Increased Activity of the Ubiquitin-Proteasome System in Patients With Symptomatic Carotid Disease Is Associated With Enhanced Inflammation and May Destabilize the Atherosclerotic Plaque

Abstract

Ubiquitin-proteasome overactivity is associated with enhanced inflammatory reaction in symptomatic plaques. The inhibition of ubiquitin-proteasome activity in lesions of symptomatic patients by rosiglitazone is associated with plaque stabilization, possibly by down-regulating NFkB-mediated inflammatory pathways.

Proteasome Activity as a Target of Hormone Replacement Therapy–Dependent Plaque Stabilization in Postmenopausal Women

“…We reported previously that oxidative stress-dependent UPS overactivity contributes to the clinical instability of atherosclerotic plaques in hypertensive, 15 diabetic, 16 and symptomatic patients 17 by promoting plaque rupture induced by NF-B-dependent inflammation. Now, in the present report, we provide evidence for the critical involvement of UPS in the process of plaque stabilization realized by HRT in postmenopausal women.…”

Lack of Endothelial Nitric Oxide Synthase Promotes Endothelin-Induced Hypertension

“…These findings may also be attributed to the fact that proteins are subjected to regulations apart from gene transcription; for example, iNOS protein levels depend on degradation by the ubiquitin-proteasome pathway (45), which is known to be altered in cardiovascular diseases such as cardiac hypertrophy (46) and atherosclerosis (47). Furthermore, our findings of an upregulation of iNOS on the protein level in ETϩ/ϩ mice are supported by previous studies of our group indicating a vital role for iNOS in counterregulating the effects of ET-1 overexpression in ETϩ/ϩ mice (26).…”

Impaired Protein Stability of 11β-Hydroxysteroid Dehydrogenase Type 2

“…Recently, increased proteasome activity was associated with enhanced inflammation in patients with symptomatic carotid disease (32) and with a role in the response to microbial stimuli such as LPS, bacterial DNA, and peptidoglycan (33,34). Whether reduced 11␤-HSD2 protein stability as a result of increased proteasome activity might contribute to glucocorticoid-dependent activation of corticosteroid receptors in kidneys and colon during inflammation or in placenta during maternal stress remains to be elucidated.…”