on lecithin:cholesterol acyltransferase (LCAT); however, the subsequent increase, phase II, was unaffected by DTNB and appears LCAT-independent. The prebeta A-I species formed in plasma containing DTNB after a 4-h incubation resulted in a polydisperse particle size distribution. The two strains, the atherosclerosis-susceptible C57BL/6 and -resistant C3H, displayed a similar elevation and induction of prebeta HDL during a dietary switch from laboratory chow to an atherogenic diet with a transient peak occurring at 7 days even when total HDL in the susceptible strain was greatly reduced.

Animals↗
PubMed1990

Synthetic low and high fat diets for the study of atherosclerosis in the mouse.

Diets currently used to produce atherosclerotic lesions in mice are often undefined and cause accumulation of fat in the liver and gallstone formation. Therefore, synthetic low and high fat diets of known composition were formulated in this study. A synthetic diet containing 50% sucrose, 15% cocoa butter, 1% cholesterol, and 0.5% sodium cholate was found to produce a depression in high density lipoprotein cholesterol (HDL-C) and an elevation of very low density lipoprotein (VLDL) and low density lipoprotein cholesterol (LDL-C) in the atherosclerosis-susceptible strain, C57BL/6J. This diet was able to consistently produce aortic lesions and led to a decrease in liver damage and gallstone formation. The synthetic low fat diet did not produce HDL-C levels as high as those found in mice fed chow, but resulted in similar VLDL/LDL-C levels. Lipoprotein and apolipoprotein parameters were compared in C57BL/6J and the atherosclerosis-resistant strain, C3H/HeJ, consuming the synthetic low fat or high fat diets. As reported earlier, when consuming a high fat diet C57BL/6J mice have significantly lower HDL-C and apoA-I levels than C3H/HeJ mice. Further analysis shows that the molar ratio of plasma HDL-C to apoA-I is significantly lower in C57BL/6J mice, suggesting that HDL in the susceptible strain has a lower cholesterol-carrying capacity. This conclusion is consistent with the observation that the HDL particle size is smaller for C57BL/6J mice than for C3H/HeJ. Both strains increased their apoE levels when fed the synthetic high fat diet, but C3H/HeJ mice had higher levels of apoE on both diets. The major response to consumption of the high fat diet for both strains was an increase in apoB-48 from 5 micrograms/ml on a low fat diet to 54 and 109 micrograms/ml for C57BL/6J and C3H/HeJ, respectively. ApoB-100 showed minimal response to the high fat diet. The defined high fat diet can be used to study atherosclerosis in the mouse since it produces aortic lesions but reduces or eliminates other pathological changes such as gallstone formation and liver damage.

Animals↗
PubMed1989

Ath-2, a second gene determining atherosclerosis susceptibility and high density lipoprotein levels in mice.

Strain C57BL/6J and A/J differ at two genes determining atherosclerosis susceptibility. The first gene, Ath-1, was described earlier and this report characterizes Ath-2. The alleles at Ath-2 are r for resistance and s for susceptibility to atherosclerosis. The resistant phenotype in female mice is characterized by high plasma high density lipoprotein-cholesterol levels (74 mg/dl +/- SEM 2) and very few lesions/mouse after 14 weeks of consumption of an atherogenic diet (0.1 +/- SEM 0.1 in a predetermined region of the aorta). The susceptible phenotype in female mice is characterized by low levels of high density lipoprotein-cholesterol (35 mg/dl +/- SEM 1) and 1.2 lesions/mouse +/- SEM 0.2 in the same region of the aorta. In Ath-2 heterozygotes, resistance is dominant to susceptibility. Recombinant inbred strains derived from C57BL/6 and A were characterized for Apoa 1, Apoa 2 and susceptibility to atherosclerosis. Ath-1 and Ath-2 interact with each other so that resistant alleles at either locus confer a resistant phenotype to the animal. The map position of Ath-2 is not known, but Ath-2 does not map near genes determining the apolipoproteins for A-I, A-II, or E.

Alleles↗
PubMed1987

Genetic analysis of strains C57BL/6J and BALB/cJ for Ath-1, a gene determining atherosclerosis susceptibility in mice.

We previously reported that mice have at least one major gene determining atherosclerosis susceptibility, Ath-1. Susceptible alleles of Ath-1 are found in strain C57BL/6J and are associated with relatively low levels of high-density lipoprotein cholesterol (HDL-C) when these mice are fed an atherogenic diet. Resistant alleles of Ath-1 are found in strains C3H/HeJ and BALB/cJ and are associated with relatively high levels of HDL-C. Data reported earlier from the set of seven recombinant inbred (RI) strains, derived from C57BL/6By and BALB/cBy, showed that these parental strains differed at Ath-1. However, due to the limited number of RI strains, it was not possible to determine with certainty whether Ath-1 was the only major gene determining atherosclerosis susceptibility in these two strains or to determine its map position accurately. In this report, examination of F1, F2, and backcross progeny from a cross between C57BL/6J and BALB/cJ demonstrates that Ath-1 is the major gene determining atherosclerotic lesion formation and HDL-C levels in female mice. The data from male animals suggest that environmental factors or modifying genes also influence male HDL-C levels and thus partly obscure the Ath-1 phenotype. HDL-C levels in F1 progeny resemble the BALB/c parent. The data from the cross provide confirmatory evidence that Ath-1 is linked to Alp-2 on chromosome 1 with a map distance of 4.8 +/- 2.3 (SE). Combining these data with a previous cross between strain C57BL/6 and strain C3H/HeJ gives a map distance between Ath-1 and Alp-2 of 4.9 +/- 1.8 based on 7 crossovers found among 144 tested chromosomes.

