Matrix metalloproteinase-9 polymorphism contributes to blood pressure and arterial stiffness in essential hypertension

Arterial stiffness is an independent predictor of cardiovascular events in a hypertensive population. Serum levels of matrix metalloproteinase (MMP)-9 are associated with arterial stiffness and predict cardiovascular risk. We investigated the role of MMP-9 polymorphism -1562C>T on blood pressure (BP) and arterial stiffness in a newly diagnosed hypertensive population. Untreated hypertensive patients (n=215, mean age 46+/-13 years) were studied. Supine BP, carotid-femoral pulse wave velocity (PWV) and augmentation index were assessed. Serum biochemistry and plasma MMP-9 concentrations were measured and genotyping performed following extraction of genomic DNA. BP, aortic PWV and serum MMP-9 levels were significantly higher in T-allele carriers of the -1562C>T polymorphism with a significant gene-dose effect (P<0.0001). In a stepwise regression model adjusting for known or likely determinants, the 1562C>T polymorphism emerged as an independent predictor of systolic BP (R(2)=0.25, P<0.0001), diastolic BP (R(2)=0.16, P<0.0001) and PWV (R(2)=0.47,P<0.0001). This is the first study to show the effect of MMP-9 polymorphism on BP and aortic stiffness in a hypertensive population. These results suggest that hypertensive patients carrying the T allele may be at increased risk of cardiovascular events.     

Matrix metalloproteinase-2 (MMP-2) and MMP-9 in pulmonary pathology

The lung is affected by a variety of disease processes that can lead to considerable morbidity and mortality. As the lung is the only organ for respiration and gas exchange, the structural and functional integrity of the lung is of primary importance. Various pathological processes affect the extracellular matrix (ECM) of the lung in an adverse manner, causing destruction of tissue integrity followed by tissue remodeling, which together impair normal pulmonary function. Matrix metalloproteinases (MMPs) are neutral proteinases that are involved in the breakdown and remodeling of the ECM under a variety of physiological and pathological conditions. MMP-2 and MMP-9, collectively known as the gelatinases, are particularly important in the pathogenesis of inflammatory, infectious, and neoplastic diseases in many organs including the lung. This review examines the expression of MMP-2 and MMP-9 in disease of the lung and discusses the role these gelatinases may play in disease progression.     

Plasma levels of MMP-2, MMP-9 and TIMP-1 are not associated with arterial stiffness in subjects with type 2 diabetes mellitus

ObjectiveIncreased arterial stiffness is a marker of atherosclerosis and is recognised early in the course of type 2 diabetes mellitus (T2DM). Matrix metalloproteinases (MMP) and their tissue inhibitors (TIMP) are a family of proteolytic enzymes which are essential for the structure and function of large arteries. In this study, we examined for relationships between MMP and TIMP-1 and indices of arterial stiffness in subjects with T2DM.Research Design and MethodsA total of 60 subjects with T2DM and 60 nondiabetic subjects were recruited. Aortic distensibility (AD) was assessed noninvasively by ultrasonography and augmentation index by pulse wave analysis.ResultsThe values of AD were lower in subjects with T2DM than in controls (P<.001), while those of augmentation index were not significantly different between the two groups. Plasma concentrations of MMP-2 and MMP-9 were not different between diabetic and nondiabetic participants, while those of TIMP-1 were lower in the diabetic patients (P=.005). In the diabetes group, no significant associations were found between either AD or augmentation index and MMPs as well as TIMP-1, while duration of diabetes emerged as the strongest predictor of AD (P<.001). In the nondiabetic group, nonsignificant associations were also found between AD or augmentation index and MMPs as well as TIMP-1.ConclusionIn patients with T2DM, plasma levels of MMP and TIMP-1 are not associated with arterial stiffness assessed by either AD or augmentation index.     

