Bioinspired artificial exosomes based on lipid nanoparticles carrying let-7b-5p promote angiogenesis in vitro and in vivo.

MicroRNAs (miRNAs) regulate gene expression by post-transcriptional inhibition of target genes. Proangiogenic small extracellular vesicles (sEVs; popularly identified with the name "exosomes") with a composite cargo of miRNAs are secreted by cultured stem cells and present in human biological fluids. Lipid nanoparticles (LNPs) represent an advanced platform for clinically approved delivery of RNA therapeutics. In this study, we aimed to (1) identify the miRNAs responsible for sEV-induced angiogenesis; (2) develop the prototype of bioinspired "artificial exosomes" (AEs) combining LNPs with a proangiogenic miRNA, and (3) validate the angiogenic potential of the bioinspired AEs. We previously reported that human sEVs from bone marrow (BM)-CD34+ cells and pericardial fluid (PF) are proangiogenic. Here, we have shown that sEVs secreted from saphenous vein pericytes and BM mesenchymal stem cells also promote angiogenesis. Analysis of miRNA datasets available in-house or datamined from GEO identified the let-7 family as common miRNA signature of the proangiogenic sEVs. LNPs with either hsa-let-7b-5p or cyanine 5 (Cy5)-conjugated Caenorhabditis elegans miR-39 (Cy5-cel-miR-39; control miRNA) were prepared using microfluidic micromixing. let-7b-5p-AEs did not cause toxicity and transferred functionally active let-7b-5p to recipient endothelial cells (ECs). let-7b-AEs also improved EC survival under hypoxia and angiogenesis in vitro and in vivo. Bioinspired proangiogenic AEs could be further developed into innovative nanomedicine products targeting ischemic diseases.

Systolic blood pressure on admission as a marker of fluid re-distribution in acute heart failure.

BACKGROUND: The relation between systolic blood pressure (sBP) on admission and the extent of fluid re-distribution in patients with acute heart failure (AHF) remains unclear. This study aimed to investigate this relation. METHODS: We enrolled consecutive patients who were admitted for AHF in our cardiology department and divided them into three groups according to the tertiles of sBP on admission as follows: low, intermediate, and high sBP groups. Weight changes and estimated relative plasma volume changes (ΔePV) on admission and 24h later were determined in each patient. ΔePV were calculated with the Strauss formula using hemoglobin and hematocrit levels. Univariate and multiple regression analyses were performed to investigate the relation between sBP and ΔePV. RESULTS: The ΔePV of low, intermediate, and high sBP groups were 104.3%, 108.2%, and 121.3%, respectively. High sBP group showed a significantly larger ΔePV than the other two groups (p<0.001 and 0.004, respectively). The body weight of patients in the high sBP group slightly but significantly decreased within 24h (-0.64±0.92kg, p=0.002). The initial sBP had a significant correlation with ΔePV (R2, 0.295; p<0.001). Multiple regression analysis showed significant association between initial sBP with ΔePV. CONCLUSIONS: These results indicate that large amounts of extravasated fluid existed on admission in patients with a high initial sBP. The sBP on admission could be a simple and useful indicator for the extent of fluid re-distribution in AHF.

Pericardial fluid of cardiac patients elicits arterial constriction: role of endothelin-1.

Recently, several vasoactive molecules have been found in pericardial fluid (PF). Thus, we hypothesized that in coronary artery disease due to ischemia or ischemia-reperfusion, the level of vasoconstrictors, mainly endothelin-1 (ET-1), increases in PF, which can increase the vasomotor tone of arteries. Experiments were performed using an isometric myograph. Vasomotor effects of PF from patients undergoing coronary artery bypass graft (PFCABG, n = 14) or valve replacement (PFVR, n = 7) surgery were examined in isolated rat carotid arteries (N = 14; n = 26). Vasomotor responses to KCl (40 or 60 mmol/L) were also tested. The selective endothelin A receptor antagonist BQ123 (10(-6) mol/L) was used to elucidate the role of ET-1. Both the first and the second additions of KCl elicited increases in the isometric force of the isolated arteries (KCl1, 6.1 ± 0.2 mN; KCl2, 6.5 ± 0.9 mN). PFCABG and PFVR elicited substantial increases in the isometric force of arteries (PFCABG, 3.1 ± 0.7 mN; PFVR, 3.0 ± 0.9 mN; p > 0.05). The presence of the selective endothelin A receptor blocker significantly reduced arterial contractions to PFCABG (before BQ123, 2.6 ± 0.5 mN vs. after BQ123, 0.8 ± 0.1 mN; p < 0.05). This study is the first to demonstrate that PFs of patients elicit substantial arterial constrictions, which is mediated primarily by ET-1. Interfering with the vasoconstrictor action of PF could be a potential therapeutic target to improve coronary blood flow in cardiac patients.