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(Circulation Research. 2008;102:e37.)
© 2008 American Heart Association, Inc.

Letter to the Editor

Targeting of the Proteasome Worsens Atherosclerosis?

Antje Ludwig, Silke Meiners

Medizinische Klinik und Poliklinik mit Schwerpunkt Kardiologie und Angiologie, Universitaetsmedizin Berlin, Charité, Germany, silke.meiners@charite.de

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

To the Editor:

In the October 26, 2007 issue of Circulation Research, Herrmann et al presented experiments suggesting that chronic inhibition of the ubiquitin proteasome system mediates proinflammatory and dysfunctional effects in coronary arteries of hypercholesteremic pigs.¹ The same group has previously demonstrated diminished inflammation and improved endothelial function in the kidney using the same model and identical experimental conditions, including the dose of inhibitor.² Their observations add another piece to the complex and controversial puzzle of proteasomal function in vascular disease, as rightly pointed out by the accompanying editorial.³ In an attempt to reconcile the divergent effects of proteasome inhibitors in clinical research, we have recently introduced the concept of proteasome inhibitors acting as poisons or remedies, depending on the dose of inhibitor applied and on the cell type and organ studied.⁴ The differential effects of the proteasome inhibitor MLN-273 in the coronary artery¹ and kidney vessels² strongly support this notion of cell type– and organ-specific effects of proteasome inhibitors. Because the same systemic dose of proteasome inhibitor mediated opposite effects in different tissues, it is likely that these divergent effects are due to a differential degree of proteasome inhibition in the coronary artery versus kidney. Unfortunately, the authors provided no data on the degree of inhibition of proteasomal activities in the kidney of hypercholesteremic pigs.² However, the impaired function of coronary arteries was accompanied by pronounced inhibition (70%) of the main proteasomal activity, the chymotrypsin-like activity. The same dose of proteasome inhibitor inhibited the chymotrypsin-like activity of . . . [Full Text of this Article]

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				K. Stangl and V. Stangl The ubiquitin proteasome pathway and endothelial (dys)function Cardiovasc Res, October 13, 2009; (2009) cvp315v2. [Abstract] [Full Text] [PDF]