Biomedical subjects

Nobuyo Maeda

Publications and source records attributed to Nobuyo Maeda.

At least 55 records · Page 3Linked to original sources

PubMed2004

The presence of leukocyte CC-chemokine receptor 2 in CCR2 knockout mice promotes atherogenesis.

OBJECTIVE: To selectively determine the role of leukocyte CC-chemokine receptor 2 (CCR2) in atherogenesis. METHODS AND RESULTS: Bone marrow progenitor cells harvested from CCR2(+/+) mice were transplanted into irradiated CCR2(-/-) mice, representing the whole-body absence of CCR2 except in leukocytes. Transplantation of CCR2(-/-) bone marrow into CCR2(-/-) mice served as control. Eight weeks after bone marrow transplantation, the diet of regular chow was switched to a high-cholesterol diet for another 10 weeks in order to induce atherosclerosis. No significant differences in serum cholesterol and triglyceride levels were observed between the two groups. However, the mean cross-sectional aortic root lesion area of CCR2(+/+)-->CCR2(-/-) mice amounted up to 12.28+/-3.28x10(4) microm(2), compared with only 3.08+/-0.74 x 10(4) microm(2) observed in the CCR2(-/-)-->CCR2(-/-) group. Thus, the presence of CCR2 exclusively on leukocytes induces a fourfold increase in aortic lesion area. This extent of lesion development was comparable to C57Bl/6 mice receiving CCR2(+/+) bone marrow (10.08+/-3.30x10(4) microm(2)). CONCLUSION: These results point at a dominant role of leukocyte CCR2 in atherogenesis, implying that CCR2 from nonleukocyte sources, like endothelial cells or smooth muscle cells, is less critical in the initiation of atherosclerosis. Pharmacological inhibition of leukocyte CCR2 function might be a promising strategy to prevent atherosclerosis.

Animals↗

PubMed2004

Defective VLDL metabolism and severe atherosclerosis in mice expressing human apolipoprotein E isoforms but lacking the LDL receptor.

Differences in affinity of human apolipoprotein E (apoE) isoforms for the low density lipoprotein receptor (LDLR) are thought to result in the differences in lipid metabolism observed in humans with different APOE genotypes. Mice expressing three common human apoE isoforms, E2, E3, and E4, in place of endogenous mouse apoE were used to investigate the relative roles of apoE isoforms in LDLR- and non-LDLR-mediated very low density lipoprotein (VLDL) clearance. While both VLDL particles isolated from mice expressing apoE3 and apoE4 bound to mouse LDLR with affinity and Bmax similar to VLDL containing mouse apoE, VLDL with apoE2 bound with only half the Bmax. In the absence of the LDLR, all lines of mice expressing human apoE showed dramatic increases in VLDL cholesterol and triglycerides (TG) compared to LDLR knockout mice expressing mouse apoE. The mechanism of the hyperlipidemia in mice expressing human apoE isoforms is due to impairment of non-LDL-receptor-mediated VLDL clearance. This results in the severe atherosclerosis observed in mice expressing human apoE but lacking the LDLR, even when fed normal chow diet. Our data show that defects in LDLR independent pathway(s) are a potential factor that trigger hyperlipoproteinemia when the LDLR pathway is perturbed, as in E2/2 mice.

Animals↗

PubMed2004

A mouse model of sitosterolemia: absence of Abcg8/sterolin-2 results in failure to secrete biliary cholesterol.

