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1.
Arterioscler Thromb Vasc Biol ; 31(12): 2806-12, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21979437

RESUMO

OBJECTIVE: ABCC6 genetic deficiency underlies pseudoxanthoma elasticum (PXE) in humans, characterized by ectopic calcification, and early cardiac disease. The spectrum of PXE has been noted in Abcc6-deficient mice, including dystrophic cardiac calcification. We tested the role of Abcc6 in response to cardiac ischemia-reperfusion (I/R) injury. METHODS AND RESULTS: To determine the role of Abcc6 in cardioprotection, we induced ischemic injury in mice in vivo by occluding the left anterior descending artery (30 minutes) followed by reperfusion (48 hours). Infarct size was increased in Abcc6-deficient mice compared with wild-type controls. Additionally, an Abcc6 transgene significantly reduced infarct size on the background of a naturally occurring Abcc6 deficiency. There were no differences in cardiac calcification following I/R, but increased cardiac apoptosis was noted in Abcc6-deficient mice. Previous studies have implicated the bone morphogenetic protein (BMP) signaling pathway in directing calcification, and here we showed that the BMP responsive transcription factors pSmad1/5/8 were increased in hearts of Abcc6 mice. Consistent with this finding, BMP4 and BMP9 were increased and activin receptor-like kinase-2 and endoglin were downregulated in cardiac extracts from Abcc6-deficient mice versus controls. CONCLUSIONS: These data identify Abcc6 as a novel modulator of cardiac myocyte survival after I/R. This cardioprotective mechanism may involve inhibition of the BMP signaling pathway, which modulates apoptosis.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/fisiologia , Apoptose/fisiologia , Regulação da Expressão Gênica/fisiologia , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Receptores de Ativinas Tipo I/metabolismo , Animais , Proteína Morfogenética Óssea 4/metabolismo , Modelos Animais de Doenças , Endoglina , Feminino , Fator 2 de Diferenciação de Crescimento/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Proteínas Associadas à Resistência a Múltiplos Medicamentos , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Miócitos Cardíacos/patologia , Transdução de Sinais/fisiologia , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta/metabolismo
2.
Circ Cardiovasc Genet ; 2(6): 573-82, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-20031637

RESUMO

BACKGROUND: Disruption of the elastic lamina, as an early indicator of aneurysm formation, and vascular calcification frequently occur together in atherosclerotic lesions of humans. METHODS AND RESULTS: We now report evidence of shared genetic basis for disruption of the elastic lamina (medial disruption) and medial calcification in an F(2) mouse intercross between C57BL/6J and C3H/HeJ on a hyperlipidemic apolipoprotein E (ApoE(-/-)) null BACKGROUND: gene, known to mediate myocardial calcification. Using transgenic complementation, we show that Abcc6 also contributes to aortic medial calcification. CONCLUSIONS: Our data indicate that calcification, though possibly contributory, does not always lead to medial disruption and that in addition to aneurysm formation, medial disruption may be the precursor to calcification.


Assuntos
Aterosclerose/genética , Aterosclerose/patologia , Calcinose , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Aorta/patologia , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Aterosclerose/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Proteínas Associadas à Resistência a Múltiplos Medicamentos , Locos de Características Quantitativas
3.
Proc Natl Acad Sci U S A ; 104(11): 4530-5, 2007 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-17360558

RESUMO

The genetic factors contributing to the complex disorder of myocardial calcification are largely unknown. Using a mouse model, we fine-mapped the major locus (Dyscalc1) contributing to the dystrophic cardiac calcification (DCC) to an 840-kb interval containing 38 genes. We then identified the causal gene by using an approach integrating genetic segregation and expression array analyses to identify, on a global scale, cis-acting DNA variations that perturb gene expression. By studying two intercrosses, in which the DCC trait segregates, a single candidate gene (encoding the ATP-binding cassette transporter ABCC6) was identified. Transgenic complementation confirmed Abcc6 as the underlying causal gene for Dyscalc1. We demonstrate that in the cross, the expression of Abcc6 is highly correlated with the local mineralization regulatory system and the BMP2-Wnt signaling pathway known to be involved in the systemic regulation of calcification, suggesting potential pathways for the action of Abcc6 in DCC. Our results demonstrate the power of the integrative genomics in discovering causal genes and pathways underlying complex traits.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/fisiologia , Calcinose/genética , Regulação da Expressão Gênica , Genômica , Cardiopatias/genética , Miocárdio/metabolismo , Animais , Proteína Morfogenética Óssea 2 , Proteínas Morfogenéticas Ósseas/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C3H , Camundongos Endogâmicos C57BL , Proteínas Associadas à Resistência a Múltiplos Medicamentos , Osteopontina/biossíntese , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Proteínas Wnt/metabolismo
4.
Genomics ; 86(3): 259-70, 2005 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16039824

