PMID- 33097483 OWN - NLM STAT- MEDLINE DCOM- 20210510 LR - 20210510 IS - 1939-327X (Electronic) IS - 0012-1797 (Linking) VI - 70 IP - 1 DP - 2021 Jan TI - CD31(+) Extracellular Vesicles From Patients With Type 2 Diabetes Shuttle a miRNA Signature Associated With Cardiovascular Complications. PG - 240-254 LID - 10.2337/db20-0199 [doi] AB - 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(+) 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 having T2DM without complications, having T2DM with complications, and control subjects. We found that 10 of the tested miRNAs are affected by T2DM, while the signature composed by miR-146a, -320a, -422a, and -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-1alpha, and TNFalpha, 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. CI - (c) 2020 by the American Diabetes Association. FAU - Prattichizzo, Francesco AU - Prattichizzo F AUID- ORCID: 0000-0002-2959-2658 AD - IRCCS MultiMedica, Milan, Italy francesco.prattichizzo@multimedica.it j.sabbatinelli@pm.univpm.it. FAU - De Nigris, Valeria AU - De Nigris V AD - Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. FAU - Sabbatinelli, Jacopo AU - Sabbatinelli J AUID- ORCID: 0000-0001-9947-6778 AD - Dipartimento di Scienze Cliniche e Molecolari, Universita Politecnica delle Marche, Ancona, Italy francesco.prattichizzo@multimedica.it j.sabbatinelli@pm.univpm.it. FAU - Giuliani, Angelica AU - Giuliani A AD - Dipartimento di Scienze Cliniche e Molecolari, Universita Politecnica delle Marche, Ancona, Italy. FAU - Castano, Carlos AU - Castano C AD - Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. AD - CIBERDEM, Barcelona, Spain. FAU - Parrizas, Marcelina AU - Parrizas M AD - Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. AD - CIBERDEM, Barcelona, Spain. FAU - Crespo, Isabel AU - Crespo I AD - Cytometry and Cell Sorting Facility, Centre Esther Koplowitz, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. FAU - Grimaldi, Annalisa AU - Grimaldi A AD - Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy. FAU - Baranzini, Nicolo AU - Baranzini N AD - Department of Biotechnology and Life Sciences, University of Insubria, Varese, Italy. FAU - Spiga, Rosangela AU - Spiga R AD - Department of Medical and Surgical Sciences, University "Magna Graecia" of Catanzaro, Catanzaro, Italy. FAU - Mancuso, Elettra AU - Mancuso E AD - Department of Medical and Surgical Sciences, University "Magna Graecia" of Catanzaro, Catanzaro, Italy. FAU - Rippo, Maria Rita AU - Rippo MR AD - Dipartimento di Scienze Cliniche e Molecolari, Universita Politecnica delle Marche, Ancona, Italy. FAU - Procopio, Antonio Domenico AU - Procopio AD AD - Dipartimento di Scienze Cliniche e Molecolari, Universita Politecnica delle Marche, Ancona, Italy. AD - Centre of Clinical Pathology and Innovative Therapy, IRCCS - INRCA, Ancona, Italy. FAU - Novials, Anna AU - Novials A AUID- ORCID: 0000-0003-0465-2949 AD - Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. AD - CIBERDEM, Barcelona, Spain. FAU - Bonfigli, Anna Rita AU - Bonfigli AR AD - Scientific Direction, IRCCS - INRCA, Ancona, Italy. FAU - Garavelli, Silvia AU - Garavelli S AD - Istituto per l'Endocrinologia e l'Oncologia Sperimentale "G. Salvatore," Consiglio Nazionale delle Ricerche, Naples, Italy. FAU - La Sala, Lucia AU - La Sala L AUID- ORCID: 0000-0002-7580-1377 AD - IRCCS MultiMedica, Milan, Italy. FAU - Matarese, Giuseppe AU - Matarese G AD - Istituto per l'Endocrinologia e l'Oncologia Sperimentale "G. Salvatore," Consiglio Nazionale delle Ricerche, Naples, Italy. AD - Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II," Naples, Italy. FAU - de Candia, Paola AU - de Candia P AUID- ORCID: 0000-0003-4767-446X AD - IRCCS MultiMedica, Milan, Italy. FAU - Olivieri, Fabiola AU - Olivieri F AD - Dipartimento di Scienze Cliniche e Molecolari, Universita Politecnica delle Marche, Ancona, Italy. AD - Centre of Clinical Pathology and Innovative Therapy, IRCCS - INRCA, Ancona, Italy. FAU - Ceriello, Antonio AU - Ceriello A AUID- ORCID: 0000-0002-7955-4684 AD - IRCCS MultiMedica, Milan, Italy. LA - eng SI - figshare/10.2337/figshare.13102910 PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20201023 PL - United States TA - Diabetes JT - Diabetes JID - 0372763 RN - 0 (Biomarkers) RN - 0 (MicroRNAs) RN - 0 (Platelet Endothelial Cell Adhesion Molecule-1) SB - IM MH - Adult MH - Aged MH - Aged, 80 and over MH - Biomarkers/metabolism MH - Cross-Sectional Studies MH - Diabetes Mellitus, Type 2/*metabolism MH - Diabetic Cardiomyopathies/*metabolism MH - Endothelial Cells/metabolism MH - Extracellular Vesicles/*metabolism MH - Female MH - Humans MH - Male MH - MicroRNAs/*metabolism MH - Middle Aged MH - Platelet Endothelial Cell Adhesion Molecule-1/*metabolism EDAT- 2020/10/25 06:00 MHDA- 2021/05/11 06:00 CRDT- 2020/10/24 05:28 PHST- 2020/02/27 00:00 [received] PHST- 2020/10/15 00:00 [accepted] PHST- 2020/10/25 06:00 [pubmed] PHST- 2021/05/11 06:00 [medline] PHST- 2020/10/24 05:28 [entrez] AID - db20-0199 [pii] AID - 10.2337/db20-0199 [doi] PST - ppublish SO - Diabetes. 2021 Jan;70(1):240-254. doi: 10.2337/db20-0199. Epub 2020 Oct 23.