BACKGROUND: Mutations in either of two genes comprising the STSL locus, ATP-binding cassette (ABC)-transporters ABCG5 (encoding sterolin-1) and ABCG8 (encoding sterolin-2), result in sitosterolemia, a rare autosomal recessive disorder of sterol trafficking characterized by increased plasma plant sterol levels. Based upon the genetics of sitosterolemia, ABCG5/sterolin-1 and ABCG8/sterolin-2 are hypothesized to function as obligate heterodimers. No phenotypic difference has yet been described in humans with complete defects in either ABCG5 or ABCG8. These proteins, based upon the defects in humans, are responsible for regulating dietary sterol entry and biliary sterol secretion. METHODS: In order to mimic the human disease, we created, by a targeted disruption, a mouse model of sitosterolemia resulting in Abcg8/sterolin-2 deficiency alone. Homozygous knockout mice are viable and exhibit sitosterolemia. RESULTS: Mice deficient in Abcg8 have significantly increased plasma and tissue plant sterol levels (sitosterol and campesterol) consistent with sitosterolemia. Interestingly, Abcg5/sterolin-1 was expressed in both liver and intestine in Abcg8/sterolin-2 deficient mice and continued to show an apical expression. Remarkably, Abcg8 deficient mice had an impaired ability to secrete cholesterol into bile, but still maintained the ability to secrete sitosterol. We also report an intermediate phenotype in the heterozygous Abcg8+/- mice that are not sitosterolemic, but have a decreased level of biliary sterol secretion relative to wild-type mice. CONCLUSION: These data indicate that Abcg8/sterolin-2 is necessary for biliary sterol secretion and that loss of Abcg8/sterolin-2 has a more profound effect upon biliary cholesterol secretion than sitosterol. Since biliary sitosterol secretion is preserved, although not elevated in the sitosterolemic mice, this observation suggests that mechanisms other than by Abcg8/sterolin-2 may be responsible for its secretion into bile.

ATP Binding Cassette Transporter, Subfamily G, Mem↗

PubMed2004

Altering the expression in mice of genes by modifying their 3' regions.

Polymorphic differences altering expression of genes without changing their products probably underlie human quantitative traits affecting risks of serious diseases, but methods for investigating such quantitative differences in animals are limited. Accordingly, we have developed a procedure for changing the expression in mice of chosen genes over a 100-fold range while retaining their chromosomal location and transcriptional controls. To develop the procedure, we first dissected the effects in embryonic stem (ES) cells of elements within and downstream of the 3' untranslated region (UTR) of a single copy transgene at the Hprt locus. As expected, protein expression varied with the steady-state level and half-life of the mRNA. The rank order of expression with various tested 3' regions is the same in ES cells, and in cardiomyocytes and trophoblastocytes derived from them. In mice having two functionally different native genes with modified 3'UTRs, the desired expression was obtained.

3' Untranslated Regions↗

PubMed2004

Apolipoprotein E isoforms and apolipoprotein AI protect from amyloid precursor protein carboxy terminal fragment-associated cytotoxicity.

Inheritance of the apolipoprotein (APO) E gene epsilon4 or epsilon2 allele alters the risk of developing Alzheimer disease (AD), while increased alpha-tocopherol (AT) intake appears to lower the risk of AD. As APOE is a major apolipoprotein in the CNS and AT in vivo is transported in lipoproteins, we tested the hypothesis that CNS lipoproteins, as modeled by relevant concentrations of high density lipoprotein (HDL), and AT would interact to suppress neurotoxicity in a cell culture model of amyloid beta (Abeta)- related toxicity. These cells conditionally express C99-derived peptides, proposed to be a key step in AD pathogenesis; this expression is closely associated with subsequent cell death. We found that physiologic concentrations of lipoproteins present in the CNS protected from C99-associated toxicity and provided evidence for two mechanisms of protection. The first was AT-independent, APOE isoform-dependent, and most potent for the APOE2 isoform. The second was a synergistic protection afforded by a combination of APOAI, or less so APOE, and AT. These data provide a novel explanation for the apparent AD-protective effect of inheriting an epsilon2 APOE allele, and suggest that optimizing AT enrichment of CNS lipoproteins or devising APOAI mimetics may augment AT efficacy in treating AD.

Alzheimer Disease↗

PubMed2004

Tamm-Horsfall protein knockout mice are more prone to urinary tract infection: rapid communication.

