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| Author(s): |
Ana Carolina Taveiros Palei
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | Campinas, SP. |
| Institution: | Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas |
| Defense date: | 2010-12-13 |
| Examining board members: |
Jose Eduardo Tanus Santos;
Mary Angela Parpinelli;
Heitor Moreno Junior;
José Xavier Neto;
Silvana Maria Quintana
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| Advisor: | Jose Eduardo Tanus Santos |
| Abstract | |
Preeclampsia is a syndrome characteriz ed by hypertension plus proteinuria. Matrix metalloproteinases (MMPs) are zinc-dependent enzymes that break down several extracellular matrix components, whose activity is modulated mainly by tissue inhibitors of metalloproteinases (TIMPs). Since MMP-2 and MMP-9 ar e essential for the processes of placental and uterine artery remodeling, and they can participate in vascular tone control, levels of these enzymes may be altered in hypertensiv e disorders of pregnancy. It is also possible that polymorphisms in the MMP-9 gene may influence susceptibility to t hese diseases. Thus, the objectives of this study were: 1) to compare plasma MMP-2, MMP-9, TIMP-1 and TIMP-2 concentrations among healthy pregnant (HP), pregnant women with gestational hypertension (GH) and preeclampsia (PE); 2) to compare the genotype and haplotype frequencies of MMP-9 polymorphisms (C T and (CA)n) among HP, GH and PE. And to correlate the MMP-9 concentrations with MMP-9 genotypes and haplotypes too; 3) to compare genotype and haplotype frequencies of these polymorphisms between GH or PE who respond or non-respond to pharmacotherapy with antihypertensives. To achieve our first goal, we determined the plasma pro-MMP-9 and pro-MMP-2 leve ls by zymography, and plasma TIMP-1 and TIMP-2 concentrations by ELISA in GS, HAG and PE. Ou r results showed a net increase in the MMP-9 activity (ratio pro-MMP-9/TIMP-1) in GH, but not in PE, compared with HP. Moreover, to achieve ou r second goal, we firstly extracted DNA from HP, GH and PE volunteers, and then we determined the genotype frequencies of C T and (CA)n polymorphisms by PCR followed by electrophoresis, and the haplotype fr equencies by the program PHASE. It was observed that CT genotype for the C T polymorphism and H4 haplotype (T H) are more frequent in GH, but not in PE, compared with the HP. When we evaluated plasma MMP-9 concentrations according to genotype and haplotype distributions, no statistically significant differences were observed in HP and GH groups; although the LH genotype for (CA) n polymorphism was associated significantly and positively with GH. To approach our third goal, we determined the genotype and haplotype frequenc ies in GH and PE patients classified as responsiveness to methyldopa or to glo bal antihypertensive treatment. We found -1562 -1562 -1562 that CT+TT genotypes are more frequent in GH patients who do not respond to antihypertensives in both approaches, compared with GH who respond. We also found that H2 haplotype (C H) is more common in GH women Who respond to global therapy, and that H4 hap lotype is more common in GH women who do not respond to global therapy. In addi tion, it was found he haplotype H2 are more frequent in PE patients who do not respond to antihypertensives in both approaches, compared with PE who respond. Therefore, our results suggest that MMP-9 has a role in the pat hophysiology of GH and the C T polymorphism and H4 haplotype are associ ated with susceptibility and non-responsiveness to antihypertensive treatment of this disease. While the H2 haplotype is associated with non-responsiveness to antihypertensives in PE (AU) | |