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(Circulation Research. 2007;101:859.)
© 2007 American Heart Association, Inc.

Editorials

Targeting Proteasome Worsens Atherosclerosis

Tohru Fukai

From the Departments of Medicine (Section of Cardiology) and Pharmacology, University of Illinois at Chicago.

Correspondence to Tohru Fukai, MD, PhD, FAHA, Departments of Medicine (Section of Cardiology) and Pharmacology, Center for Cardiovascular Research, University of Illinois at Chicago, 835 S. Wolcott, M/C868, E403MSB, Chicago, IL 60612. E-mail tfukai@uic.edu

See related article, pages 865–874

Key Words: ubiquitin • proteasome • atherosclerosis • oxidative stress

An extract of the first 250 words of the full text is provided, because this article has no abstract.

The ubiquitin–proteasome system is the major pathway (up to 80% to 90%) of nonlysosomal degradation of intracellular and oxidized proteins^1–3 (Figure). For a protein to be recognized by the proteasome, a small peptide (ubiquitin) must first be attached to the target protein. The process of ubiquitination which transfers polyubiquitin chains to target proteins requires various enzymes such as ubiquitin-activating enzyme (E1), ubiquitin carrier protein (E2), and ubiquitin-protein lipase (E3). The ubiquitinated substrate is rapidly hydrolyzed by the 26S proteasome, an ATP-dependent multiprotein complex containing the proteolytically active 20S proteasome that is capped by 1 or 2 19S regulatory complexes.⁴ The 20S proteasome has 3 distinct proteolytic activities harbored by ß subunits which consist of caspase-like (ß1 subunit), trypsin-like (ß2 subunit), and chymotrypsin-like (ß5 subunit) activities.⁵ The primary inhibitory effect of overall proteasome proteolytic function is mediated through chymotrypsin-like function of the 20S proteasome.⁵ Indeed, most of synthetic and natural inhibitors of the proteasome such as MLN-273 and PS-341 act predominantly on the chymotrypsin-like activity.¹ In particular, PS-341 (bortezomib [Velcade]) was approved for the treatment of therapy-refractory multiple myeloma in 2003.⁶

View larger version (16K):   Figure. Role of ubiquitin-proteasome system in atherosclerosis. The protein substrates such as cell mediators involved in atherosclerosis and oxidized protein are first conjugated to multiple molecules of ubiquitin in a reaction involving ubiquitin-activating enzyme (E1), ubiquitin carrier protein (E2), and ubiquitin-protein ligase (E3). The ubiquitinated substrate is rapidly hydrolyzed by the 26S proteasome containing the core 20S proteasome (formed by 2 outer subunits and 2 inner ß subunits) . . . [Full Text of this Article]

Related Article:

Chronic Proteasome Inhibition Contributes to Coronary Atherosclerosis

Joerg Herrmann, Ardan M. Saguner, Daniele Versari, Timothy E. Peterson, Alejandro Chade, Monica Olson, Lilach O. Lerman, and Amir Lerman
Circ. Res. 2007 101: 865-874. [Abstract] [Full Text] [PDF]

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