BACKGROUND: Human colon contains many bacteria that commonly colonize the perineum and frequently enter the urinary tract. Uropathogenic Escherichia coli are the most common cause of urinary tract infection. Type 1 fimbriated E. coli have been associated with cystitis, and P fimbriated E. coli with pyelonephritis. Factors involved in clearing bacteria from the urinary tract are poorly understood. Tamm-Horsfall protein (THP), the most abundant protein in mammalian urine, has been postulated to play a role in defense against urinary tract infection but definitive proof for this idea has been lacking. METHODS: In this study, we generated THP gene knockout mice by the technique of homologous recombination, and examined if the THP-deficient (THP-/-) mice were more prone to urinary tract infection. Various strains of E. coli expressing type 1 or P fimbriae were introduced transurethrally into the bladders of the THP-/- and genetically similar wild-type (THP+/+) mice. Urine, bladder, and kidney tissues were obtained from the mice and cultured for bacterial growth. RESULTS: THP-/- mice inoculated with type 1 fimbriated E. coli had a longer duration of bacteriuria, and more intense colonization of the urinary bladder in comparison with THP+/+ mice. When inoculated with a P fimbriated strain of E. coli, the THP-/- mice showed no difference in kidney bacterial load when compared with the THP+/+ mice. CONCLUSION: These findings support the idea that THP serves as a soluble receptor for type 1 fimbriated E. coli and helps eliminate bacteria from the urinary tract.

Animals↗

PubMed2004

Hypertension and abnormal fat distribution but not insulin resistance in mice with P465L PPARgamma.

Peroxisome proliferator-activated receptor gamma (PPARgamma), the molecular target of a class of insulin sensitizers, regulates adipocyte differentiation and lipid metabolism. A dominant negative P467L mutation in the ligand-binding domain of PPARgamma in humans is associated with severe insulin resistance and hypertension. Homozygous mice with the equivalent P465L mutation die in utero. Heterozygous mice grow normally and have normal total adipose tissue weight. However, they have reduced interscapular brown adipose tissue and intra-abdominal fat mass, and increased extra-abdominal subcutaneous fat, compared with wild-type mice. They have normal plasma glucose levels and insulin sensitivity, and increased glucose tolerance. However, during high-fat feeding, their plasma insulin levels are mildly elevated in association with a significant increase in pancreatic islet mass. They are hypertensive, and expression of the angiotensinogen gene is increased in their subcutaneous adipose tissues. The effects of P465L on blood pressure, fat distribution, and insulin sensitivity are the same in both male and female mice regardless of diet and age. Thus the P465L mutation alone is sufficient to cause abnormal fat distribution and hypertension but not insulin resistance in mice. These results provide genetic evidence for a critical role for PPARgamma in blood pressure regulation that is not dependent on altered insulin sensitivity.

Adipose Tissue↗

PubMed2004

In vivo role of myeloperoxidase for the host defense.

Myeloperoxidase (MPO) is located within neutrophils capable of producing HOCl. To define the in vivo role of MPO, we have generated MPO-knockout (MPO-KO) mice. The mice without MPO developed normally. However, MPO-KO mice showed severely reduced cytotoxicity to various microorganisms such as Candida albicans, Aspergillus fumigatus, and Klebsiella pneumoniae, demonstrating that MPO-dependent oxidative system is important for host defense against fungi and bacteria, although the effect varies from species to species of pathogens. To compare the importance of MPO and NADPH-oxidase for host defense, MPO-KO and chronic granulomatous disease (CGD) mice were infected with different doses of C. albicans, and their infection severity was analyzed. CGD mice exhibited increased mortality and tissue fungal burden in a dose-dependent manner, whereas normal mice showed no symptoms. Interestingly, at the highest dose, the mortality of MPO-KO mice was comparable to CGD mice, but was the same as normal mice at the lowest dose. These results suggest that MPO and NADPH-oxidase are equally important for early host defense against a large inocula of Candida.

Animals↗

PubMed2003

An intronic endogenous retrovirus-like sequence attenuates human haptoglobin-related gene expression in an orientation-dependent manner.