RESUMO

In the analysis of complex traits, congenic strains are powerful tools because they allow characterization of a single locus in the absence of genetic variation throughout the remainder of the genome. Here, we report the construction and initial characterization of a genome-wide panel of congenic strains derived from the donor strain DBA/2J on the background strain C57BL/6J. For many strains, we have carried out high-density SNP genotyping to precisely map the congenic interval and to identify any contaminating regions. Certain strains exhibit striking variation in litter size and in the ratio of females to males. We illustrate the utility of the set by "Mendelizing" the complex trait of myocardial calcification. These 65 strains cover more than 95% of the autosomal genome and should facilitate the analysis of the many genetic trait differences that have been reported between these parental strains.


Assuntos
Genômica , Camundongos Congênicos/genética , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Animais , Feminino , Genoma , Genótipo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA
5.
Hypertension ; 45(3): 451-9, 2005 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-15655120

RESUMO

Previously, a blood pressure (BP) quantitative trait locus (QTL) on rat chromosome 9 (RNO9) was localized to a <2.4 cM interval using congenic strains generated by introgressing segments of RNO9 from the Dahl salt-resistant (R) rat into the background of the Dahl salt-sensitive (S) rat. Renal gene expression using Affymetrix gene chips was profiled on S and a congenic strain spanning the 2.4-cM BP QTL interval. This analysis identified 20 differentially expressed genes/expressed sequence tags. Of these, the locus with the greatest differential expression (30- to 35-fold) was regulated endocrine-specific protein 18 (Resp18), which also mapped in the 2.4-cM BP QTL interval. Additional substitution mapping located the QTL to <0.4 cM or approximately 493 kb. This newly defined QTL region still included Resp18. Nucleotide variants were identified between S and R genomic DNA of Resp18 in the coding, 5' regulatory and 3' untranslated regions. The coding sequence variation (T/C) occurs in exon 2 and predicts an amino acid change (Ile/Val) in the protein product. Resp18 was considered a differentially expressed positional candidate for the QTL. To fine-map the BP QTL, we constructed a congenic strain with a smaller introgressed region. Compared with the S rat, this strain (1) had significantly lower BP, (2) did not contain the R form of Resp18, and (3) did not retain the rather spectacular differential expression of Resp18. Together, these results demonstrate that a BP QTL independent of Resp18 exists within the newly defined 117-kb QTL region on RNO9.


Assuntos
Pressão Sanguínea/genética , Mapeamento Cromossômico , Expressão Gênica , Genoma , Rim/metabolismo , Locos de Características Quantitativas , Animais , Animais Congênicos , Mapeamento Cromossômico/métodos , Perfilação da Expressão Gênica , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , Polimorfismo de Nucleotídeo Único , Ratos , Ratos Endogâmicos Dahl , Ratos Endogâmicos , Especificidade da Espécie
6.
Genomics ; 81(2): 210-20, 2003 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-12620399

RESUMO

A blood pressure (BP) quantitative trait locus (QTL) was previously found on rat chromosome 9 using Dahl salt-sensitive (S) and Dahl salt-resistant (R) rats. A congenic strain, S.R(chr9), constructed by introgressing an R chromosomal segment into the S background, previously proved the existence of a BP QTL in a large 34.2-cM segment of chromosome 9. In the current work congenic substrains were constructed from the progenitor congenic strain, S.R(chr9). BP and heart weight comparisons between these congenic substrains and their S control localized the BP QTL to a 4.6-cM interval. Two solute carrier (Na(+)/H(+) exchanger) genes, Nhe2 and Nhe4, were excluded as candidates based on their map locations. A second iteration of congenic substrains was used to localize the QTL further to a 2.4-cM interval. Another solute carrier (Cl(-)/HCO3- exchanger) gene, Ae3, is in this reduced interval and was sequenced for both S and R strains, but no coding sequence variations were found. Ae3 mRNA was not differentially expressed in the kidney of congenic compared to S rats. Although the identity of the QTL remains unknown its map location has been reduced from an interval of 34.2 to 2.4 cM.


Assuntos
Pressão Sanguínea/genética , Mapeamento Cromossômico , Locos de Características Quantitativas , Animais , Animais Congênicos , Antiporters/genética , Repetições de Microssatélites , Isoformas de Proteínas/genética , Ratos
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