基质金属蛋白酶9在大鼠单纯收缩期高血压模型发生中的作用

目的 研究基质金属蛋白酶9（MMP-9）在单纯收缩期高血压形成中的作用.方法 选用8周龄Wistar 雄性大鼠20只作为研究对象,随机分成两组,模型组（n=10）和对照组（n=10）.应用华法林和维生素K1诱导动脉中层钙化,8周后右侧颈动脉插管进行有创血压和心室内压力的检测.以及取材主动脉,Von Kossa染色分析动脉钙化程度;采用原子吸收光谱法测定血管组织中钙含量.采用弹性纤维染色法观察主动脉组织中弹性纤维形状;应用免疫组织化学和Western blot检测主动脉组织中MMP-9的表达水平.结果 模型组大鼠血压与对照组相比明显增高[收缩压：（ 151±9） vs （113±7） mmHg,P＜0.01,舒张压：（122±10） vs （98±8） mmHg,P＜0.05];而各组间平均左室内压无明显变化.模型组大鼠血压变化的同时伴有动脉形态结构的改变,主动脉和颈动脉中层钙化明显,模型组主动脉钙含量明显高于对照组[（17.9±1.8）vs（5.8±0.6）mg/g,P＜0.01].弹力纤维断裂变直,失去波浪形状.Western免疫印迹法分析模型组MMP-9蛋白表达较对照组明显升高.结论 利用华法林和维生素K1诱导的单纯收缩期高血压大鼠是可重复性好,便捷,以及与人体衰老相似较为理想的模型.MMP-9酶表达明显增多可促使大动脉中层弹力蛋白降解和钙在弹力纤维薄层的沉积,从而在单纯收缩期高血压形成中发挥着一定作用.     

High serum pentosidine concentrations are associated with increased arterial stiffness and thickness in patients with type 2 diabetes

Accumulation of advanced glycation end products in vessel walls may increase arterial stiffness and/or thickness, contributing to a high incidence of cardiovascular disease (CVD) in patients with diabetes. We investigated whether serum concentrations of pentosidine, a well-defined advanced glycation end product, are associated with arterial stiffness or thickness in patients with type 2 diabetes. Pentosidine was measured in sera from 98 patients with type 2 diabetes and 61 age-matched control subjects by a competitive enzyme-linked immunosorbent assay. Arterial stiffness was evaluated by heart-brachial and brachial-ankle pulse wave velocities (PWVs) measured using an automatic device. Arterial thickness was determined ultrasonographically as carotid intima-media wall thickness (IMT). Serum concentrations of pentosidine were significantly higher in patients with diabetes than in control subjects (64.4 +/- 21.0 vs 22.8 +/- 7.0 microg/L; P < .0001). In patients with diabetes, serum pentosidine correlated positively with heart-brachial PWV (r = 0.304; P < .01) but not with brachial-ankle PWV. Serum pentosidine also correlated positively with carotid IMT in patients with diabetes (r = 0.300; P < .01). Serum pentosidine concentrations were significantly higher in patients with diabetes with CVD than in those without (72.3 +/- 23.7 vs 62.3 +/- 19.8 microg/L; P = .0453). By multivariate analysis, only age (partial coefficient = 0.308; P < .05) and serum creatinine (partial coefficient = 0.328; P < .01) retained significant influence on serum pentosidine. After adjustment for renal function, carotid IMT still correlated positively with serum pentosidine (partial coefficient = 0.2736; P = .021). In conclusion, serum pentosidine was positively associated with both arterial stiffness and thickness and CVD in patients with type 2 diabetes.     

Impact of the metalloproteinase-9/tissue inhibitor of metalloproteinase-1 system on large arterial stiffness in patients with essential hypertension.

The extracellular matrix is vital for maintaining tissue integrity, and the matrix metalloproteinases/tissue inhibitors of metalloproteinases (MMPs/TIMPs) system is involved in the regulation of extracellular matrix metabolism. Extracellular matrix turnover plays an important role in the change of large arterial mechanical properties in hypertension. However, the association of the metalloproteinase-9/tissue inhibitor of metalloproteinase-1 (MMP-9/TIMP-1) system and arterial stiffness is not straightforward and existing data are rather limited. Our objective is to explore the impact of the MMP-9/TIMP-1 system on large arterial stiffness in patients with essential hypertension. An automatic pulse wave velocity (PWV) measuring system was used to examine carotid-femoral PWV (CFPWV) and carotid-radial PWV (CRPWV) as the parameters reflecting central elastic large arterial and peripheral muscular medium-sized arterial elasticity, respectively; and serum MMP-9 and TIMP-1 levels, along with a number of other established biomarkers, were measured by enzyme-linked immunosorbent assay (ELISA) in 202 essential hypertensive patients and 54 age and gender-matched control subjects. Compared with the control subjects, hypertensive patients exhibited higher levels of MMP-9 (p=0.001) and TIMP-1 (p=0.002). Spearman's correlation analysis showed that serum levels of MMP-9 (p=0.014) and TIMP-1 (p=0.005) were significantly and positively correlated with CFPWV in hypertensive patients. A stepwise multiple regressive analysis demonstrated that age, systolic blood pressure, heart rate and TIMP-1 were independent predictors of CFPWV in patients with essential hypertension (adjusted r2=0.458). In conclusion, our results imply that the MMP-9/TIMP-1 system may play an important role in the determination of arterial function, and these findings may have implications for the involvement of MMP-9/TIMP-1 system in the pathophysiology of cardiovascular disease.     