The human haptoglobin-related gene (HPR) gene codes for a haptoglobin-related protein (Hpr), a component of trypanosome lytic factor which circulates in plasma in small quantities. Except for the presence of a retrovirus-like element, RTVL-Ia, in intron 1, HPR is 92% identical in sequence to the closely linked human haptoglobin gene (HP) gene coding for haptoglobin. We have explored experimentally in tissue culture and in vivo in mice and in humans the influence of the retroviral-like sequence type Ia (RTVL-Ia) element on HPR expression. Transient expression in HepG2 cells of plasmids carrying the HPR promoter joined by a shortened version of intron 1 to the chloramphenicol acetyltransferase (CAT) vector showed that fragments containing the 5' long terminal repeat (LTR) had no significant effect. In contrast, a gag-pol related part and a pol-env-3'LTR related part of RTVL-Ia decreased expression to 20% and 40% of that in their absence but only when they were in naturally occurring orientation. The latter fragment that contains sequences reminiscent of elements essential for retrovirus viability, such as a splicing acceptor site, TATA box and polyA addition signal sequence, was further tested in site-specific transgenic mice. Similar to in vitro experiment, insertion of this fragment into an HPR transgene in mice reduced HPR expression to 50% compared to a transgene without the insert, but none of the viral sequence motifs appear to explain this effect. Instead, we found within the fragment two cryptic splicing donor sites whose products were present in transgenic mouse and in human liver RNA. Our data suggest that a combination of multiple small effects of RTVL-Ia including aberrant splicing accounts for the low (6%) expression of the present-day HPR relative to HP.

Alternative Splicing↗

PubMed2003

Harmful effects of increased LDLR expression in mice with human APOE4 but not APOE3.

OBJECTIVE: Increased expression of the low-density lipoprotein receptor (LDLR) is generally considered beneficial for reducing plasma cholesterol and atherosclerosis, and its downregulation has been thought to explain the association between apolipoprotein (apo) E4 and increased risk of coronary heart disease in humans. METHODS AND RESULTS: Contrary to this hypothesis, doubling Ldlr expression caused severe atherosclerosis with marked accumulation of cholesterol-rich, apoE-poor remnants in mice with human apoE4, but not apoE3, when the animals were fed a Western-type diet. The increased Ldlr expression enhanced in vivo clearance of exogenously introduced remnants in mice with apoE4 only when the remnants were already enriched with apoE4. The rates of nascent lipoprotein production were the same. The adverse effects of increased LDLR suggest a possibility that the receptor can trap apoE4, reducing its availability for the transfer to nascent lipoproteins needed for their rapid clearance, thereby increasing the production of apoE-poor remnants that are slowly cleared. The lower affinity for the LDLR of apoE3 compared with apoE4 could then explain why increased receptor expression had no adverse effects with apoE3. CONCLUSIONS: Our results emphasize the occurrence of important and unexpected interactions between APOE genotype, LDLR expression, and diet.

Animals↗

PubMed2003

Targeted deletion of the ileal bile acid transporter eliminates enterohepatic cycling of bile acids in mice.

The ileal apical sodium bile acid cotransporter participates in the enterohepatic circulation of bile acids. In patients with primary bile acid malabsorption, mutations in the ileal bile acid transporter gene (Slc10a2) lead to congenital diarrhea, steatorrhea, and reduced plasma cholesterol levels. To elucidate the quantitative role of Slc10a2 in intestinal bile acid absorption, the Slc10a2 gene was disrupted by homologous recombination in mice. Animals heterozygous (Slc10a2+/-) and homozygous (Slc10a2-/-) for this mutation were physically indistinguishable from wild type mice. In the Slc10a2-/- mice, fecal bile acid excretion was elevated 10- to 20-fold and was not further increased by feeding a bile acid binding resin. Despite increased bile acid synthesis, the bile acid pool size was decreased by 80% and selectively enriched in cholic acid in the Slc10a2-/- mice. On a low fat diet, the Slc10a2-/- mice did not have steatorrhea. Fecal neutral sterol excretion was increased only 3-fold, and intestinal cholesterol absorption was reduced only 20%, indicating that the smaller cholic acid-enriched bile acid pool was sufficient to facilitate intestinal lipid absorption. Liver cholesteryl ester content was reduced by 50% in Slc10a2-/- mice, and unexpectedly plasma high density lipoprotein cholesterol levels were slightly elevated. These data indicate that Slc10a2 is essential for efficient intestinal absorption of bile acids and that alternative absorptive mechanisms are unable to compensate for loss of Slc10a2 function.

