| 1. |
- D'Assante, R., et al.
(författare)
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Myocardial expression of somatotropic axis, adrenergic signalling, and calcium handling genes in heart failure with preserved ejection fraction and heart failure with reduced ejection fraction
- 2021
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Ingår i: Esc Heart Failure. - : Wiley. - 2055-5822. ; 8:2, s. 1681-1686
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Tidskriftsartikel (refereegranskat)abstract
- Aims Limited data are available regarding cardiac expression of molecules involved in heart failure (HF) pathophysiology. The majority of the studies have focused on end-stage HF with reduced ejection fraction (HFrEF) without comparison with healthy subjects, while no data are available with regard to HF with preserved ejection fraction (HFpEF). HFpEF is a condition whose multiple pathophysiological mechanisms are still not fully defined, with many proposed hypotheses remaining speculative due to limited access to human heart tissue. This study aimed at evaluating cardiac expression levels of key genes of interest in human biopsy samples from patients affected with HFrEF and HFpEF in order to possibly point out distinct phenotypes. Methods and results Total RNA was extracted from left ventricular cardiac biopsies collected from stable patients with HFrEF (n = 6) and HFpEF (n = 7) and healthy subjects (n = 9) undergoing elective cardiac surgery for valvular replacement, mitral valvuloplasty, aortic surgery, or coronary artery bypass. Real-time PCR was performed to evaluate the mRNA expression levels of genes involved in somatotropic axis regulation [IGF-1, IGF-1 receptor (IGF-1R), and GH receptor (GHR)], in adrenergic signalling (GRK2, GRK5, ADRB1, and ADRB2), in myocardial calcium handling (SERCA2), and in TNF-alpha. Patients with HFrEF and HFpEF showed reduced serum IGF-1 circulating levels when compared with controls (102 +/- 35.6, 138 +/- 11.5, and 160 +/- 13.2 ng/mL, P < 0.001, respectively). At myocardial level, HFrEF showed significant decreased GHR and increased IGF-1R expressions when compared with HFpEF and controls (0.54 +/- 0.27, 0.94 +/- 0.25, and 0.84 +/- 0.2, P < 0.05 and 1.52 +/- 0.9, 1.06 +/- 0.21, and 0.72 +/- 0.12, P < 0.05, respectively), while no differences in the local expression of IGF-1 mRNA were detected among the groups (0.80 +/- 0.45, 0.97 +/- 0.18, and 0.63 +/- 0.23, P = 0.09, respectively). With regard to calcium handling and adrenergic signalling, HFrEF displayed significant decreased levels of SERCA2 (0.19 +/- 0.39, 0.82 +/- 0.15, and 0.87 +/- 0.32, P < 0.01) and increased levels of GRK2 (3.45 +/- 2.94, 0.93 +/- 0.12, and 0.80 +/- 0.14, P < 0.01) and GRK5 (1.32 +/- 0.70, 0.71 +/- 0.14, and 0.77 +/- 0.15, P < 0.05), while no significant difference was found in ADRB1 (0.66 +/- 0.4, 0.83 +/- 0.3, and 0.86 +/- 0.4) and ADRB2 mRNA expression (0.65 +/- 0.3, 0.66 +/- 0.2, and 0.68 +/- 0.1) when compared with HFpEF and controls. Finally, no changes in the local expression of TNF-alpha were detected among groups. Conclusions Heart failure with reduced ejection fraction and HFpEF patients with stable clinical condition display a distinct molecular milieu of genes involved in somatotropic axis regulation, calcium handling, and adrenergic derangement at a myocardial level. The unique opportunity to compare these results with a control group, as reference population, may contribute to better understand HF pathophysiology and to identify novel potential therapeutic targets that could be modulated to improve ventricular function in patients with HF.
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| 2. |
- Farroni, C., et al.
(författare)
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Dysregulated miR-155 and miR-125b are related to impaired B-cell responses in down syndrome
- 2018
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Children with Down Syndrome (DS) suffer from immune deficiency with a severe reduction in switched memory B cells (MBCs) and poor response to vaccination. Chromosome 21 (HSA21) encodes two microRNAs (miRs), miR-125b, and miR-155, that regulate B-cell responses. We studied B- and T- cell subpopulations in tonsils of DS and age-matched healthy donors (HD) and found that the germinal center (GC) reaction was impaired in DS. GC size, numbers of GC B cells and Follicular Helper T cells (TFH) expressing BCL6 cells were severely reduced. The expression of miR-155 and miR-125b was increased in tonsillar memory B cells and miR-125b was also higher than expected in plasma cells (PCs). Activation-induced cytidine deaminase (AID) protein, a miR-155 target, was significantly reduced in MBCs of DS patients. Increased expression of miR-155 was also observed in vitro. MiR-155 was significantly overexpressed in PBMCs activated with CpG, whereas miR-125b was constitutively higher than normal. The increase of miR-155 and its functional consequences were blocked by antagomiRs in vitro. Our data show that the expression of HSA21-encoded miR-155 and miR-125b is altered in B cells of DS individuals both in vivo and in vitro. Because of HSA21-encoded miRs may play a role also in DS-associated dementia and leukemia, our study suggests that antagomiRs may represent pharmacological tools useful for the treatment of DS. © 2007 - 2018 Frontiers Media S.A. All Rights Reserved.
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| 3. |
- Grimsholm, O., et al.
(författare)
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The Interplay between CD27(dull) and CD27(brig)(ht) B Cells Ensures the Flexibility, Stability, and Resilience of Human B Cell Memory
- 2020
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Ingår i: Cell Reports. - : Elsevier BV. - 2211-1247. ; 30:9
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Tidskriftsartikel (refereegranskat)abstract
- Memory B cells (MBCs) epitomize the adaptation of the immune system to the environment. We identify two MBC subsets in peripheral blood, CD27(dull) and CD27(bright) MBCs, whose frequency changes with age. Heavy chain variable region (VH) usage, somatic mutation frequency replacement-to-silent ratio, and CDR3 property changes, reflecting consecutive selection of highly antigen-specific, low cross-reactive antibody variants, all demonstrate that CD27(du)(ll) and CD27(bright) MBCs represent sequential MBC developmental stages, and stringent antigen-driven pressure selects CD27(du)(ll) into the CD27(bright) MBC pool. Dynamics of human MBCs are exploited in pregnancy, when 50% of maternal MBCs are lost and CD27(du)(ll) MBCs transit to the more differentiated CD27 bright stage. In the postpartum period, the maternal MBC pool is replenished by the expansion of persistent CD27(du)(ll) clones. Thus, the stability and flexibility of human B cell memory is ensured by CD27(du)(ll) MBCs that expand and differentiate in response to change.
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