Compression force sensing regulates integrin alpha(IIb)beta(3) adhesive function on diabetic platelets

• Type of Material: Article
• Authors: Lining Ju, Heart Research Institute; James D. McFadyen, Monash University; Saheb Al-Daher, Monash University; Imala Alwis, Heart Research Institute; Yunfeng Chen, Heart Research Institute; Lotte L. Tonnesen, Heart Research Institute; Sophie Maiocchi, Heart Research Institute; Brianna Coulter, Heart Research Institute; Anna C. Calkin, Monash University; Eric Ian Felner, Emory University; Neale Cohen, Baker Heart and Diabetes Institute; Yuping Yuan, Heart Research Institute; Simone M. Schoenwaelder, Heart Research Institute; Mark E. Cooper, Monash University; Cheng Zhu, Heart Research Institute; Shaun P. Jackson, Heart Research Institute
• Language: English
• Date: 2018-03-14
• Publisher: Nature Publishing Group: Nature Communications
• Publication Version: Final Published Version
• Copyright Statement: © 2018 The Author(s).
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-018-03430-6
• Title of Journal or Parent Work: Nature Communications
• ISSN: 2041-1723
• Volume: 9
• Issue: 1
• Start Page: 1087
• End Page: 1087
• Grant/Funding Information: A.C.C. is a National Heart Foundation Future Leader Fellow (100067).; S.A.-M was supported by Wheaton Scholarship.; This work was supported by grants from the National Health and Medical Research Council (NHMRC) of Australia (APP1028564; APP1048574 - S.P.J.), the Australian Research Council (LE120100043 - S.P.J.), the National Institutes of Health/National Heart, Lung and Blood Institute, USA (HL132019 and CA214354 – C.Z.), the Royal College of Pathologists of Australasia Kanematsu research award, Diabetes Australia Research Trust grant G179720, Sydney Medical School early-career researcher kickstart grant—L.J. J.D.M was supported by a Wheaton Scholarship and CSL Behring Global Research Scholarship.; L.J. is a National Heart Foundation of Australia postdoctoral fellow (101798).; S.P.J. is an NHMRC Senior Principal Research Fellow.
• Keywords: Science & Technology - Other Topics; AGGREGATION; TISSUE FACTOR; RECEPTOR; THROMBUS FORMATION; Multidisciplinary Sciences; MICE; THROMBOXANE; MELLITUS; Science & Technology; MECHANISM; SHEAR; GLYCOPROTEIN IB-ALPHA
• Research Categories: Engineering, Biomedical; Health Sciences, General; Health Sciences, Medicine and Surgery

Abstract

Diabetes is associated with an exaggerated platelet thrombotic response at sites of vascular injury. Biomechanical forces regulate platelet activation, although the impact of diabetes on this process remains ill-defined. Using a biomembrane force probe (BFP), we demonstrate that compressive force activates integrin α IIb β 3 on discoid diabetic platelets, increasing its association rate with immobilized fibrinogen. This compressive force-induced integrin activation is calcium and PI 3-kinase dependent, resulting in enhanced integrin affinity maturation and exaggerated shear-dependent platelet adhesion. Analysis of discoid platelet aggregation in the mesenteric circulation of mice confirmed that diabetes leads to a marked enhancement in the formation and stability of discoid platelet aggregates, via a mechanism that is not inhibited by therapeutic doses of aspirin and clopidogrel, but is eliminated by PI 3-kinase inhibition. These studies demonstrate the existence of a compression force sensing mechanism linked to α IIb β 3 adhesive function that leads to a distinct prothrombotic phenotype in diabetes.