Alleles↗

PubMed2003

Altered gene expression in liver from a murine model of hyperhomocysteinemia.

Cystathionine beta-synthase (CBS) deficiency causes severe hyperhomocysteinemia and other signs of homocystinuria syndrome, in particular a premature atherosclerosis with multiple thrombosis. However, the molecular mechanisms by which homocysteine could interfere with normal cell function are poorly understood in a whole organ like the liver, which is central to the catabolism of homocysteine. We used a combination of differential display and cDNA arrays to analyze differential gene expression in association with elevated hepatic homocysteine levels in CBS-deficient mice, a murine model of hyperhomocysteinemia. Expression of several genes was found to be reproducibly abnormal in the livers of heterozygous and homozygous CBS-deficient mice. We report altered expression of genes encoding ribosomal protein S3a and methylthioadenosine phosphorylase, suggesting such cellular growth and proliferation perturbations may occur in homozygous CBS-deficient mice liver. Many up- or down-regulated genes encoded cytochromes P450, evidence of perturbations of the redox potential in heterozygous and homozygous CBS-deficient mice liver. The expression of various genes involved in severe oxidative processes was also abnormal in homozygous CBS-deficient mice liver. Among them, the expression of heme oxygenase 1 gene was increased, concomitant with overexpression of heme oxygenase 1 at the protein level. Commensurate with the difference in hepatic mRNA paraoxonase 1 abundance, the mean hepatic activity of paraoxonase 1, an enzyme that protects low density lipoprotein from oxidation, was 3-fold lower in homozygous CBS-deficient mice. Heterozygous CBS-deficient mice, when fed a hyperhomocysteinemic diet, have also reduced PON1 activity, which demonstrates the effect of hyperhomocysteinemia in the paraoxonase 1 activity.

Animals↗

PubMed2003

Increased atherosclerosis and smooth muscle cell hypertrophy in natriuretic peptide receptor A-/-apolipoprotein E-/- mice.

OBJECTIVE: Natriuretic peptide signaling is important in the regulation of blood pressure as well as in the growth of multiple cell types. To examine the role of natriuretic peptide signaling in atherosclerosis, we crossbred mice that lack natriuretic peptide receptor A (NPRA; Npr1-/-) with atherosclerosis-prone mice that lack apolipoprotein E (apoE; Apoe-/-). METHODS AND RESULTS: Doubly deficient Npr1-/-Apoe-/- mice have increased blood pressure relative to Npr1+/+Apoe-/- mice (118+/-4 mm Hg compared with 108+/-2 mm Hg, P<0.05) that is coincident with a 64% greater atherosclerotic lesion size (P<0.005) and more advanced plaque morphology. Additionally, aortic medial thickness is increased by 52% in Npr1-/-Apoe-/- mice relative to Npr1+/+Apoe-/- mice (P<0.0001). Npr1-/-Apoe-/- mice also have significantly greater cardiac mass (9.0+/-0.3 mg/g body weight) than either Npr1+/+Apoe-/- mice (5.8+/-0.2 mg/g) or Npr1-/-Apoe+/+ mice (7.1+/-0.2 mg/g), suggesting that the lack of both NPRA and apoE synergistically enhances cardiac hypertrophy. CONCLUSIONS: These data provide evidence that NPR1 is an atherosclerosis susceptibility locus and represents a potential link between atherosclerosis and cardiac hypertrophy. Our results also suggest roles for Npr1 as well as Apoe in regulation of hypertrophic cell growth.

