Abstract
Although the advent of combined antiretroviral therapy has substantially improved the survival of HIV-1-infected individuals, non-AIDS-related diseases are becoming increasingly prevalent in HIV-1-infected patients. Persistent abnormalities in coagulation appear to contribute to excess risk for a broad spectrum of non-AIDS defining complications. Alterations in coagulation biology in the context of HIV infection seem to be largely a consequence of a chronically inflammatory microenvironment leading to endothelial cell (EC) dysfunction. A possible direct role of HIV-1 proteins in sustaining EC dysfunction has been postulated but not yet investigated. The HIV-1 matrix protein p17 (p17) is secreted from HIV-1-infected cells and is known to sustain inflammatory processes by activating ECs. The aim of this study was to investigate the possibility that p17-driven stimulation of human ECs is associated with increased production of critical coagulation factors. Here we show the involvement of autophagy in the p17-induced accumulation and secretion of von Willebrand factor (vWF) by ECs. In vivo experiments confirmed the capability of p17 to exert a potent pro-coagulant activity soon after its intravenous administration.
Highlights
Autophagy has been largely known as a degradative process serving a pro-survival, metabolite-generating role
It is well known that certain stresses can induce cells to release autophagic vacuoles [41,42] and, silencing of either Beclin-1, GRASP55 and Rab8a resulted in reduced Weibel-Palade bodies (WPBs) storage and secretion of von Willebrand factor (vWF) promoted by p17 stimulation
This demonstrates that vWF secretion in p17-treated endothelial cell (EC) is dependent on the activation of an autophagy-based pathway
Summary
Autophagy has been largely known as a degradative process serving a pro-survival, metabolite-generating role. Von Willebrand factor (vWF) is a glycoprotein stored in specific secretory granules known as Weibel-Palade bodies (WPBs) [7,8] This molecule is contained mainly in endothelial cells (ECs) and once secreted it multimerizes and assembles into long strings which tether to the underlying connective tissue, playing a crucial role in platelet trapping to maintain normal homeostasis [9]. Inhibition of the autophagic flux in ECs with chloroquine resulted in a marked down-modulation of vWF secretion, and chloroquine administration in mice resulted in an increased bleeding time [13]. These findings demonstrated, for the first time, that transient pharmacological inhibition of autophagic flux may be a useful strategy to prevent thrombotic events [13]
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