MMPs and TIMPs levels are correlated with anthropometric parameters, blood pressure, and endothelial function in obesity.

The association between matrix metalloproteinases (MMPs), tissue inhibitor of metalloproteinases (TIMPs) and obesity as well as obesity-related disease including metabolic syndrome is not fully explored. Our aims are that: (i) to evaluate the plasma levels of MMP-1, MMP-2, MMP-3, MMP-9, TIMP-1, TIMP-2 and their ratios in non-obese people, overweight and obese people with or without metabolic syndrome, (ii) to investigate correlations between MMPs or TIMPs levels and several anthropometric parameters, blood pressure, endothelial function. Anthropometric and biochemical parameters were determined in 479 randomly selected participants, subdividing according to body mass index (BMI) and metabolic syndrome status. Plasma MMPs and TIMPs levels were measured. The assessment of endothelial function was characterized in people with obesity, overweight and non-obese, using laser Doppler Flowmetry. Obese people have elevated MMP-1, MMP-2, TIMP-1, TIMP-2 levels and decreased MMP-3/TIMP-1 and MMP-9/TIMP-1 ratios compared with non-obese people. MMP-1 levels and MMP-1/TIMP-1 ratio were positively correlated with BMI and waist circumference (WC) while MMP-2 levels were negatively correlated with BMI and WC values in obese people. MMP-3 levels and MMP-3/TIMP-1 ratio were positively correlated with systolic blood pressure (SBP) or diastolic blood pressure (DBP) in obese and metabolic syndrome people. Additionally, MMP-9 levels and MMP-9/TIMP-1 ratio were negatively correlated with endothelium-dependent response in obese and metabolic syndrome people. MMP-1, MMP-2, TIMP-1, TIMP-2 levels were increased in obese subjects. Significant correlations between anthropometric parameters and MMP-1 as well as MMP-1/TIMP-1 ratio supported these results. MMP-3 and -9 levels as well as their ratios with TIMP-1 were associated with blood pressure and endothelial-dependent response, respectively. In conclusion, our results demonstrated that MMP-1, MMP-3 and MMP-9 levels were correlated with several obesity-related parameters including BMI, WC, blood pressure and endothelial-dependent response. Our findings will hopefully provide new aspects for the use of MMPs and TIMPs as clinical biomarkers in obesity-related cardiovascular diseases such as metabolic syndrome and hypertension. The lack of measure of MMPs activity in plasma and relevant organs/tissues in obesity and metabolic syndrome is considered as a limitation in this report.

Prostaglandin Endoperoxide H Synthase-2 (PGHS-2) Variants and Risk of Obesity and Microvascular Dysfunction Among Tunisians: Relevance of rs5277 (306G/C) and rs5275 (8473T/C) Genetic Markers.

The purpose of this study was to determine the impact of six PGHS-2 genetic variants on obesity development and microvascular dysfunction. The study included 305 Tunisian subjects (186 normal weights, 35 overweights and 84 obeses). PCR analyses were used for allelic discrimination between polymorphisms. Prostaglandin (PGE2, PGI2), leptin, and matrix metalloproteinase (MMP1, 2, 3, 9) levels were evaluated by ELISA. Fatty acid composition was performed by gas chromatography-mass spectrometry. Our results revealed that subjects carrying the PGHS-2 306CC (rs5277) and 8473CC (rs5275) genotypes present higher anthropometric values compared to wild-type genotypes (306GG, BMI (Kg/m2): 27.11 ± 0.58; WC (cm): 93.09 ± 1.58; 306CC, BMI: 33.83 ± 2.46; WC: 109.93 ± 5.41; 8473TT, BMI: 27.75 ± 0.68; WC: 93.96 ± 1.75; 8473CC, BMI: 33.72 ± 2.2; WC: 117.89 ± 2.94). A reduced microvascular reactivity and a higher PGE2 level were also found in individuals with the 306CC and 8473CC genotypes in comparison to 306GG and 8473TT carriers (306GG, Peak Ach-CVC (PU/mmHg): 0.46 ± 0.03; PGE2 (pg/ml): 7933.1 ± 702; 306CC, Peak Ach-CVC: 0.24 ± 0.01; PGE2: 13,380.3 ± 966.2; 8473TT, Peak Ach-CVC: 0.48 ± 0.05; PGE2: 7086.41 ± 700.31; 8473CC, Peak Ach-CVC: 0.23 ± 0.01; PGE2: 13,175.7 ± 1165.8). Fatty acid analysis showed a significant increase of palmitic acid (PA) (34.2 ± 2.09 vs. 16.82% ± 1.76, P < 0.001), stearic acid (SA) (25.76 ± 3.29 vs. 9.05% ± 2.53, P < 0.001), and linoleic acid (LA) (5.25 ± 1.18 vs. 0.5% ± 0.09, P < 0.001) levels in individuals carrying the PGHS-2 306CC genotype when compared to GG genotype individuals. Subjects with the 8473CC genotype showed also a significant increase of PA, SA ,and LA levels when compared to TT genotype carriers (PA: 38.02 ± 1.51 vs. 12.65% ± 1.54, P < 0.001; SA: 32.96 ± 1.87 vs. 1.38% ± 0.56, P < 0.001; LA: 26.84 ± 2.09 vs. 3.7% ± 1.54, P < 0.001). Logistic regression analysis revealed that PGHS-2 306CC and 8473CC variants are significantly associated with obesity status (OR 6.25, CI (1.8-21.6), P = 0.004; OR 3.01, CI (1.13-8.52), P = 0.03, respectively). Haplotypes containing the C306:T8473 (OR 2.91; P = 0.01) and G306:C8473 (OR 5.25; P = 0.002) combinations were associated with an enhanced risk for obesity development in the studied population. In conclusion, our results highlight that PGHS-2 306G/C and 8473T/C variants could be useful indicators of obesity development, inflammation, and microvascular dysfunction among Tunisians.

