CORRESPONDENCE: LETTER TO THE EDITOR
Possible Dual Role of Ubiquitin-Proteasome System in the Atherosclerotic Plaque Progression
Clara Di Filippo, PhD,
Raffaele Marfella, MD and
Michele D'Amico, PhD*
* Department of Experimental Medicine, Second University of Naples, Via Costantinopoli 16, 80138 Naples, Italy (Email: michele.damico{at}unina2.it).
In the May 27, 2008, issue of the Journal, Herrmann et al. (1) presented atherosclerosis as a protein-quality disease caused by the accumulation at the vascular level of unfolded/misfolded proteins linking ubiquitin-proteasome system (UPS) activity to atherosclerotic plaque formation. Although the investigators raised an interesting scientific concern in this review that the loss of function for proteins is important in cellular and tissue functions, we believe that they present only one side of the dual role that the UPS has in vascular lesion formation and plaque instability. In our opinion, one should distinguish between the initial stage of the plaque formation in which tissue begins to react to damaging stimuli (e.g., cell stresses) and the late stage of plaque characterized by progression of plaque toward destabilization and rupture. In this context, it is conceivable that the first stage is characterized by deposition and accumulation of proteins in cells and tissues when they are produced in large amounts in response to a noxious stimulus. It is conceivable that during this transient stage, the UPS physiologically serves as a compensatory circuit acting to avoid low-quality protein aggregations within the endothelium of the vessel walls. This hypothesis is counteracted by the limited amount of evidence in humans as well as by the conflicting translation of animal data to humans. Plaque progression, however, occurs when the insufficiency of UPS to degrade the excess of damaged proteins becomes a persistently stressful condition for the endothelium. This leads to progressive accumulation of ubiquitinated proteins, autophagic death, and ultimately to plaque rupture triggered by a local inflammatory process (2). It is well known that an inflammatory process may activate UPS (3), leading to an overactivity of the system that in turn can develop a vicious circle in atherosclerotic vessels. It may further increase inflammatory activity through de novo synthesis of the nuclear factor kappa B, which in turn leads to further increments of oxidative stress and consequently an increase of the ubiquitinated proteins. Indeed, increased UPS activity in plaque macrophage as a consequence of the persistent stress may enhance the synthesis of nuclear factor kappa B in the same cell, possibly representing a crucial step in the pathophysiology of atherosclerosis progression toward instability. Nevertheless, these are only hypotheses. Specific clinical studies evaluating the effect of an intervention to selectively modulate the UPS, in relation to the stage of disease, are the only ones able to give a definite answer to the question whether an increase and/or a decrease in UPS activity may be responsible for atherosclerosis progression.
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References
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- Herrmann J, Soares SM, Lerman LO, Lerman A. Potential role of the ubiquitin-proteasome system in atherosclerosis: aspects of a protein quality disease J Am Coll Cardiol 2008;51:2003-2010.[Abstract/Free Full Text]
- Marfella R, D'Amico M, Di Filippo C, et al. Increased activity of the ubiquitin-proteasome system in patients with symptomatic carotid disease is associated with enhanced inflammation and may destabilize the atherosclerotic plaque: effects of rosiglitazone treatment J Am Coll Cardiol 2006;47:2444-2455.[Abstract/Free Full Text]
- Wojcik C, Di Napoli M. Ubiquitin-proteasome system and proteasome inhibition: new strategies in stroke therapy Stroke 2004;35:1506-1518.[Abstract/Free Full Text]
Related Article
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Reply
- Joerg Herrmann, Sandra M. Soares, Lilach O. Lerman, and Amir Lerman
J. Am. Coll. Cardiol. 2008 52: 1351.
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