P66Shc mediates increased platelet activation and aggregation in hypercholesterolemia

Santosh Kumar; Ajit Vikram; Young-Rae Kim; Julia S Jacobs; Kaikobad Irani

doi:10.1016/j.bbrc.2014.05.029

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P66Shc mediates increased platelet activation and aggregation in hypercholesterolemia

Journal article

Peer reviewed

P66Shc mediates increased platelet activation and aggregation in hypercholesterolemia

Santosh Kumar, Ajit Vikram, Young-Rae Kim, Julia S Jacobs and Kaikobad Irani

Biochemical and biophysical research communications, Vol.449(4), pp.496-501

07/11/2014

DOI: 10.1016/j.bbrc.2014.05.029

PMID: 24845561

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Abstract

Hypercholesterolemia leads to a prothrombotic phenotype. Platelet hyperactivity associated with hypercholesterolemia has been attributed, in part, to oxidative stress. P66Shc is a well-known determinant of cellular and organismal oxidative stress. However, its role in platelet biology is not known. We hypothesized that p66Shc mediates platelet hyperactivation and hyperaggregation in hypercholesterolemia. P66Shc was expressed in both human and mouse platelets, as determined by qRT-PCR and immunoblotting. Mouse platelet p66Shc expression was upregulated by hypercholesterolemia induced by high-fat diet feeding. Compared to wild-type mice, high-fat diet-induced p66Shc expression in platelets was suppressed in transgenic mice expressing a short hairpin RNA targeting p66Shc (p66ShcRNAi). High-fat diet feeding of wild-type mice amplified surface P-selectin expression on platelets stimulated by the thrombin receptor agonist protease-activated receptor-4 (PAR4), and increased aggregation of platelets induced by thrombin. These exaggerated platelet responses induced by high-fat diet feeding were significantly blunted in p66ShcRNAi mice. Finally, thrombin-stimulated platelet reactive oxygen species were suppressed in p66ShcRNAi mice. Hypercholesterolemia stimulates p66Shc expression in platelets, promoting platelet oxidative stress, hyperreactivity and hyperaggregation via p66Shc.

Platelet Aggregation

Receptors, Proteinase-Activated - metabolism

Shc Signaling Adaptor Proteins - metabolism

Animals

Src Homology 2 Domain-Containing, Transforming Protein 1

Platelet Activation

Diet, High-Fat

Humans

Mice, Transgenic

Hypercholesterolemia - physiopathology

Mice

Details

Title: Subtitle: P66Shc mediates increased platelet activation and aggregation in hypercholesterolemia
Creators: Santosh Kumar - Cardiovascular Division, Department of Internal Medicine, University of Iowa Carver College of Medicine, IA City, IA 52242, USA. Electronic address: santosh-kumar@uiowa.edu
Ajit Vikram - Cardiovascular Division, Department of Internal Medicine, University of Iowa Carver College of Medicine, IA City, IA 52242, USA
Young-Rae Kim - Cardiovascular Division, Department of Internal Medicine, University of Iowa Carver College of Medicine, IA City, IA 52242, USA
Julia S Jacobs - Cardiovascular Division, Department of Internal Medicine, University of Iowa Carver College of Medicine, IA City, IA 52242, USA
Kaikobad Irani - Cardiovascular Division, Department of Internal Medicine, University of Iowa Carver College of Medicine, IA City, IA 52242, USA. Electronic address: Kaikobad-irani@uiowa.edu
Resource Type: Journal article
Publication Details: Biochemical and biophysical research communications, Vol.449(4), pp.496-501
Publisher: United States
DOI: 10.1016/j.bbrc.2014.05.029
PMID: 24845561
ISSN: 0006-291X
eISSN: 1090-2104
Grant note: DOI: 10.13039/100000968, name: American Heart Association, award: 11POST6880001
Language: English
Date published: 07/11/2014
Academic Unit: Cardiovascular Medicine; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
Record Identifier: 9984047633602771

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