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      Decreased thromboembolic stroke but not atherosclerosis or vascular remodelling in mice with ROCK2-deficient platelets

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          Abstract

          Aims

          Rho-associated coiled-coil containing kinase (ROCK)-2 is an important mediator of the actin cytoskeleton. Because changes in the actin cytoskeleton are critical for platelet function, we hypothesized that ROCK2 in platelets will play important role in thrombosis and can be potentially a target for therapeutic intervention in thromboembolic stroke.

          Methods and results

          We generated platelet-specific ROCK2-deficient mice (ROCK2 Plt−/− ) from conditional ROCK2 fl° x/fl° x and platelet factor (PF)-4-Cre transgenic mice. Platelets from ROCK2 Plt−/− mice were less responsive to thrombin stimulation in terms of pseudopodia formation, collagen adhesion, and in the formation of homotypic and heterotypic aggregates. This corresponded to prolonged bleeding time and delayed vascular occlusion following vessel injury. To determine whether these changes in platelet function could affect thrombotic disease, we utilized a clot-embolic model of ischaemic stroke. When pre-formed clots from ROCK2 Plt−/− mice were injected into the middle cerebral artery of control mice, cerebral blood flow recovery occurred more rapidly, leading to decreased cerebral injury and neurological deficits, compared to pre-formed clots from control mice. Interestingly, pre-formed clots from control mice produced similar degree of cerebral injury when injected into control or ROCK2 Plt−/− mice, suggesting that platelet ROCK2 deficiency affects clot formation but not propagation. Indeed, in a non-thrombotic intra-filament MCA occlusion model of stroke, platelet ROCK2 deletion was not protective. Furthermore, ROCK2 Plt−/− mice exhibit similar atherosclerosis severity and vascular remodeling as control mice.

          Conclusion

          These findings indicate that platelet ROCK2 plays important role in platelet function and thrombosis, but does not contribute to the pathogenesis of atherosclerosis and vascular remodeling.

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          Author and article information

          Contributors
          Journal
          Cardiovasc Res
          Cardiovasc. Res
          cardiovascres
          Cardiovascular Research
          Oxford University Press
          0008-6363
          1755-3245
          September 2017
          14 April 2017
          01 September 2018
          : 113
          : 11
          : 1307-1317
          Affiliations
          [1 ]Department of Medicine, Section of Cardiology, University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, USA;
          [2 ]Department of Medicine, Vascular Medicine Research Unit, Brigham and Women’s Hospital and Harvard Medical School, 65 Landsdowne Street, Cambridge, MA 02139, USA;
          [3 ]Department of Life Science, Ewha Womans University, 52 Ewhayeodae-gil, Daehyeon-dong, Seodaemun-gu, Seoul, Korea;
          [4 ]Department of Medicine, University of Massachusetts Medical School, 55 N. Lake Avenue, Worcester, MA 01655, USA;
          [5 ]Division of Hematology, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA;
          [6 ]Department of Population Medicine, Medical University of Bialystok, Jana Kilinskiego 1, 15-089, Bialystok, Poland
          Author notes
          [* ] Corresponding author. Tel: +773 702 8950; fax: +773 702 1385, E-mail: jliao@ 123456medicine.bsd.uchicago.edu
          [†]

          The first three authors contributed equally to the study.

          Time for primary review: 22 days

          Article
          PMC5852540 PMC5852540 5852540 cvx071
          10.1093/cvr/cvx071
          5852540
          28430966
          Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For Permissions, please email: journals.permissions@oup.com.
          Page count
          Pages: 11
          Funding
          Funded by: National Institutes of Health 10.13039/100000002
          Award ID: NS070001
          Award ID: A1078894
          Award ID: HL126743
          Award ID: HL059561
          Award ID: HL104145
          Award ID: T32-HL0722
          Funded by: National Research Foundation of Korea 10.13039/501100003725
          Award ID: 2012R1A3A2026454
          Funded by: Foundation for Polish Science 10.13039/501100001870
          Funded by: American Heart Association 10.13039/100000968
          Funded by: American Society of Hematology 10.13039/100001422
          Funded by: Brigham Research Institute 10.13039/100008552
          Categories
          Original Articles
          Integrative Physiology and Pathophysiology
          Editor's Choice

          Stroke, Atherosclerosis, Rho kinase, Platelet, Thrombosis

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