Impact of cathepsin D activity and C224T polymorphism (rs17571) on chronic obstructive pulmonary disease: correlations with oxidative and inflammatory markers.

BACKGROUND: Cathepsin D (CTSD) is an aspartyl proteinase that plays an important role in protein degradation, antigen processing and apoptosis. It has been associated with several pathologies such as cancer, Alzheimer's disease and inflammatory disorders. Its function in lung diseases remains, however, controversial. In the current study, we determined CTSD activity in serum of patients with chronic obstructive pulmonary disease (COPD) and evaluated the correlations between this proteinase and inflammatory and oxidative parameters. We also investigated the impact of a CTSD C224T polymorphism on enzyme activity and clinicopathological parameters. METHODS: Our population included 211 healthy controls and 138 patients with COPD. CTSD activity, MMPs (-1/-7/-12), cytokines (IL-6, TNF-α), malondialdehyde (MDA), nitric oxide and peroxynitrite levels were measured in patients and controls using standard methods. Genotyping of CTSD C224T polymorphism was determined using PCR-RFLP. RESULTS: Our results showed an increased CTSD activity in COPD patients compared to healthy controls (4.87 [3.99-6.07] vs. 3.94 [2.91-5.84], respectively, p < 0.001). COPD smokers presented also a higher CTSD activity when compared to nonsmokers (4.91[3.98-6.18] vs. 4.65[4.16-5.82], respectively, p = 0.01), while no differences were found when subjects were compared according to their GOLD stages. The activity of this proteinase was not dependent on the C224T polymorphism because we did not found any influence of this SNP on proteinase activity among patients and controls. Furthermore, our data provide the first evidence of the interrelationships between CTSD activity and both MMPs and TNF-α levels (MMP-1[r = - 0.4; p = 0.02], MMP-7[r = 0.37; p = 0.04], MMP-12[r = 0.43; p = 0.02], TNF-α [r = 0.89, p = 0.001]) in COPD smokers. There were no correlations, however, between CTSD activity and oxidative stress parameters in controls and patients. CONCLUSION: Our findings suggest that CTSD could be a relevant marker for COPD disease. Alteration of CTSD activity may be related to increased MMPs and TNF-α levels, particularly in COPD smokers.

Role of MMP-1 (-519A/G, -1607 1G/2G), MMP-3 (Lys45Glu), MMP-7 (-181A/G), and MMP-12 (-82A/G) Variants and Plasma MMP Levels on Obesity-Related Phenotypes and Microvascular Reactivity in a Tunisian Population.

AIMS: The impact of MMP-1 (-519A/G, -1607 1G/2G), MMP-3 Lys45Glu (A/G), MMP-7 -181A/G, and MMP-12 -82A/G variants and plasma MMP levels on obesity and microvascular reactivity in Tunisians. METHODS: Our population included 202 nonobese and 168 obese subjects. Anthropometric, biochemical, and microvascular parameters were determined according to standard protocols. PCR-RFLP and ELISA were used to determine the genetic variants and levels of MMPs, respectively. RESULTS: The MMP-3 45Glu (G) allele associates with higher anthropometric values and MMP-3 levels compared to AA genotype carriers (BMI (kg/m2): 30 ± 0.51 versus 27.33 ± 0.8, P = 0.004; MMP-3 levels: 7.45 (4.77-11.91) versus 5.21 (3.60-10.21) ng/ml, P = 0.006). The MMP-12 -82G allele was also associated with higher BMI values when compared to subjects carrying the AA genotype (31.41 ± 0.85 versus 28.76 ± 0.43, P < 0.001). Individuals carrying the MMP-3 45G or MMP-12 -82G variants were also associated with a higher risk for severe forms of obesity (MMP-3: OR = 1.9, P = 0.002; MMP-12: OR = 2.63, P = 0.003). Similarly, the MMP-7 -181G allele was associated with a higher MMP-7 level and an increased risk for morbid obesity when compared to AA genotype carriers (0.32 (0.31-0.60) versus 0.18 (0.17-0.24) ng/ml, P = 0.01; OR = 1.67, P = 0.02, resp.). CONCLUSION: MMP-3, MMP-7, and MMP-12 polymorphisms associate with obesity risk and its severity.

Role of eNOS- and NOX-containing microparticles in endothelial dysfunction in patients with obesity.

OBJECTIVE: To explore the pathophysiological profile of patients who have obesity and to investigate the potential role of circulating microparticles (MPs) in endothelial dysfunction in patients who have obesity. METHODS: The inflammatory and oxidative status and the cutaneous microvascular blood flow were characterized in 69 patients with android obesity and 46 subjects with normal weight (controls) by using laser Doppler flowmetry. Circulating MP levels were measured by flow cytometry, and endothelial nitric oxide synthase (eNOS) and NADPH oxidase (NOX) expression in MPs was investigated by Western blotting. MP effect on vascular reactivity was assessed in rat aorta rings. RESULTS: Patients with obesity showed endothelial dysfunction, hyperglycemia, inflammation, and oxidative stress. In controls, low MP levels were positively correlated with normal microvascular function. Western blot analysis revealed reduced eNOS and increased NOX4D expression in MPs from subjects with obesity compared with controls. However, this was not correlated with endothelial dysfunction parameters and did not impair ex vivo endothelium-dependent vasodilation. CONCLUSIONS: These results suggest that MPs do not contribute directly to endothelial dysfunction associated with obesity. Conversely, eNOS- and NOX-containing MPs could be involved in the compensatory mechanism of vascular endothelial cells to counteract the pathologic mechanisms underlying endothelial dysfunction.