Autophagy regulates endothelial cell processing, maturation and secretion of von Willebrand factor

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Abstract

Endothelial secretion of von Willebrand factor (VWF) from intracellular organelles known as Weibel-Palade bodies (WPBs) is required for platelet adhesion to the injured vessel wall. Here, we demonstrate that WPBs are in some cases found near or within autophagosomes and that endothelial autophagosomes contain abundant VWF protein. Pharmacological inhibitors of autophagy, or knockdown of the essential autophagy genes Atg5 or Atg7, inhibits the in vitro secretion of VWF. Furthermore, while mice with an endothelial specific deletion of Atg7 have normal vessel architecture and capillary density, these animals exhibit impaired epinephrine-stimulated VWF release, reduced levels of high molecular weight VWF multimers and a corresponding elevation of their bleeding times. Endothelial deletion of Atg5 or pharmacological inhibition of autophagic flux results in a similar in vivo alteration of hemostasis. Thus, autophagy regulates endothelial VWF secretion and transient pharmacological inhibition of autophagic flux may be a useful strategy to prevent thrombotic events.

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Most cited references 30

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Physiological significance of selective degradation of p62 by autophagy.

Masaaki Komatsu, Yoshinobu Ichimura (2010)

Autophagy is a highly conserved bulk protein degradation pathway responsible for the turnover of long-lived proteins, disposal of damaged organelles, and clearance of aggregate-prone proteins. Thus, inactivation of autophagy results in cytoplasmic protein inclusions, which are composed of misfolded proteins and excess accumulation of deformed organelles, leading to liver injury, diabetes, myopathy, and neurodegeneration. Although autophagy has been considered non-selective, growing lines of evidence indicate the selectivity of autophagy in sorting vacuolar enzymes and in the removal of aggregate-prone proteins, unwanted organelles and microbes. Such selectivity by autophagy enables diverse cellular regulations, similar to the ubiquitin-proteasome pathway. In this review, we introduce the selective turnover of the ubiquitin- and LC3-binding protein 'p62' through autophagy and discuss its physiological significance. Copyright 2010 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

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Atg7 modulates p53 activity to regulate cell cycle and survival during metabolic stress.

Alexander J R Bishop, David I. Lee, Yazmin I. Rovira … (2012)

Withdrawal of nutrients triggers an exit from the cell division cycle, the induction of autophagy, and eventually the activation of cell death pathways. The relation, if any, among these events is not well characterized. We found that starved mouse embryonic fibroblasts lacking the essential autophagy gene product Atg7 failed to undergo cell cycle arrest. Independent of its E1-like enzymatic activity, Atg7 could bind to the tumor suppressor p53 to regulate the transcription of the gene encoding the cell cycle inhibitor p21(CDKN1A). With prolonged metabolic stress, the absence of Atg7 resulted in augmented DNA damage with increased p53-dependent apoptosis. Inhibition of the DNA damage response by deletion of the protein kinase Chk2 partially rescued postnatal lethality in Atg7(-/-) mice. Thus, when nutrients are limited, Atg7 regulates p53-dependent cell cycle and cell death pathways.

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Mitochondrial dysfunction and oxidative stress mediate the physiological impairment induced by the disruption of autophagy

J. Julie Wu, Celia Quijano, Edmund Chen … (2009)

Impaired or deficient autophagy is believed to cause or contribute to aging, as well as a number of age-related pathologies. The exact mechanism through which alterations in autophagy induce these various pathologies is not well understood. Here we describe the creation of two in vivo mouse models that allow for the characterization of the alteration in mitochondrial function and the contribution of the corresponding oxidative stress following deletion of Atg7. Using these models we demonstrate that isolated mitochondria obtained from Atg7-/- skeletal muscle exhibit a significant defect in mitochondrial respiration. We further show that cells derived from Atg7-/- mice have an altered metabolic profile characterized by decreased resting mitochondrial oxygen consumption and a compensatory increase in basal glycolytic rates. Atg7-/-cells also exhibit evidence for increased steady state levels of reactive oxygen species. The observed mitochondrial dysfunction and oxidative stress is also evident in a mouse model where Atg7 is deleted within the pancreatic β cell. In this model, the simple administration of an antioxidant can significantly ameliorate the physiological impairment in glucose-stimulated insulin secretion. Taken together, these results demonstrate the potential role of mitochondrial dysfunction and oxidative stress in autophagy related pathology.

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Author and article information

Journal

Journal ID (nlm-journal-id): 9502015

Journal ID (pubmed-jr-id): 8791

Journal ID (nlm-ta): Nat Med

Journal ID (iso-abbrev): Nat. Med.

Title: Nature medicine

ISSN (Print): 1078-8956

ISSN (Electronic): 1546-170X

Publication date Nihms-submitted: 31 July 2013

Publication date (Electronic): 22 September 2013

Publication date (Print): October 2013

Publication date PMC-release: 01 April 2014

Volume: 19

Issue: 10

Pages: 1281-1287

Affiliations

[1 ] Center for Molecular Medicine, NHLBI, NIH Bethesda, MD 20892

[2 ] Light Microscopy Core, NHLBI, NIH Bethesda, MD 20892

[3 ] Cell Biology and Physiology Center, NHLBI, NIH Bethesda, MD 20892

[4 ] Intracellular Membrane Trafficking Unit, NIDCR, NIH Bethesda, MD 20892

[5 ] Electron Microscopy Core Facility, NHLBI, NIH , Bethesda, MD 20892, USA

[6 ] Laboratory of Frontier Science, Tokyo Metropolitan Institute of Medical Sciences, Tokyo, Japan

[7 ] Key Laboratory of Medical Cell Biology, China Medical University, Shengyang, 110001, China

Author notes

[*]

These authors contributed equally

Address Correspondence: Toren Finkel Center for Molecular Medicine Bldg 10/CRC 5-3330 Bethesda, MD 20892 T: 301-402-4081 finkelt@ 123456nih.gov

Article

Manuscript ID: NIHMS500271

DOI: 10.1038/nm.3288

PMC ID: 3795899

PubMed ID: 24056772

SO-VID: fef5f571-933d-486a-b6ad-b248acda0a86

License:

Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

History

Funding

Funded by: National Heart, Lung, and Blood Institute : NHLBI

Award ID: ZIA HL005012-16 || HL

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