Assuntos
Sistemas CRISPR-Cas/genética , Edição de Genes/métodos , Edição de Genes/tendências , Terapia Genética/métodos , Terapia Genética/tendências , Cardiopatias/genética , Cardiopatias/prevenção & controle , Substituição de Aminoácidos , Proteína 3 Semelhante a Angiopoietina , Proteínas Semelhantes a Angiopoietina/deficiência , Proteínas Semelhantes a Angiopoietina/genética , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Apolipoproteína B-100/deficiência , Apolipoproteína B-100/genética , Apolipoproteínas C/genética , LDL-Colesterol/sangue , Modelos Animais de Doenças , Distrofina/genética , Distrofina/metabolismo , Cardiopatias/sangue , Cardiopatias/terapia , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/genética , Hipercolesterolemia/prevenção & controle , Lipoproteína(a)/deficiência , Lipoproteína(a)/genética , Camundongos , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/terapia , Mutação , Isquemia Miocárdica/tratamento farmacológico , Isquemia Miocárdica/genética , Isquemia Miocárdica/prevenção & controle , Inibidores de PCSK9 , Segurança do Paciente , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertase 9/metabolismo , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/prevenção & controleRESUMO
Cancer progression is characterized by loss of extracellular matrix (ECM) integrity, which is a precondition for tumor growth and metastasis. In order to elucidate the precise mechanisms of ECM degradation in cancer we used a genetically modified mouse mimicking two distinct human metabolic features associated with carcinogenesis, the lack of endogenous vitamin C synthesis and the production of human Lp(a). Female Lp(a)+; Gulo(-/-) and control wild-type Balb/c mice without these two metabolic features were orthotopically inoculated with 4T1 breast cancer cells (5x105). The transgenic and control mice were divided into 4 different dietary groups in respect to dietary vitamin C intake: i) low ascorbate intake for 6 weeks; ii) high ascorbate intake for 6 weeks; iii) low ascorbate intake for 3 weeks followed by high ascorbate for 3 weeks; iv) high ascorbate intake for 3 weeks followed by low ascorbate for 3 weeks. After 6 weeks, all wild-type mice developed tumors. In contrast, Lp(a)+; Gulo(-/-) mice developed one third less primary tumors (low ascorbate diet) or no primary tumors at all (high ascorbate diet). Significantly, tumors from Lp(a)+; Gulo(-/-) mice immunostained positively for Lp(a) and their size was inversely proportional to Lp(a) serum levels. The results implicate that Lp(a) may play a role in controlling tumor growth and expansion. The most likely mechanism is the competitive inhibition of plasmin-induced ECM degradation due to the homology of Lp(a) components to plasminogen. The confirmation of this pathomechanism could lead to a universal therapeutic target for the prevention and treatment of cancer.
Assuntos
Apolipoproteínas A/genética , Apolipoproteínas B/genética , Ácido Ascórbico/administração & dosagem , Lipoproteína(a)/deficiência , Neoplasias Mamárias Experimentais/prevenção & controle , Animais , Apolipoproteínas A/sangue , Apolipoproteínas B/sangue , Linhagem Celular Tumoral , Matriz Extracelular/efeitos dos fármacos , Feminino , Humanos , Neoplasias Mamárias Experimentais/sangue , Neoplasias Mamárias Experimentais/genética , Camundongos , Camundongos TransgênicosRESUMO
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Assuntos
Feminino , Humanos , Masculino , Lipoproteína(a)/administração & dosagem , Lipoproteína(a)/deficiência , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/metabolismo , Dislipidemias/complicações , Dislipidemias/patologia , Terapêutica/métodos , Prevenção Primária/métodos , Cardiopatias/metabolismo , Lipoproteína(a) , Lipoproteína(a)/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos , Dislipidemias/diagnóstico , Dislipidemias/metabolismo , Terapêutica/instrumentação , Prevenção Primária , Cardiopatias/complicaçõesRESUMO
