Common matrix metalloproteinase 2 gene haplotypes may modulate left ventricular remodelling in hypertensive patients

Abstract

Matrix metalloproteinases (MMPs) are involved in cardiac remodelling. We examined whether MMP-2 genetic polymorphisms are associated with hypertension and left ventricular (LV) remodelling in hypertensive patients. We studied 160 hypertensive patients and 123 healthy controls. Echocardiography was performed in all patients and the C À1306 T (rs243865) and C À735 T (rs 2285053) MMP-2 polymorphisms were analysed. Haplo.stats analysis was used to evaluate whether MMP-2 haplotypes are associated with hypertension and with extremes in LV mass index (LVMI). Multiple linear regression analysis was performed to assess whether MMP-2 genotypes or haplotypes affect LVMI and other echocardiography parameters. The C À1306 T 'CC' genotype was associated with reduced LVMI and LV end-diastolic diameter (EDD) (P ¼ 0.0365 and P ¼ 0.0438, respectively). The haplotype 'C, C' was associated with reduced LVMI and EDD (P ¼ 0.0278 and P ¼ 0.0322, respectively). The comparison of upper and lower extremes of the LVMI phenotype showed that the 'C, C' haplotype was more common in the lower LVMI group (P ¼ 0.0060), whereas the 'T, C' haplotype was more common in the higher quartile of LVMI (P ¼ 0.0187), and this haplotype was associated with increased risk of higher LVMI values (odds ratio ¼ 3.5121, 95% confidence interval ¼ 1.3193-9.3494). The findings suggest that MMP-2 polymorphisms affect hypertension-induced LV remodelling.

Effects of Matrix Metalloproteinase (MMP)‐2 Polymorphisms on Responsiveness to Antihypertensive Therapy of Women with Hypertensive Disorders of Pregnancy

“…Moreover, the lack of significant association between these MMP-2 polymorphisms or MMP-2 haplotypes and hypertensive disorders of pregnancy aligns with a previous study showing that the same polymorphisms and haplotypes are not associated with chronic hypertension [14]. Together, these findings suggest that these functional MMP-2 polymorphisms may affect circulating MMP-2 levels in hypertensive conditions, possibly as a result of their interaction with pathogenetic mechanisms promoting hypertensive phenotypes, but not in normotensive patients, as previously shown [36].…”

“…Genotypes for the MMP-2 g.-1306C>T (rs243865) and g.-735C>T (rs2285053) polymorphisms were determined by real-time polymerase chain reaction (RT-PCR), using Taqman allele discrimination assays (Applied Biosystems, Carlsbad, CA, USA) [14,22]. Probes and primers for genotyping of the g.-1306C>T polymorphism were customized as follows: forward 5′-GCCATT GTCAATGTTCCCTAAAACA-3′, reverse 5′-TGACTTCTGAGCTG AGACCT GAA-3′ and probes 5′-CAGCACTC(T/C)ACCTCT-3′.…”

“…In this respect, two functional MMP-2 genetic polymorphisms apparently affect MMP-2 transcriptional levels: the g.-1306C>T and the g.-735C>T. In vitro studies showed that the 'C' to 'T' substitutions at 1306 and 735 positions in promoter region of MMP-2 gene, respectively, result in increased MMP-2 transcription [11,12]. Interestingly, while both polymorphisms have been associated with hypertension-related complications [13][14][15], there is very little information concerning the effects of MMP-2 polymorphisms on pre-eclampsia or gestational hypertension [16], and no information with respect to the effects of these polymorphisms on the responsiveness to therapeutic approaches in hypertensive disorders of pregnancy.The current treatment of pre-eclampsia includes antihypertensive drugs, and methyldopa and nifedipine are commonly used in such patients [17]. While some antihypertensive drugs, including calcium channel blockers may affect MMP activity [18][19][20], no previous study has examined whether MMP-2 polymorphisms affect the therapeutic responses to drugs used in hypertensive disorders of pregnancy.…”

“…In this respect, two functional MMP-2 genetic polymorphisms apparently affect MMP-2 transcriptional levels: the g.-1306C>T and the g.-735C>T. In vitro studies showed that the 'C' to 'T' substitutions at 1306 and 735 positions in promoter region of MMP-2 gene, respectively, result in increased MMP-2 transcription [11,12]. Interestingly, while both polymorphisms have been associated with hypertension-related complications [13][14][15], there is very little information concerning the effects of MMP-2 polymorphisms on pre-eclampsia or gestational hypertension [16], and no information with respect to the effects of these polymorphisms on the responsiveness to therapeutic approaches in hypertensive disorders of pregnancy.…”

Matrix Metalloproteinase-2 Mediates a Mechanism of Metabolic Cardioprotection Consisting of Negative Regulation of the Sterol Regulatory Element–Binding Protein-2/3-Hydroxy-3-Methylglutaryl-CoA Reductase Pathway in the Heart

“…Two striking examples are (1) functional genetic polymorphisms, which increase MMP-2 gene expression, reportedly protects against cardiac remodeling including increases in end-diastolic diameter and left ventricular mass index in hypertensive subjects and 22 (2) a rare panethnic genetic disease of deficiency in human MMP-2 enzyme activity affects some Saudi Arabian, Indian, and Turkish family with congenital heart disease, including atrial and ventricular septal defects. 23 Our findings suggest a metabolic basis for the presentation of deleterious proinflammatory cardiac phenotypes in MMP-2-deficient humans.…”