Matrix metalloproteinase-9 and metalloproteinase-2 activity and expression is reduced by melatonin during experimental colitis

Abstract:  Matrix metalloproteinases (MMPs) are associated with matrix turnover in both physiological and pathological conditions. Several data indicate that MMPs play an important role in the pathogenesis of colitis. Various evidence has documented that the pineal secretory product melatonin exerts an important anti-inflammatory effect in different experimental models including colitis. However, no reports are available on the relationship between the activity and expression of MMPs and anti-inflammatory effect of melatonin. The aim of the present study was to evaluate whether melatonin prevents the experimental colitis in rats by regulating MMP-9 and MMP-2 activity and expression. Colitis was induced by intracolonic instillation of dinitrobenzene sulphonic acid (DNBS). Four days after DNBS administration, colon TNF- α production was associated with colon damage. Biochemical methods and zymography were used to analyse MMP-9 and MMP-2 activities in colon tissues from DNBS-injured rats. Our studies reveal that melatonin prevented colon injury and lipid peroxidation in rats at 4 days after DNBS-induced colitis. Melatonin also reduced proMMP-9 and MMP-2 activities that were induced in the colon tissues by DNBS administration. Reduced MMP-9 and MMP-2 activities were associated with reduced expression of TNF- α . We conclude that melatonin's ability to reduce DNBS-induced colon injury in rats is related to a reduction in proMMP-9 and MMP-2 activities and expression.     

Isolated systolic hypertension, pulse pressure, and arterial stiffness as risk factors for cardiovascular disease

Arterial stiffening with age is responsible for isolated systolic hypertension, for elevation of systolic pressure with age, and for the majority of cardiovascular events in the elderly, especially left ventricular failure. Change in brachial pulse pressure with age underestimates change in aortic pulse pressure; change with vasodilator agents, especially nitrates, underestimates beneficial effects of these agents on the heart. New methods based on pulse wave analysis complement sphygmomanometry in assessing ill effects of aging and benefits of drug therapy for hypertension.     

Matrix metalloproteinase-3 serum levels are correlated with disease activity and predict clinical response in rheumatoid arthritis

OBJECTIVE: To demonstrate that serum matrix metalloproteinase-3 (MMP-3) is a variable associated with disease activity and with the response to treatment in rheumatoid arthritis (RA). METHODS: Serum MMP-3 levels were measured and compared to biological and clinical disease activity variables in 20 patients with active RA assessed serially during a one year prospective open label trial with methotrexate or tenidap. RESULTS: MMP-3 levels were significantly correlated with C-reactive protein (CRP) and interleukin 6 serum levels as well as with the disease activity score (DAS), not only at start in untreated patients but also during the 12 month followup period in both treated groups. Early changes (after 0.5, 1, 2, or 3 months) in MMP-3 levels were significantly associated with change in DAS observed 4 to 6 months later. CONCLUSION: In addition to CRP, a systemic marker of inflammation, serum MMP-3 may serve as a consistent synovial derived marker of RA disease activity, early changes of which predict disease outcome.     