Las lipoproteínas de alta densidad (HDL) transportan colesterol desde la periferia hasta el hígado. Los estudios transversales relacionando las concentraciones bajas de colesterol unido a las HDL (cHDL) con una mayor prevalencia de enfermedad coronaria (EC) datan de los años cincuenta del siglo pasado. Posteriores estudios poblacionales establecieron que el cHDL bajo es un predictor independiente de EC, y así se reconoce en las guías clínicas de prevención cardiovascular. Muchas publicaciones, pero no todas, han establecido una correlación inversa entre incidencia de ictus isquémicos, mortales o no. La proteína transferidora de ésteres de colesterol (CETP) intercambia cHDL por triglicéridos de lipoproteínas de muy baja densidad. Algunas familias con trastornos genéticos de CETP tienen cHDL elevados y menor incidencia de EC. Posteriores estudios observacionales, aunque no todos, han mostrado que sujetos con las anomalías funcionales de CETP tienen cHDL elevado y menor incidencia de EC. Eso ha despertado interés por la inhibición de CETP como intervención para reducir la enfermedad coronaria (AU)
High-density lipoproteins (HDL) transport cholesterol from the periphery to the liver. Cross-sectional studies relating low HDL-cholesterol (HDL-c) concentrations to a higher prevalence of cardiovascular disease (CVD) date back to the 1950s. Subsequent populationbased studies established that low HDL-c levels are an independent predictor of CVD, a finding that is recognized in clinical guidelines for cardiovascular prevention. Many publications, although not all, have established an inverse correlation between the incidence of ischemic stroke, whether fatal or non-fatal, and HDL-c. Cholesteryl ester transfer protein (CETP) facilitates the exchange of triglyceride (for cholesteryl ester) from very low density lipoprotein (VLDL) particles to HDL particles. Some families with genetic CETP alterations have high HDL-c concentrations and a lower incidence of CVD. Some observational studies, but not all, have shown that persons with functional CETP anomalies have high HDL-c levels and a lower incidence of CVD. This observation has prompted interest in CETP inhibition as an intervention to reduce coronary heart disease (AU)
Assuntos
Feminino , Humanos , Masculino , Lipoproteína(a)/deficiência , Lipoproteína(a) , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Colesterol/deficiência , Estudos Transversais/métodos , Acidente Vascular Cerebral/metabolismo , Abetalipoproteinemia/metabolismo , Lipoproteína(a)/farmacologia , Lipoproteína(a)/normas , Doenças Cardiovasculares/diagnóstico , Colesterol/metabolismo , Estudos Transversais/instrumentação , Acidente Vascular Cerebral/líquido cefalorraquidiano , Abetalipoproteinemia/patologiaRESUMO
Apolipoprotein(a) [apo(a)] is a highly polymorphic glycoprotein which has been suggested to play a role in Alzheimer's disease (AD). Plasma lipoprotein(a) [Lp(a)] levels and the differential expression of apo(a) isoforms were analyzed in 73 sporadic AD patients compared with 73 age- and gender-matched healthy controls. The distribution of apo(a) isoforms and Lp(a) concentrations were similar in the two groups. However, we observed that AD patients with no apo(a) isoform from immunoblots (subjects with the 'null phenotype') had a mean age at onset of 76.8+/-8.8 versus 66.9+/-9.6 years of those who expressed at least one apo(a) band (P = 0.010). Multivariate analysis showed that this effect was independent of apolipoproteinE epsilon4 allele. We conclude that the expression of at least one apo(a) isoform may interact with other pathogenic mechanisms involved in controlling the age at onset of AD.
