BACKGROUND AND PURPOSEThe side effects of cyclooxygenase-2 (COX-2) inhibitors on the cardiovascular system could be associated with reduced prostaglandin (PG)I 2 synthesis. Microsomal PGE synthase-1 (mPGES-1) catalyses the formation of PGE 2 from COX-derived PGH 2 . This enzyme is induced under inflammatory conditions and constitutes an attractive target for novel anti-inflammatory drugs. However, it is not known whether mPGES-1 inhibitors could be devoid of cardiovascular side effects. The aim of this study was to compare, in vitro, the effects of mPGES-1 and COX-2 inhibitors on vascular tone in human blood vessels.
EXPERIMENTAL APPROACHThe vascular tone and prostanoid release from internal mammary artery (IMA) and saphenous vein (SV) incubated for 30 min with inhibitors of mPGES-1 or COX-2 were investigated under normal and inflammatory conditions.
KEY RESULTSIn inflammatory conditions, mPGES-1 and COX-2 proteins were more expressed, and increased levels of PGE 2 and PGI 2 were released. COX-2 and NOS inhibitors increased noradrenaline induced vascular contractions in IMA under inflammatory conditions while no effect was observed in SV. Interestingly, the mPGES-1 inhibitor significantly reduced (30-40%) noradrenalineinduced contractions in both vessels. This effect was reversed by an IP (PGI 2 receptor) antagonist but not modified by NOS inhibition. Moreover, PGI 2 release was increased with the mPGES-1 inhibitor and decreased with the COX-2 inhibitor, while both inhibitors reduced PGE 2 release.
CONCLUSIONS AND IMPLICATIONSIn contrast to COX-2 inhibition, inhibition of mPGES-1 reduced vasoconstriction by increasing PGI 2 synthesis. Targeting mPGES-1 could provide a lower risk of cardiovascular side effects, compared with those of the COX-2 inhibitors.
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.
Background and purpose: In patients with pulmonary hypertension (PH) associated with lung disease and/or hypoxia (Group III), a reduction of pulmonary vascular tone and tissue hypoxia are considered therapeutically beneficial. Prostaglandin (PG) E2 and PGI2 induce potent relaxation of human bronchi from non-PH (control) patients via EP4 and IP receptors, respectively. However, the effects of PGE2/PGI2 and their mimetics on human bronchi from PH-patients are unknown. Our aim was to compare the relaxant effects of several PGI2mimetics approved for treating PH-Group I with several PGE2-mimetics in bronchial preparations derived from PH-Group III and control patients. Experimental approach: Using an organ bath system, the tone of bronchial muscle was investigated in tissue from either control or PH-Group III patients. Expression of prostanoid receptors were analyzed by Western blot and real-time PCR and endogenous PGE2, PGI2 and cAMP levels were determined by ELISA.
The purpose of this study was to investigate the long- and short-term inflammatory and apoptotic effects of whey protein on the livers of non-exercising rats. Thirty rats were divided into three groups namely (1) control group, (2) short-term whey (WS) protein diet (252 g/kg for 5 days), and (3) long-term whey (WL) protein diet (252 g/kg for 4 weeks). Interleukin 1β (IL-1β), IL-6, tumor necrosis factor α (TNF-α), and cytokeratin 18 (CK-18-M30) were assessed using enzyme-linked immunosorbent assay and immunohistochemical methods. Apoptosis was evaluated using the terminal transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) method. Hepatotoxicity was evaluated by quanitation of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Based on the biochemical levels and immunohistochemical results, the highest level of IL-1β was identified in the WL group ( p < 0.01). The IL-6 and TNF-α results were slightly lower in the WS group than in the control group and were highest in the WL group ( p < 0.01). The CK-18-M30 and TUNEL results were highest in the WS group and exhibited medium intensity in the WL group ( p < 0.01). AST results were statistically significant for all groups, while our ALT groups were particularly significant between the WL and control groups ( p < 0.01). The results showed that when whey protein is used in an uninformed manner and without exercising, adverse effects on the liver may occur by increasing the apoptotic signal in the short term and increasing inflammatory markers and hepatotoxicity in the long term.
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