Matrix metalloproteinase-9 promoter polymorphism associated with upper lung dominant emphysema

RATIONALE: Matrix metalloproteinase 9 (MMP-9) has proteolytic activity against connective tissue proteins and appears to play an important role in the development of chronic obstructive pulmonary disease (COPD). The functional polymorphism of MMP-9 (C-1562T) is considered as one of the candidate genes in the susceptibility to COPD. OBJECTIVES: To determine if MMP-9 (C-1562T) is related to the development of COPD in the Japanese population and whether it is associated with development of pulmonary emphysema assessed by high-resolution computed tomographic (HRCT) parameters. METHODS: MMP-9 (C-1562T) genotypes of 84 patients with COPD and 85 healthy smokers (control subjects) were determined by the restriction fragment length polymorphism method. We investigated the relationship between the genotypes using automatically analyzed HRCT parameters, such as percentage of low attenuation area (LAA%) and average computed tomography (CT) value density (Hounsfield units; mean CTv) in upper, middle, and lower lung fields in all patients with COPD. MEASUREMENTS AND MAIN RESULTS: There was no difference in polymorphism of MMP-9 (C-1562T) between patients with COPD and control subjects. In the HRCT study, patients with COPD with a T allele (C/T or T/T) showed larger LAA% (95% confidence interval of difference, 0.5-18.7; p = 0.04), and smaller mean CTv (confidence interval, -34.3 to -1.0; p = 0.04) in the upper lung compared with patients without T alleles (C/C). However, pulmonary function tests showed no difference between the two patient groups. Patients with a T allele showed a decrease in LAA% and an increase in mean CTv from upper to lower lung fields (p = 0.006 and p = 0.002, respectively). CONCLUSIONS: Polymorphism of MMP-9 (C-1562T) was associated with upper lung dominant emphysema in patients with COPD.     

Decreased serum bilirubin is associated with arterial stiffness in men

Background and aimsThe brachial-ankle pulse wave velocity (baPWV) is a marker for early atherosclerotic changes. Serum total bilirubin (TB) is an effective antioxidant and has been associated with carotid intima-media thickness, cardiovascular disease, stroke and peripheral arterial disease, all of which may be caused by arteriosclerosis. This study aimed to investigate the association of TB with arterial stiffness.Methods and resultsIn this cross-sectional study, we investigated the relationship between TB and baPWV in 2207 participants (1331 men, 876 women) in a general health examination. Different metabolic parameters were compared across TB quartiles. Age-adjusted mean values of baPWV gradually decreased with TB quartiles in men (Q1 = 1348, Q2 = 1266, Q3 = 1215, and Q4 = 1154 cm/s). However, the age-adjusted means of baPWV had no significance in women according to TB quartiles. Univariate analysis showed that age, smoking status, BMI, SBP, DBP, AST, ALT, GGT, TB, TG, and HDL-C were significantly associated with baPWV in men, whereas only age, BMI, SBP, DBP, TG and FPG were significantly associated with baPWV in women. In addition, BMI, SBP, TB, age, TG, and AST were significant factors in the multivariate model with baPWV in men; only BMI and FPG were significant factors with baPWV in women.ConclusionThe findings show that serum total bilirubin concentration is negatively correlated to arterial stiffness in Chinese men. Early detection of abnormal bilirubin levels could potentially serve as an early biomarker for arterial stiffness.     

B-vitamin levels and genetics of hyperhomocysteinemia are not associated with arterial stiffness

Background and aimsHyperhomocysteinemia is associated with arterial stiffness, but underlying pathophysiological mechanisms explaining this association are to be revealed. This study was aimed to explore two potential pathways concerning the one-carbon metabolism. A potential causal effect of homocysteine was explored using a genetic risk score reflecting an individual's risk of having a long-term elevated plasma homocysteine level and also associations with B-vitamin levels were investigated.Methods and resultsBaseline cross-sectional data of the B-PROOF study were used. In the cardiovascular subgroup (n = 567, 56% male, age 72.6 ± 5.6 yrs) pulse wave velocity (PWV) was determined using applanation tonometry. Plasma concentrations of vitamin B12, folate, methylmalonic acid (MMA) and holo transcobalamin (holoTC) were assessed and the genetic risk score was based on 13 SNPs being associated with elevated plasma homocysteine. Associations were examined using multivariable linear regression analysis. B-vitamin levels were not associated with PWV. The genetic risk score was also not associated with PWV. However, the homocysteine–gene interaction was significant (p < 0.001) in the association of the genetic risk score and PWV. Participants with the lowest genetic risk of having long-term elevated homocysteine levels, but with higher measured homocysteine levels, had the highest PWV levels.ConclusionHomocysteine is unlikely to be causally related to arterial stiffness, because there was no association with genetic variants causing hyperhomocysteinemia, whereas non-genetically determined hyperhomocysteinemia was associated with arterial stiffness. Moreover, the association between homocysteine and arterial stiffness was not mediated by B-vitamins. Possibly, high plasma homocysteine levels reflect an unidentified factor, that causes increased arterial stiffness.     

