Author + information
- Joerg Herrmann, MD⁎ (, )
- Sandra M. Soares, MD,
- Lilach O. Lerman, MD, PhD and
- Amir Lerman, MD
- ↵⁎Department of Internal Medicine, Mayo Clinic Rochester, 200 First Street SW, Rochester, Minnesota 55906
We thank Dr. Di Filippo and colleagues for their comment on our recent article (1) that a loss of the function of the ubiquitin-proteasome system may present only one aspect of its role in the atherosclerotic disease process. They outline that the ubiquitin-proteasome system serves a compensatory role to prevent the aggregation of low-quality proteins in the vascular wall in the initial disease stage. This function is lost in the more advanced disease stages as the ubiquitin-proteasome system becomes insufficient to degrade the excess amounts of damaged proteins, reducing cell and tissue viability and fostering progression of atherosclerosis. Then again, inflammation, which has been so tightly linked to atherosclerosis, may activate the ubiquitin-proteasome system, which in turn can increase inflammatory activity through synthesis of nuclear factor kappa B (NFkB) and the generation of substrates for the ubiquitin-proteasome system. Via this positive feedback cycle, the ubiquitin-proteasome system takes a more active, contributing role to the atherosclerotic disease process.
The presented viewpoint of their letter is in fact well aligned with the conceptual theme of our article. In support of a possible compensatory role of the ubiquitin-proteasome system in the initial stage of atherosclerosis, we described pro-atherosclerotic effects of chronic proteasome inhibition in experimental hypercholesterolemia (2). Further confirmation should be given by future studies showing a vasoprotective effect of the stimulation of the system. Also, there is a need for studies on the modulation of the system in the more advanced disease stages to truly confirm its causal role. In this, we are in full agreement with Dr. Di Filippo and colleagues.
Regarding inflammation, the ubiquitin-proteasome system indeed takes center stage in the classical activation pathway of NFkB, and its inhibition is thought to contribute to the efficacy of proteasome inhibitors in chemotherapy. However, proteasome-independent NFkB activation can still occur through the nonclassical activation pathways that are stimulated under conditions of enhanced oxidative stress (3). This reconciles the possible contradiction of an insufficiency of the ubiquitin-proteasome system and yet increased NFkB activation in advanced atherosclerosis. Certainly, an unimpaired and even stimulated ubiquitin-proteasome system can contribute further to NFkB activation and inflammation in the initial stage of atherosclerosis as we outlined. Thus, the points made by Dr. Dr Filippo and colleagues are well taken and emphasize the nuances of the topic and the need for further studies in this area.
- American College of Cardiology Foundation
- Herrmann J.,
- Soares S.M.,
- Lerman L.O.,
- Lerman A.
- Herrmann J.,
- Saguner A.M.,
- Versari D.,
- et al.