Altered microRNA dynamics in acute coronary syndrome.

INTRODUCTION: In the course of acute myocardial infarction (AMI) cardiomyocyte injury, activation and destruction of endothelial cells together with inflammation lead to miRNA expression alterations. AIM: To assess levels of circulating cardiac-specific (miR-1) and endothelial-specific (miR-126) miRNAs in the acute phase of AMI and after a follow-up period. MATERIAL AND METHODS: Seventeen AMI patients (mean age: 64.24 ±13.83 years, mean left ventricle ejection fraction (LVEF): 42.6 ±9.65%), treated with primary percutaneous coronary intervention within the first 12 h, had plasma miRNAs isolated (quantitative real-time PCR, Exiqon) on admission and after 19.2 ±5.9 weeks. Measurements were also performed in a control group of healthy volunteers matched for age and sex. RESULTS: Concentrations of both miRNAs were significantly higher in AMI patients as compared to healthy controls: miR-1: 5.93 (3.15-14.92) vs. 1.46 (0.06-2.96), p = 0.04; miR-126: 4.5 (3.11-7.64) vs. 0.54 (0.36-0.99), p = 0.00003, respectively. Levels of both miRNAs significantly decreased after the follow-up period: miR-1: 5.93 (3.15-14.92) vs. 1.34 (0.04-2.34), p = 0.002; miR-126: 4.5 (3.11-7.64) vs. 1.18 (0.49-1.68), p = 0.0005). Moreover, miR-1 correlated positively with maximal troponin I concentration (r = 0.59, p = 0.02) and negatively with LVEF (r = -0.76, p = 0.0004). CONCLUSIONS: In our study, miR-1 emerged as a marker of cardiomyocyte injury and loss of myocardial contractility, whereas dynamics of miR-126 concentration may reflect endothelial activation and damage in the most extreme stage of atherosclerosis, followed by angiogenesis in ischemic myocardium. However, to fully elucidate the role of miR-1 and miR-126 as biomarkers of AMI and future therapeutic targets, further research is required.

The relationships among monocyte subsets, miRNAs and inflammatory cytokines in patients with acute myocardial infarction.

BACKGROUND: Acute myocardial infarction (AMI) causes irreversible myocardial damage and release of inflammatory mediators, including cytokines, chemokines and miRNAs. We aimed to investigate changes in the levels of cytokines (IL-6, TNF-α and IL-10), miRNAs profiles (miR-146 and miR-155) and distribution of different monocyte subsets (CD14++CD16-, CD14++CD16+, CD14+CD16++) in the acute and post-healing phases of AMI. METHODS: In eighteen consecutive AMI patients (mean age 56.78 ± 12.4 years, mean left ventricle ejection fraction - LVEF: 41.9 ± 9.8%), treated invasively, monocyte subsets frequencies were evaluated (flow cytometry), cytokine concentrations were analyzed (ELISA) as well as plasma miRNAs were isolated twice - on admission and after 19.2 ± 5.9 weeks of follow-up. Measurements were also performed among healthy volunteers. RESULTS: AMI patients presented significantly decreased frequencies of classical cells in comparison to healthy controls (median 71.22% [IQR: 64.4-79.04] vs. 84.35% [IQR: 81.2-86.7], p = 0.001) and higher percent of both intermediate and non-classical cells, yet without statistical significance (median 6.54% [IQR: 5.14-16.64] vs. 5.87% [IQR: 4.48-8.6], p = 0.37 and median 5.99% [IQR: 3.39-11.5] vs. 5.26% [IQR: 3.62-6.2], p = 0.42, respectively). In AMI patients both, analyzed plasma miRNA concentrations were higher than in healthy subjects (miR-146: median 5.48 [IQR: 2.4-11.27] vs. 1.84 [IQR: 0.87-2.53], p = 0.003; miR-155: median 25.35 [IQR: 8.17-43.15] vs. 8.4 [IQR: 0.08-16.9], p = 0.027, respectively), and returned back to the values found in the control group in follow-up. miR-155/miR-146 ratio correlated with the frequencies of classical monocytes (r=0.6, p = 0.01) and miR-155 correlated positively with the concentration of inflammatory cytokines - IL-6 and TNF-α. CONCLUSIONS: These results may suggest cooperation of both pro-inflammatory and anti-inflammatory signals in AMI in order to promote appropriate healing of the infarcted myocardium.

Elevated Numbers of Circulating Very Small Embryonic-Like Stem Cells (VSELs) and Intermediate CD14++CD16+ Monocytes in IgA Nephropathy.

IgA nephropathy (IgAN) is recognized as most frequent form of primary glomerulonephritis worldwide. IgAN is associated with renal degradation occurring due to irreversible pathological changes leading to glomerulosclerosis and interstitial fibrosis. It remains poorly understood whether and to what extent these changes are followed by the activation of regenerative mechanisms. Therefore, in this study we aimed to evaluate regenerative potential of IgAN patients by quantitating the frequencies of several stem cell types, namely circulating very small embryonic-like stem cells (VSELs), hematopoietic stem cells (HSCs), endothelial progenitor cells (EPCs) as well as different monocyte subsets with varying maturation and angiopoietic potential. Moreover, we analyzed whether changes in stem cell and monocyte frequencies were related to alterations of several chemotactic factors (stromal derived-factor (SDF-1), angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2)) and a marker of monocyte/macrophage activation, namely soluble form of CD163 receptor (sCD163). We showed that IgAN patients presented with enhanced levels of VSELs, but not other stem cell types. We also demonstrated significantly elevated numbers of intermediate monocytes known for their M2-like properties as well as high angiopoietic potential and CD163 expression. This finding was accompanied by detection of elevated sCD163 plasma levels in IgAN patients. Taking together, we demonstrated here that IgAN is associated with selective mobilization of VSELs and increased maturation of monocytes towards M2-like and angiopoietic phenotype. These findings contribute to better understanding of the role of regenerative mechanisms in the pathogenesis of chronic inflammation in the course of IgAN.

Involvement of BAFF and APRIL in Resistance to Apoptosis of Acute Myeloid Leukemia.

B-cell activation factor of the TNF family (BAFF), and a proliferation-inducing ligand (APRIL), two members of the tumour necrosis factor (TNF) superfamily, beyond playing a significant role in normal B-cell development, promote survival and proliferation of malignant B cells. Both ligands interact with 3 receptors: BAFF-R, specific to BAFF, and TACI and BCMA which are shared by both BAFF and APRIL. Here we wished to investigate the potential role of these proteins in resistance of acute myeloid leukaemia (AML) blasts to apoptosis. We found that the levels of both mRNA and proteins of APRIL, BAFF and their receptors were expressed in leukaemic cells of 24 newly diagnosed, untreated AML patients. We also demonstrated that patients who did not further respond to induction therapy (NR) presented with significantly higher baseline APRIL and BAFF expression on AML blasts as compared to these subjects who, after induction, achieved complete remission (CR) following induction therapy. Moreover, we observed striking differences in baseline levels of BCMA between CR and NR patients as we did not find detectable expression of this receptor in the latter group of patients. Interestingly, we found that AML blasts collected at baseline from NR patients cultured in presence of exogenous BAFF and APRIL were significantly more resistant to spontaneous or drug-induced apoptosis as compared with cells derived from CR patients. Altogether, our data confirm that BAFF and APRIL signaling play important role in AML pathogenesis and susceptibility to cytotoxic therapy while measuring of BCMA expression on AML cells can become a novel prognostic factor for chemotherapy response.