Animals↗

PubMed2003

Transplantation of monocyte CC-chemokine receptor 2-deficient bone marrow into ApoE3-Leiden mice inhibits atherogenesis.

OBJECTIVE: To determine the role of leukocyte CC-chemokine receptor 2 (CCR2) in the early development of atherosclerosis METHODS AND RESULTS: Bone marrow cells harvested from CCR2 (-/-) and CCR2 (+/+) mice were transplanted into ApoE3-Leiden mice, a mouse strain susceptible for diet-induced atherosclerosis. Eight weeks after bone marrow transplantation, the diet of regular chow was switched to a high-cholesterol diet (1% cholesterol, 15% fat, 0.5% cholate) for another 8 weeks to induce atherosclerosis. No significant differences in serum cholesterol and triglyceride levels were observed between the CCR2 (+/+) --> ApoE3-Leiden and CCR2 (-/-) --> ApoE3-Leiden mice. However, the mean cross-sectional aortic root lesion area of CCR2 (-/-) --> ApoE3-Leiden mice was only 2.94+/-1.94x10(4) microm2 compared with 20.94+/-12.71x10(4) microm2, for CCR2 (+/+) --> ApoE3-Leiden mice. Thus, the absence of CCR2 on leukocytes induces an 86% reduction of aortic lesion area as compared with controls (n=10, P<0.01). CONCLUSIONS: These results provide direct evidence that CCR2 expressed by leukocytes plays a critical role in the initiation of early atherosclerosis and that pharmacological intervention in CCR2 function represents an attractive target to inhibit atherogenesis.

Animals↗

PubMed2003

Impaired hepatic granuloma formation in mice deficient in C-C chemokine receptor 2.

Granulomas are characterized histologically by a nodular collection of macrophages with occasional admixture of epithelioid cells, multinucleate giant cells, and other immunocompetent cells. Chemokines are considered to play an important role in the recruitment of these constituent cells of granulomas. The present study has examined the effect of a deficiency of C-C chemokine receptor-2 (CCR2) on hepatic granuloma formation induced by a single injection of Zymosan A. In CCR2+/+ mice, the number and the size of granulomas gradually increased until they reached peak values at 10 days after the injection. In contrast, both the number and the size of granulomas were smaller in CCR2-/- mice than in CCR2+/+ mice from days 5 to 21. They showed low peaks at day 5, after which the number and the size of the granulomas gradually decreased. Immunohistochemical analysis of the constituent granuloma cells using cell type-specific monoclonal antibodies revealed rapid accumulation of blood monocytes, with subsequent differentiation to macrophages, in CCR2+/+ mice during days 2-10. This process was greatly impaired in CCR2-/- mice and granulomas remained small. At all time points, the percentage of polymorphonuclear cells in granulomas was higher in CCR2-/- mice than in CCR2+/+ mice. Interestingly, multinucleate giant cells were frequently observed in granulomas in CCR2-/- mice, whereas they rarely appeared in CCR2+/+ mice. Profiles of liver cytokine RNA levels as well as serum cytokine levels revealed reduced expression of the Th1 cytokine IFN-gamma in CCR2-/- mice. These data clearly indicate that signalling through CCR2 has many effects on the normal growth and development of hepatic granulomas.

Animals↗

PubMed2003

CCR5 deficiency is not protective in the early stages of atherogenesis in apoE knockout mice.