Assuntos
Doença de Alzheimer/genética , Apolipoproteínas/deficiência , Predisposição Genética para Doença/genética , Lipoproteína(a)/deficiência , Idade de Início , Idoso , Doença de Alzheimer/sangue , Doença de Alzheimer/epidemiologia , Apolipoproteína E4 , Apolipoproteínas/sangue , Apolipoproteínas/genética , Apolipoproteínas E/sangue , Apolipoproteínas E/genética , Apoproteína(a) , Análise Mutacional de DNA , Feminino , Testes Genéticos , Humanos , Lipoproteína(a)/sangue , Lipoproteína(a)/genética , Masculino , Fenótipo , Isoformas de Proteínas/sangue , Isoformas de Proteínas/genéticaRESUMO
High plasma concentrations of lipoprotein(a) [Lp(a)], a covalent low-density lipoprotein-apolipoprotein(a) [apo(a)] complex, are associated with coronary heart disease and stroke. Heritability of Lp(a) levels is high and the major locus determining Lp(a) concentrations is the apo(a) gene. We here demonstrate that a G-->A substitution at the +1 donor splice site of the apo(a) kringle (K) IV type 8 intron occurs with a high frequency ( approximately 6%) in Caucasians but not in Africans and is associated with congenital deficiency of Lp(a) in plasma. This mutation alone accounts for a quarter of all 'null' apo(a) alleles in Caucasians. RT-PCR analysis based on apo(a) illegitimate transcription in lympho- blastoid cells demonstrated that the donor splice site mutation results in an alternative splicing of the K IV type 8 intron and encodes a truncated form of apo(a). Expression of the alternatively spliced cDNA analogue in HepG2 cells showed that the truncated apo(a) form is secreted but is unable to form the covalent Lp(a) complex. Immunoprecipitated plasma apo(a) from homozygotes for the mutation was almost completely fragmented. Taken together, our data indicate that a failure in complex formation followed by fast degradation in plasma of the truncated free apo(a) is one mechanism which underlies the null Lp(a) type associated with the donor splice site mutation.
Assuntos
Apolipoproteínas A/genética , Lipoproteína(a)/genética , Mutação Puntual , Alelos , Sequência de Aminoácidos , Substituição de Aminoácidos , Sequência de Bases , População Negra/genética , Carcinoma Hepatocelular/patologia , Clonagem Molecular , Etnicidade/genética , Éxons/genética , Frequência do Gene , Humanos , Íntrons/genética , Kringles/genética , Lipoproteína(a)/deficiência , Neoplasias Hepáticas/patologia , Substâncias Macromoleculares , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Característica Quantitativa Herdável , Splicing de RNA , Transfecção , Células Tumorais Cultivadas , População Branca/genéticaRESUMO
Apolipoprotein A-I (apo A-I) and apolipoprotein A-II (apo A-II) represent 80 90% of the protein content of high density lipoproteins (HDL). Previously we have identified a Finnish family with an apo A-I variant (Lys107-->0) associated with reduced plasma HDL cholesterol level and decreased lipoprotein (Lp)(AI w AII) concentration compared to unaffected family members. To determine the in vivo metabolism of apo A-I and apo A-II in the carriers of apo A-I (Lys107-->0) variant we radioiodinated normal apo A-I with 125I and apo A-II with 131I and compared the kinetic data of two heterozygous apo A-I(Lysl07-->0) patients (HDL cholesterol leves 0.31 and 0.69 mmol/l) to that of eight normolipidemic, healthy control subjects. Plasma radioactivity curves of 125I-labelled normal apo A-I of the patients demonstrated accelerated clearance of apo A-I compared to control subjects. In the two patients the fractional catabolic rates (FCR) of apo A-I were 0.347/day and 0.213/day, respectively, while the mean FCR of apo A-I of the control subjects was 0.151 +/- 0.041/day. Similarly, the plasma decay curves of the 131I-labelled apo A-II showed more rapid clearance of apo A-II in the two patients than in control subjects. The FCR of apo A-II in the two patients were 0.470/day and 0.234/day, while the mean FCR of apo A-II in control subjects was 0.154 +/- 0.029/day. The calculated production rates of apo A-I were similar in patients and in control subjects, and the production rates of apo A-II were significantly higher in patients than in control subjects. Our results show that the Lp(AI w AII) deficiency in patients with the apo A-I(Lys107-->0) is associated with increased fractional catabolic rates of normal apo A-I and apo A-II, while the production rates of these apolipoproteins are normal (apo A-I) or slightly increased (apo A-II).