Publication
Molecular targeting of proteins by homocysteine: implications in familial and clinical hypercholesterolemia
| dc.contributor.advisor | Pereira, Sofia | |
| dc.contributor.advisor | Bourbon, Mafalda | |
| dc.contributor.author | Marques Lemos, Ana Rita | |
| dc.date.accessioned | 2016-03-22T15:18:39Z | |
| dc.date.available | 2016-03-22T15:18:39Z | |
| dc.date.issued | 2015-11-18 | |
| dc.description | Dissertação de Mestrado em Genética Molecular e Biomedicina, apresentado à Faculdade de Ciências e Tecnologia da Universidade Nova de Lisboa, 2015. Defendida e aprovada em 18 de novembro de 2015. | pt_PT |
| dc.description | Trabalho de investigação realizado em colaboração com Departamento de Promoção da Saúde e Prevenção de Doenças Não Transmissíveis do Instituto Nacional de Saúde Doutor Ricardo Jorge, Grupo de Investigação Cardiovascular (Setembro 2014 – Setembro 2015). | pt_PT |
| dc.description | Co-orientadora Mafalda Bourbon: Departamento de Promoção da Saúde e Prevenção de Doenças não Transmissíveis, do Instituto Nacional de Saúde Doutor Ricardo Jorge. | pt_PT |
| dc.description.abstract | [PT] As doenças cardiovasculares (DCVs) são uma das principais causas de morte mundialmente e um dos factores que esta na sua origem e a hipercolesterolémia. A hipercolesterolémia pode ter uma base genética (hipercolesterolémia familiar, HF) e não genética (hipercolesterolémia clinica, HC), sendo a primeira muito mais severa, originando aterosclerose prematura. Se por um lado a função patofisiológica da homocisteína (Hcy) na DCV e ainda controversa, por outro, a S e N-homocisteinilacão de proteínas oferece um novo paradigma a ser considerado na patogénese vascular da hipercolesterolémia. Neste sentido, o presente estudo ambiciona revelar novos conceitos sobre a ligação de Hcy a proteínas, na HC e HF. Foram incluídos no estudo 187 indivíduos: 65 normolipidémicos e 122 hipercolesterolémicos. As fraccões de Hcy total (tHcy) e livre (fHcy) foram quantificadas em amostras de soro apos validação de um método de HPLC-FD, para avaliar a S-homocisteinilacão. A actividade de lactonase (LACase) da enzima paraoxonase-1 (PON1) foi quantificada por um ensaio colorimétrico para avaliar a N-homocisteinilacão. Os níveis de tHcy não diferem entre grupos. Não obstante, a fraccão fHcy diminui nos grupos hipercolesterolémicos, com maior evidencia para a população HF. Consequentemente, parece haver um aumento de S-homocisteinilacão, independentemente da terapia de redução lipídica (TRL). Também a actividade LACase e mais baixa neste grupo, mesmo com TRL, por isso, o risco de Nhomocisteinilacão parece ser maior. Alem disso, a diminuição dos rácios LACase/ApoA1 e LACase/HDL na população HF mostra que a lipoproteína de alta densidade (HDL) esta disfuncional nesta população apesar da concentração ser normal. Os resultados suportam a hipótese de que a função patofisiológica da Hcy na Hipercolesterolemia pode residir na sua capacidade de fazer modificações pos-traducionais em proteínas. Este fenómeno e particularmente evidente na condição de HF. No futuro será interessante identificar quais as proteínas-alvo envolvidas na progressão da patologia vascular. ABSTRACT - Cardiovascular diseases (CVDs) are one of the leading causes of death and disability worldwide and one of its underlying causes is hypercholesterolemia. Hypercholesterolemia can have genetic (familial hypercholesterolemia, FH) and non-genetic causes (clinical hypercholesterolemia, CH), the first much more severe, with occurrence of premature atherosclerosis. While the pathophysiological role of homocysteine (Hcy) on CVD is still controversial, molecular targeting of protein by S and N-homocysteinylation offers a new paradigm to be considered in the vascular pathogenesis of hypercholesterolemia. On this regard, the present study aims to give new insights on protein targeting by Hcy in both CH and FH conditions. A total of 187 subjects were included: 65 normolipidemic and 122 hypercholesterolemic. Total (tHcy) and free (fHcy) fractions were quantified in serum samples after validation of an HPLCFD method, to assess S-homocysteinylation. Also, the lactonase (LACase) activity of paraoxonase-1 (PON1) was quantified by a colorimetric assay, as a surrogate of N-homocysteinylation. tHcy does not differ among groups. Nevertheless, fHcy declines in the hypercholesterolemic groups, with more evidence to the FH population. Consequently, there seems to be an increase of Shomocysteinylation, regardless of lipid lowering therapy (LLT). Also, despite of LLT use, LACase activity is lower in FH, thus the risk for protein N-homocysteinylation seems to be higher. Moreover, the decrease in LACase/ApoA1 and LACase/HDL ratios in FH, shows that HDL is dysfunctional in this population, despite its normal concentration values. Data supports that the pathophysiological role of Hcy on hypercholesterolemia may reside in its ability to post-translationally modify proteins. This role is particularly evident in FH condition. In the future, it will be interesting to identify which target proteins are modified and thus involved