The accumulation of macrophages and T lymphocytes in vessel walls is a hallmark of atherogenesis. It has recently been demonstrated in mouse models of atherosclerosis that full disease potential is dependent on several regulators of leukocyte trafficking, including the chemokine monocyte chemotactic protein 1 (MCP-1) and the chemokine receptors CCR2 and CXCR2. A possible role for the chemokine receptor CCR5 in atherogenesis has been suggested by CCR5 expression on macrophages, T cells, coronary endothelial cells and aortic smooth muscle cells and by the presence of CCR5 ligands in atherosclerotic plaques. Moreover, individuals who are naturally deficient in CCR5 were reported to be at reduced risk for severe coronary artery disease (CAD) and early myocardial infarction (MI). To investigate whether CCR5 is pro-atherogenic in mice, we generated CCR5-deficient mice and crossed them with atherosclerosis-prone apoE-deficient mice. Although CCR5-deficient mice exhibit defects in induced macrophage trafficking, mean atherosclerotic lesion area did not differ significantly between apoE-deficient mice and apoE/CCR5-deficient mice after 16 weeks on a diet of normal chow. Ribonuclease protection assays (RPA) on RNA isolated from plaques from both apoE-deficient and apoE/CCR5-deficient animals showed strong signals for the macrophage marker F4/80 but no evidence for expression of prominent markers of T and B lymphocytes. These results indicate that the early stages of plaque formation in this model of lipid-mediated atherogenesis do not depend on CCR5.

Analysis of Variance↗

PubMed2002

The atheroprotective effect of dietary soy isoflavones in apolipoprotein E-/- mice requires the presence of estrogen receptor-alpha.

OBJECTIVE: Although the mechanisms by which dietary soy inhibits atherosclerosis are unclear, one line of evidence implicates an important role for its phytoestrogenic isoflavones. We sought to determine whether soy isoflavones exert atheroprotective effects through estrogen receptor-dependent processes and, if so, which estrogen receptor subtype (ie, alpha or beta) is involved. METHODS AND RESULTS: We compared the effects of diets rich in soy protein that were either isoflavone depleted (0.04 mg/g protein isolate) or isoflavone-replete, or Soy(+IF) (1.72 mg/g protein isolate) in apolipoprotein E-deficient (ee) mice that had been crossed with estrogen receptor-alpha- and -beta-deficient mice to produce double-knockout alphaalphaee and betabetaee mice and (estrogen receptor) wild-type controls (AAee and BBee). Both male and ovariectomized female mice were studied (n=10 to 17 per treatment group; total n=201). After 16 weeks, atherosclerosis was assessed by quantifying the aortic content of esterified cholesterol. Atherosclerosis was reduced 20% to 27% (P<0.05) by Soy(+IF) in betabetaee, BBee, and AAee mice but was unaffected in alphaalphaee mice. The inhibitory effect of Soy(+IF) was unrelated to sex, total plasma cholesterol, VLDL, LDL, and HDL cholesterol. CONCLUSIONS: The results indicate a necessary role for estrogen receptor-alpha-dependent processes in mediating the atheroprotective effects of dietary soy isoflavones.

Animals↗

PubMed2002

Common variations in noncoding regions of the human natriuretic peptide receptor A gene have quantitative effects.

Genetic susceptibility to common conditions, such as essential hypertension and cardiac hypertrophy, is probably determined by various combinations of small quantitative changes in the expression of many genes. NPR1, coding for natriuretic peptide receptor A (NPRA), is a potential candidate, because NPRA mediates natriuretic, diuretic, and vasorelaxing actions of the nariuretic peptides, and because genetically determined quantitative changes in the expression of this gene affect blood pressure and heart weight in a dose-dependent manner in mice. To determine whether there are common quantitative variants in human NPR1, we have sequenced the entire human NPR1 gene and identified 10 polymorphic sites in its non-coding sequence by using DNA from 34 unrelated human individuals. Five of the sites are single nucleotide polymorphisms; the remaining five are length polymorphisms, including a highly variable complex dinucleotide repeat in intron 19. There are three common haplotypes 5' to this dinucleotide repeat and three 3' to it, but the 5' haplotypes and 3' haplotypes appear to be randomly associated. Transient expression analysis in cultured cells of reporter plasmids with the proximal promoter sequences of NPR1 and its 3' untranslated regions showed that these polymorphisms have functional effects. We conclude that common NPR1 alleles can alter expression of the gene as much as two-fold and could therefore significantly affect genetic risks for essential hypertension and cardiac hypertrophy in humans.

Animals↗