Cigarette smoking represses expression of cytokine IL-12 and its regulator miR-21-An observational study in patients with coronary artery disease.

RATIONALE: The heterodimer IL-12 is an inducer of Th1 responses and stimulates INFÆ´ production. Micro-RNA-21 (miR-21) is described as a key regulator of the pro-inflammatory response and has IL-12p35 mRNA as one of its main targets. The IL-12p40 1188A/C genetic variant located in 3'untranslated region (UTR), thus environmentally exposed, has further been reported to modify IL-12 levels. We have previously reported on the lowering effect of cigarette smoke on circulating IL-12 in patients with coronary artery disease (CAD). OBJECTIVES: To explore if cigarette smoking affects IL-12p35, IL-12p40, INFÆ´ and miR-21 gene-expression and further modulates any effect of the IL-12p40 polymorphism on circulating IL-12 levels. METHODS AND RESULTS: The IL-12p40 1188A/C polymorphism was analyzed in 1001 stable CAD patients, of which 330 subjects were included for IL-12p35, IL-12p40 and INFÆ´ gene-expression analyses in circulating leukocytes and 200 were further selected for plasma miR-21 analysis. Smoking associated with lower expression of miR-21 and its target IL-12p35 mRNA (adjusted p<0.05, both) whereas the influence on INFÆ´ expression tended to be high-dose reliant (p = 0.057). The IL-12p40 CC genotype associated with elevated circulating IL-12 levels, however, when stratified according to smoking, only in the non-smoking group (adjusted p < 0.05). Although the markers were mainly downregulated in current smokers, their inter-correlations were potentiated. CONCLUSION: Smoking associated with reduced miR-21 gene-repression and the results can therefore not explain the previously observed reduction in circulating IL-12. Smoking attenuated the IL-12 pro-inflammatory axis in which the investigated IL-12p40 genetic variant may have different clinical impact in smokers vs non-smokers.

Genes expressed in coronary thrombi are associated with ischemic time in patients with acute myocardial infarction.

INTRODUCTION: Reports on the content of aspirated coronary thrombi have until now mainly focused on cellular components. We investigated the genetic expression of selected mediators and proteases actively involved in the pathophysiological process of acute myocardial infarction in aspirated coronary thrombi. MATERIALS AND METHODS: In this cross-sectional study, RNA from coronary thrombi in 67 subjects with acute myocardial infarction was isolated. Gene expression arrays of selected markers were performed by RT-PCR with relative quantification. RESULTS: Twenty of 22 markers were expressed in >50% of the samples. The relative quantification of P-selectin correlated negatively to total ischemic time (p=0.01), while genes related to fibrinolysis (t-PA, u-PA, PAI-1), inflammation (PTX3, CXCL9, MCP-1, IL18, TNFα) and plaque instability (MMP-2 and TIMP-1) correlated positively to total ischemic time (all<0.05). Long ischemic time (>4.0 hours) associated with a relative reduction in the expression of P-selectin and a relative increase in the expression of t-PA, u-PA, PAI-1, PTX3, CXCL9, MCP-1, IL-18, TNFα, MMP-2 and TIMP-1. The presence of type 2 diabetes associated with 3.2-fold increased PAI-1 expression (adjusted p=0.033), while the presence of hypertension associated with about 50% reduction of IL-8 and TIMP-1. Smoking and overweight did not affect any markers. CONCLUSIONS: The gene expression profile from coronary thrombi differed according to ischemic time, shown by reduced content of platelet markers and increased content of fibrinolytic, inflammatory and plaque instability mediators over time. Patients with type 2 diabetes showed increased expression of PAI-1, indicative of reduced fibrinolysis.

Withdrawal of chronic beta-adrenoceptorblockade: effects on haemodynamics, blood lipids and haemostatic variables.

The effect of cessation of chronic beta-adrenoceptorblockade on heart rate, blood pressure, blood lipids and selected haemostatic factors have been measured in 22 patients recovering from myocardial infarction. Clinical examination and blood tests were performed before and 12 weeks after withdrawal of beta-adrenoceptor-blockade, which had lasted for an average of 3 y. No effect was found on blood pressure. There was a significant increase in heart rate of 12%. Total cholesterol declined by 9%, high density lipoprotein (HDL-cholesterol) increased by 12%, and triglycerides decreased by 6%. The triglyceride dependent factors, plasminogen activator inhibitor (PAI-1) and factor VII-phospholipid complex, were not affected.

Influence of highly concentrated n-3 fatty acids on serum lipids and hemostatic variables in survivors of myocardial infarction receiving either oral anticoagulants or matching placebo.

Forty patients with previous myocardial infarction were given 4 capsules with 1 g concentrated fish oil preparation daily for 4 weeks. No special diet was applied. The supplementation was equivalent to 3.4 grams of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) daily. Twenty-two of the 40 subjects received concomitant treatment with long-term oral anticoagulants (OAC). The fatty acid composition of serum after the supplementation period showed a significant increase in the proportion of EPA and DHA, while arachidonic acid (AA) remained essentially constant. This resulted in a rise of the EPA/AA ratio from 0.59 to 1.49 (p less than 0.001), confirming satisfying absorption of the concentrate. Blood lipids showed an overall decrease of triglycerides (TG) by 25% (p = 0.02), while total cholesterol rose by 5% (p = 0.03) and HDL-cholesterol was unaffected. Blood glucose and the TG associated factors plasminogen activator inhibitor and factor VII-phospholipid complex revealed trends towards reduction. Ivy bleeding time showed a significant prolongation, the median increasing from 240 to 270 seconds. A significant increase of fibrinogen was seen, as was a decrease of clotting time in the combined prothrombin test in patients receiving concomitant OAC. Thus, given for 4 weeks, the investigated concentrate of n-3 fatty acids exerts not merely beneficial effects as far as the risk profile for atherosclerotic disease is concerned. The results also point towards interactions with OAC that may be of clinical relevance.(ABSTRACT TRUNCATED AT 250 WORDS)