in vascular pathology progression. Cardiovascular diseases (CVDs) are one of the leading causes of death and disability worldwide and one of its underlying causes is hypercholesterolemia. Hypercholesterolemia can have genetic (familial hypercholesterolemia, FH) and non-genetic causes (clinical hypercholesterolemia, CH), the first much more severe, with occurrence of premature atherosclerosis. While the pathophysiological role of homocysteine (Hcy) on CVD is still controversial, molecular targeting of protein by S and N-homocysteinylation offers a new paradigm to be considered in the vascular pathogenesis of hypercholesterolemia. On this regard, the present study aims to give new insights on protein targeting by Hcy in both CH and FH conditions. A total of 187 subjects were included: 65 normolipidemic and 122 hypercholesterolemic. Total (tHcy) and free (fHcy) fractions were quantified in serum samples after validation of an HPLCFD method, to assess S-homocysteinylation. Also, the lactonase (LACase) activity of paraoxonase-1 (PON1) was quantified by a colorimetric assay, as a surrogate of N-homocysteinylation. tHcy does not differ among groups. Nevertheless, fHcy declines in the hypercholesterolemic groups, with more evidence to the FH population. Consequently, there seems to be an increase of Shomocysteinylation, regardless of lipid lowering therapy (LLT). Also, despite of LLT use, LACase activity is lower in FH, thus the risk for protein N-homocysteinylation seems to be higher. Moreover, the decrease in LACase/ApoA1 and LACase/HDL ratios in FH, shows that HDL is dysfunctional in this population, despite its normal concentration values. Data supports that the pathophysiological role of Hcy on hypercholesterolemia may reside in its ability to post-translationally modify proteins. This role is particularly evident in FH condition. In the future, it will be interesting to identify which target proteins are modified and thus involved in vascular pathology progression. | pt_PT |
| dc.description.abstract | [EN] Cardiovascular diseases (CVDs) are one of the leading causes of death and disability worldwide and one of its underlying causes is hypercholesterolemia. Hypercholesterolemia can have genetic (familial hypercholesterolemia, FH) and non-genetic causes (clinical hypercholesterolemia, CH), the first much more severe, with occurrence of premature atherosclerosis. While the pathophysiological role of homocysteine (Hcy) on CVD is still controversial, molecular targeting of protein by S and N-homocysteinylation offers a new paradigm to be considered in the vascular pathogenesis of hypercholesterolemia. On this regard, the present study aims to give new insights on protein targeting by Hcy in both CH and FH conditions. A total of 187 subjects were included: 65 normolipidemic and 122 hypercholesterolemic. Total (tHcy) and free (fHcy) fractions were quantified in serum samples after validation of an HPLCFD method, to assess S-homocysteinylation. Also, the lactonase (LACase) activity of paraoxonase-1 (PON1) was quantified by a colorimetric assay, as a surrogate of N-homocysteinylation. tHcy does not differ among groups. Nevertheless, fHcy declines in the hypercholesterolemic groups, with more evidence to the FH population. Consequently, there seems to be an increase of Shomocysteinylation, regardless of lipid lowering therapy (LLT). Also, despite of LLT use, LACase activity is lower in FH, thus the risk for protein N-homocysteinylation seems to be higher. Moreover, the decrease in LACase/ApoA1 and LACase/HDL ratios in FH, shows that HDL is dysfunctional in this population, despite its normal concentration values. Data supports that the pathophysiological role of Hcy on hypercholesterolemia may reside in its ability to post-translationally modify proteins. This role is particularly evident in FH condition. In the future, it will be interesting to identify which target proteins are modified and thus involved in vascular pathology progression. | pt_PT |
| dc.identifier.uri | http://hdl.handle.net/10400.18/3702 | |
| dc.language.iso | eng | pt_PT |
| dc.relation.publisherversion | http://run.unl.pt/handle/10362/16330 | pt_PT |
| dc.subject | Hipercolesterolémia | pt_PT |
| dc.subject | Doença Cardiovascular | pt_PT |
| dc.subject | Homocisteinilação de Proteínas | pt_PT |
| dc.subject | Paraoxonase-1 | pt_PT |
| dc.subject | Actividade Lactonase | pt_PT |
| dc.subject | Doenças Cardio e Cérebro-vasculares | pt_PT |
| dc.subject | Hypercholesterolemia | pt_PT |
| dc.subject | Cardiovascular Disease | pt_PT |
| dc.subject | Protein Homocysteinylation | pt_PT |
| dc.subject | Paraoxonase-1 | pt_PT |
| dc.subject | Lactonase Activity | pt_PT |
| dc.title | Molecular targeting of proteins by homocysteine: implications in familial and clinical hypercholesterolemia | pt_PT |
| dc.type | master thesis | |
| dspace.entity.type | Publication | |
| oaire.citation.endPage | 47 | pt_PT |
| oaire.citation.startPage | xx, 1 | pt_PT |
| rcaap.rights | openAccess | pt_PT |
| rcaap.type | masterThesis | pt_PT |
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