Published online before print September 6, 2007, doi: 10.1161/CIRCRESAHA.107.152959
© 2007 American Heart Association, Inc.
Molecular Medicine |
Chronic Proteasome Inhibition Contributes to Coronary Atherosclerosis
From the Divisions of Cardiovascular Diseases (J.H., A.M.S., D.V., T.E.P., M.O., A.L.) and Nephrology and Hypertension (A.C., L.O.L.), Department of Internal Medicine, Mayo Clinic and College of Medicine, Rochester, Minn.
Correspondence to Amir Lerman, MD, Division of Cardiology, Mayo Clinic Rochester, 200 First St SW, Rochester, MN 55905. E-mail lerman.amir{at}mayo.edu
The proteasome is responsible for the degradation of oxidized proteins, and proteasome inhibition has been shown to generate oxidative stress in vitro. Atherosclerosis is thought to be initiated as a consequence of increased endogenous oxidative stress. The current study was designed to assess whether chronic proteasome inhibition is associated with early coronary atherosclerosis. Female pigs, 3 months of age, were randomized to a normal (N) or high-cholesterol (HC) diet (2% cholesterol, 15% lard) without or with twice weekly subcutaneous injections of the proteasome inhibitor (PSI) MLN-273 (0.08 mg/kg, N+PSI and HC+PSI) for a period of 12 weeks (n=5 per group). Coronary vasorelaxation to bradykinin (10–10.5 to 10–6.5 mol/L) and sodium nitroprusside (10–9 to 10–5 mol/L) was assessed by in vitro organ chamber experiments, intima–media ratio by morphometric analysis of Elastica–van Gieson–stained slides, and intima superoxide production by dihydroethidium fluorescence. Vasorelaxation to 10–6.5 mol/L bradykinin was reduced in HC compared with N (69±7 versus 90±2%, P<0.05) and further reduced in N+PSI and HC+PSI (57±6 and 48±13%, P<0.05 versus N and HC for each). Compared with N (0.03±0.01), intima–media ratio was higher in N+PSI (0.09±0.04, P<0.01) and HC+PSI (0.15±0.06, P<0.05). Compared with N (0.6±0.9% of intima area), dihydroethidium fluorescence was higher in HC, N+PSI, and HC+PSI (8.9±1.6, 6.0±3.5, and 7.2±3.9% of intima area, P<0.05 for all). Thus, chronic proteasome inhibition is associated with increased coronary artery oxidative stress and early atherosclerosis. These findings support the significance of the proteasome and related protein quality control for vascular biology and pathology.
Key Words: atherosclerosis • endothelial dysfunction • oxidative stress • proteasome • ubiquitin
Related Article:
Circ. Res. 2007 101: 859-861.
This article has been cited by other articles:
 |
|
 |
|
  J. Lin, X. Zhu, A. R. Chade, K. L. Jordan, R. Lavi, E. Daghini, M. E. Gibson, A. Guglielmotti, A. Lerman, and L. O. Lerman Monocyte Chemoattractant Proteins Mediate Myocardial Microvascular Dysfunction in Swine Renovascular Hypertension Arterioscler Thromb Vasc Biol, November 1, 2009; 29(11): 1810 - 1816. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Stangl and V. Stangl The ubiquitin proteasome pathway and endothelial (dys)function Cardiovasc Res, October 13, 2009; (2009) cvp315v2. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Kloss, S. Meiners, A. Ludwig, and B. Dahlmann Multiple cardiac proteasome subtypes differ in their susceptibility to proteasome inhibitors Cardiovasc Res, July 31, 2009; (2009) cvp217v2. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Herrmann, S. M. Soares, L. O. Lerman, and A. Lerman Reply J. Am. Coll. Cardiol., October 14, 2008; 52(16): 1351 - 1351. [Full Text] [PDF]
|
|
|
|
|
|
J. Herrmann, S. M. Soares, L. O. Lerman, and A. Lerman Potential Role of the Ubiquitin-Proteasome System in Atherosclerosis: Aspects of a Protein Quality Disease J. Am. Coll. Cardiol., May 27, 2008; 51(21): 2003 - 2010. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Ludwig and S. Meiners Targeting of the Proteasome Worsens Atherosclerosis? Circ. Res., February 15, 2008; 102(3): e37 - e37. [Full Text] [PDF]
|
|
|
|
|
|
T. Fukai Targeting Proteasome Worsens Atherosclerosis Circ. Res., October 26, 2007; 101(9): 859 - 861. [Full Text] [PDF]
|
|