MicroRNA-21/PDCD4 proapoptotic signaling from circulating CD34+ cells to vascular endothelial cells: a potential contributor to adverse cardiovascular outcomes in patients with critical limb ischemia

Gaia Spinetti*, Elena Sangalli, Elena Tagliabue, Davide Maselli, Ornella Colpani, David Ferland-Mccollough, Franco Carnelli, Patrizia Orlando, Agostino Paccagnella, Anna Furlan, Piero Maria Stefani, Luisa Sambado, Maria Sambataro, Paolo R Madeddu*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

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Abstract

Objective. In patients with type 2 diabetes (T2D) and critical limb ischemia (CLI), migration of circulating CD34+ cells predicted cardiovascular mortality at 18 months post-revascularization. This study aimed to provide long-term validation and mechanistic understanding of the biomarker.
Research Design and Methods. The association between CD34+ cell migration and cardiovascular mortality was reassessed at 6 years post-revascularization. In a new series of T2D-CLI and control subjects, immuno-sorted bone marrow (BM)-CD34+ cells were profiled for microRNA expression and assessed for apoptosis and angiogenesis activity. The differentially regulated microRNA-21, and its pro-apoptotic target PDCD4, were titrated to verify their contribution in transferring damaging signals from CD34+ cells to endothelial cells.
Results. Multivariable regression analysis confirmed CD34+ cell migration forecasts long-term cardiovascular mortality. CD34+ cells from T2D-CLI patients were more apoptotic and less proangiogenic than controls and featured microRNA-21 downregulation, modulation of several long non-coding RNAs acting as microRNA-21 sponges, and upregulation of the microRNA-21 proapoptotic target PDCD4. Silencing miR-21 in control CD34+ cells phenocopied the T2D-CLI cell behavior. In coculture, T2D-CLI CD34+ cells imprinted naïve endothelial cells, increasing apoptosis, reducing network formation, and modulating the TUG1 sponge/microRNA-21/PDCD4 axis. Silencing PDCD4 or scavenging ROS protected endothelial cells from the negative influence of T2D-CLI CD34+ cells
Conclusions. Migration of CD34+ cells predicts long-term cardiovascular mortality in T2D-CLI patients. An altered paracrine signalling conveys anti-angiogenic and pro-apoptotic features from CD34+ cells to the endothelium. This damaging interaction may increase the risk for life-threatening complications.
Original languageEnglish
Pages (from-to)1520-1529
Number of pages10
JournalDiabetes Care
Volume43
Issue number7
Early online date11 May 2020
DOIs
Publication statusPublished - 1 Jul 2020

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