Effects of MMP-2 and TIMP-2 levels and -1575 G/A; -1306 C/T and -735 C/T MMP-2 polymorphisms in resistant hypertension

Introduction: The lack of blood pressure control (BP) (? 140/90 mmHg) - even with the use of three or more antihypertensive drugs of different classes - define the group of resistant hypertension (RH), a group of high cardiovascular (CV) risk and high incidence of target organ damage (TOD). Studies suggest the involvement of metalloproteinase 2 (MMP-2) in hypertension and in CV remodeling associated with TOD. Hypertension is a multifactorial condition in which genetic factors may have a great contribution to the development of the disease. Single nucleotide polymorphisms (SNPs) of MMP-2 were associated with cardiovascular changes, but few studies have assessed the impact of MMP-2 polymorphisms in clinical conditions and their influence in RH. Objective: The objective of this study was to compare MMP-2 and TIMP-2 (tissue inhibitor of metalloproteinase-2) levels in mild-moderate hypertensive (HT) patients and RH patients, as well as the association of MMP 2 and TIMP-2 with TOD such as arterial stiffness and cardiac hypertrophy. We also evaluated the frequency of MMP-2 SNPs (-1575G / A; -1306C / T, and -735C / T) in these groups and we analyzed the association of these three polymorphisms in the RH group. Finally, we identified which polymorphisms of MMP-2 may be related to arterial stiffness and cardiac hypertrophy in the RH population. Methods: One hundred and nineteen RH patients and one hundred thirty six HT patients were included and underwent clinical and laboratory analysis. Genotypes were evaluated by allelic discrimination assay using the technique of real time polymerase chain reaction (RT-PCR). Clinical and laboratory characteristics were compared according to the genotypes / haplotypes of SNPs (rs243865, rs243866 and rs2285053). Target organ damage was categorized by the Left Ventricular Mass Index (LVMI) (women> 95 g / m2 and men> 115g / m2) and arterial stiffness (PWV> 10 m/s). Results: MMP-2 levels showed no differences among NT, HT and RH groups, while TIMP-2 levels were higher in RH compared to HT and NT (90.0 (76.1-107.3) vs. 70.1 (57.7-88.3) vs.54.7 (40.9-58.1) ng/mL, p<0.01), respectively. MMP-2/TIMP-2 ratio was reduced in RH group compared to HT and NT subjects (2.7 (1.9-3.4) vs.3.3 (2.6-4.2) vs.4.9 (4.5-5.3), p<0.01), respectively. No associations were found between MMP-2 levels, TIMP-2 and MMP-2/TIMP-2 ratio with cardiac hypertrophy and arterial stiffness in both groups. Finally, in a regression analysis reduced MMP-2/TIMP-2 ratio and increased TIMP-2 levels were independently associated with RH. Regarding the studied polymorphisms, there was no difference between the allelic and genotypic frequencies in both groups, however the haplotype frequencies of polymorphisms -1575G / A, rs243866; -1306C / T, rs243865, and -735C / T, rs2285053 respectively, were different between groups (GCC vs GCT vs ATC, p = 0.003). In addition, no association between the studied SNPs and TOD was found. Finally, regression analysis demonstrated that GCC haplotype, the CC genotype and C allele (both for the polymorphism rs2285053, - 735C / T) were associated with the presence of RH. Furthermore, GCT haplotype was associated with reduced risk for the presence of RH. Conclusion: The findings suggest that TIMP-2 is associated with the phenotype of resistant hypertension and can be explored as a possible biomarker in RH. Furthermore, our findings suggest that the MMP-2 polymorphism rs2285053 (-735C/T) is associated with the resistance of antihypertensive treatment and may represent an additional risk for the presence of HAR (AU)