Low plasma renin activity and high aldosterone/renin ratio are associated with untreated isolated systolic hypertension

Abstract Objective. Isolated systolic hypertension (ISH) is generally encountered in elderly patients and there are scarce data regarding the renin-angiotensin-aldosterone system (RAAS) activity in patients with ISH. We aimed to determine the plasma renin activity (PRA), plasma aldosterone levels (PAL) and aldosterone/PRA ratio (PAL/PRA) in patients (age >50 years) with ISH and to compare these values with patients with essential hypertension (EH) as well as subjects with normal blood pressure values (control) who have similar age and cardiovascular risk profile. Methods. Consecutively, 42 untreated ISH patients, 30 patients with EH and 29 normal subjects were included in the study. Parameters were presented as median (interquartile range). Results. There were no significant differences regarding age, gender and other cardiovascular risk factors among groups. As expected, systolic, diastolic blood pressure and pulse pressure values were significantly different among groups. Besides, PRA values were found to be significantly lower in patients with ISH (0.4 [0.2-1.1] ng/ml/h) compared with the EH (0.95 [0.5-2.6] ng/ml/h, p =0.024) and control (1.3 [0.7-2.1] ng/ml/h, p =0.001) groups. Although, PAL were similar among groups, PAL/PRA ratio was significantly higher in ISH group (134.1 [73-224]) compared with those with EH (42.2 [35-84], p <0.001) and the control group (53.3 [30-106], p =0.001). No significant difference was present with respect to PAL/PRA ratio between EH and control groups. Conclusions. Our findings suggested that in patients with ISH, despite lower PRA levels, PAL/PRA ratio is significantly higher compared with the patients with EH and subjects with normal blood pressure. Since higher PAL/PRA levels is an indicator of relative aldosterone excess, medications blocking RAAS activity including aldosterone antagonists may have useful cardiovascular consequences in addition to their antihypertensive effects in ISH.     

Unexplained pulmonary hypertension is associated with systolic arterial hypertension in patients undergoing routine Doppler echocardiography

STUDY OBJECTIVE: To determine the validity of the association between systemic hypertension (HTN) and unexplained pulmonary hypertension (PHTN) as identified with Doppler echocardiography. METHODS: All patients with a reported systolic pulmonary artery pressure (SPAP) on routine Doppler echocardiography from our 1997 echocardiographic database were identified. Exclusions included all diseases known to be associated with PHTN. Of 1,174 patients, 503 had PHTN (defined as a SPAP of >/= 40 mm Hg), of whom 42 (8.4%) had unexplained PHTN. These PHTN patients were matched for age (mean [+/- SD] age, 70 +/- 11 years) with 84 randomly selected patients from the same database who had normal SPAP values and no diseases associated with PHTN. RESULTS: The mean SPAP of those patients with unexplained PHTN was 48 +/- 9 mm Hg vs 31 +/- 5 mm Hg for those without unexplained PHTN. HTN was more prevalent in those with PHTN (98% vs 72%, respectively; p = 0.0008). Patients with unexplained PHTN had significantly higher mean systolic BP, as routinely measured at the end of the echo (154 +/- 26 vs 138 +/- 21 mm Hg, respectively; p = 0.0006), but they did not differ in diastolic BP (80 +/- 14 vs 78 +/- 11 mm Hg, respectively; p = 0.39). PHTN patients and control subjects did not differ with respect to gender (women, 74% vs 70%, respectively), race (white, 64% vs 65%, respectively), body mass index (30 +/- 8 vs 28 +/- 8 kg/m(2), respectively), or left ventricular ejection fraction (64 +/- 6% vs 63 +/- 7%, respectively). When only those with known HTN were considered, PHTN patients still had higher systolic arterial BP (155 +/- 25 vs 143 +/- 21 mm Hg, respectively; p = 0.013) and tended to be on more BP medications (1.6 +/- 1.1 vs 1.2 +/- 0.9, respectively; p = 0.09). CONCLUSIONS: Unexplained PHTN occurs mostly in the elderly, is associated with systolic HTN, and those hypertensive patients with concomitant PHTN have higher systolic arterial pressures.