Alleles↗
PubMed1987

Genetic analysis of murine strains C57BL/6J and C3H/HeJ to confirm the map position of Ath-1, a gene determining atherosclerosis susceptibility.

Previous results suggested that strains C57BL/6J and C3H/HeJ differed in a single gene for atherosclerosis susceptibility, called Ath-1. Based on data from recombinant inbred strains Ath-1 was tentatively assigned to chromosome 1 linked to Alp-2. In this report, a cross between C57BL/6 and C3H/HeJ was carried out in order to test whether the tentative map position was correct. Parental strains and F1 and F2 progeny were examined. Susceptible alleles of Ath-1, found in C57BL/6, are associated with relatively low levels of high-density lipoprotein (HDL)-cholesterol in animals fed an atherogenic diet; resistant alleles of Ath-1 are associated with relatively high levels of HDL-cholesterol. F1 progeny have HDL levels that are intermediate between these of the two parental strains. Among the F2 progeny, Alp-2 and Ath-1 cosegregated, providing confirmatory evidence that Ath-1 is linked to Alp-2 on chromosome 1. Three mice recombinant for Alp-2 and Ath-1 were found among the 60 chromosomes tested, giving an estimated map distance between these two genes of 5.0 +/- 2.8 (SE) cM. The phenotypic characteristics of Ath-1 resemble a genetic trait in humans, hyperalphalipoproteinemia, which is characterized by elevated levels of HDL-cholesterol, reduced risk of heart disease, and increased longevity.

Animals↗
PubMed1987

Quantitative assessment of atherosclerotic lesions in mice.

The well-defined genetic systems of the mouse are proving useful in experimental studies of atherosclerosis. Inbred mouse strains differ in atherosclerosis susceptibility, and several variants of apolipoproteins have been identified and mapped. This report explores the location and timing of lesion formation in the mouse in an effort to provide a basis for quantitatively comparing groups of mice. After 14 weeks on an atherogenic diet containing 1.25% cholesterol, 15% fat, and 0.5% cholic acid, C57BL/6J female mice had aortic lesions at each of the intercostal arteries, at the junction of the aorta to the heart, and in scattered areas covering 1.1% +/- 0.5 (SD) of the aortic surface. After 9 months on the atherogenic diet, those lesions near the heart and intercostal arteries were extensive, 8% +/- 3 (SD) of the remainder of the aorta was involved in lesions, and lesions were found in the coronary arteries. Results indicated that one suitable location for scoring lesions was in a 300 micron area of the aorta just beyond the aortic sinus. The mean number of lesions/mouse in the selected area after 14 weeks on the atherogenic diet was 1.1 +/- 0.3 (SD). The results were reproducible over 10 separate experiments. The number of lesions per mouse fit a Poisson distribution indicating that the presence of one lesion did not predispose the mouse to acquiring a second lesion. Lesion formation and cholesterol levels did not vary with the season of the year as demonstrated by 9 separate experiments over more than 12 months. Methods of evaluating the number and size of lesions were compared including sizing with a microscope eyepiece grid and computer-assisted planimetry. The resulting data provide reproducible methods of quantitatively comparing lesion formation in various strains or groups of mice, thereby increasing the usefulness of the mouse as an experimental system for atherosclerosis research.

Animals↗
PubMed1987

Characterization of a genetic difference in the platelet aggregation response of two inbred mouse strains, C57BL/6 and C3H/He.

An in vitro platelet aggregation assay has been used to characterize the platelet response of two inbred mouse strains, C57BL/6J and C3H/J. Arachidonic acid, ADP, ristocetin, and collagen, but not epinephrine, were effective inducers of platelet aggregation in C57BL/6 mice. In C3H mice, however, platelets responded differently to some, but not all, inducers of platelet aggregation. The difference between the two strains was particularly striking for arachidonic acid; at 0.375 microM arachidonic acid, platelets from C57BL/6 mice aggregated well, but platelets from C3H mice failed to aggregate. The two strains also differed in serotonin release from platelets. When the pool of platelet serotonin was labeled by incubating platelets with [14C]serotonin, the amount of label subsequently released from platelets in response to 0.375 microM arachidonic acid was 20.5% +/- 2.5 SE for C57BL/6 mice and 1.5% +/- 1.5 SE for C3H mice. The platelets from F1 progeny of a cross between C57BL/6 and C3H mice were indistinguishable in aggregation response from the C57BL/6 parent. The defect in aggregation response found in C3H mice appears to reside in the platelets rather than in the plasma. Experiments which involved adding the plasma of one strain to the washed platelets of the other strain indicated that C57BL/6 platelets aggregated well whether they were resuspended in plasma from C57BL/6 or C3H mice, while C3H platelets failed to aggregate regardless of the origin of the plasma. Strain C57BL/6 is susceptible to diet-induced formation of atherosclerotic lesions, but strain C3H is resistant to lesion formation. This genetic difference in atherosclerosis susceptibility is not related to the genetic difference in platelet aggregation since a recombinant inbred strain, BXH-9, is susceptible to atherosclerosis like the C57BL/6 parent but has the reduced platelet aggregation response of the C3H parent.

Animals↗