posted on 2020-10-23, 15:20authored byAda AdminAda Admin, Francesco Prattichizzo, Valeria De Nigris, Jacopo Sabbatinelli, Angelica Giuliani, Carlos Castaño, Marcelina Párrizas, Isabel Crespo, Annalisa Grimaldi, Nicolò Baranzini, Rosangela Spiga, Elettra Mancuso, Maria Rita Rippo, Antonio Domenico Procopio, Anna Novials, Anna Rita Bonfigli, Silvia Garavelli, Lucia La Sala, Giuseppe Matarese, Paola de Candia, Fabiola Olivieri, Antonio Ceriello
Innovative biomarkers are needed to improve the
management of patients with type 2 diabetes mellitus (T2DM). Blood circulating
miRNAs have been proposed as a potential tool to detect T2DM complications but
the lack of tissue specificity, among other reasons, has hampered their
translation to clinical settings. Extracellular vesicle (EV)-shuttled miRNAs
have been proposed as an alternative approach. Here, we adapted an
immunomagnetic bead-based method to isolate plasma CD31 positive (+)
EVs to harvest vesicles deriving from tissues relevant for T2DM complications. Surface marker
characterization showed that CD31+ EVs were also positive for a
range of markers typical of both platelets and activated endothelial cells. After
characterization, we quantified 11 candidate miRNAs associated with vascular
performance and shuttled by CD31+EVs in a large (n=218),
cross-sectional cohort of patients categorized as T2DM without complications,
T2DM with complications, and controls. We found that 10 of the tested miRNAs
are affected by T2DM, while the signature composed by miR-146a, -320a, -422a,
-451a efficiently identified T2DM patients with complications. Furthermore,
another CD31+EV-shuttled miRNA signature, i.e. miR-155, -320a,
-342-3p, -376, and -422a, detected T2DM patients with a previous major adverse
cardiovascular event. Many of these miRNAs significantly correlate with
clinical variables held to play a key role in the development of complications.
In addition, we show that CD31+ EVs from patients with T2DM are able
to promote the expression of selected inflammatory mRNAs, i.e.CCL2,
IL-1α, and TNFα, when administered to endothelial cells in
vitro. Overall, these data suggest that the miRNA cargo of plasma CD31+
EVs is largely affected by T2DM and related complications, encouraging further research to explore the diagnostic
potential and the functional role of these alterations.
Funding
This work was supported by grants from La Maratò de TV3 to A.C and by the Italian Ministry of Health (Ricerca Corrente) to IRCCS MultiMedica.