Targeting of the Proteasome Worsens Atherosclerosis?
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 peripheral blood cells by only 40%, indicating a more potent inhibition of the proteasome in the coronary artery.1 Interestingly, a similar 70% inhibition of the chymotrypsin-like activity was previously achieved in the kidney and spleen of UbG76VGFP reporter mice with high and toxic doses of proteasome inhibitors.5 These data suggest that the divergent effects of proteasome inhibition may be explained by a differential responsiveness of organs to proteasome inhibitors: pronounced inhibition of the proteasome in coronary arteries is harmful for vessel function whereas moderate inhibition of the proteasome is beneficial. Accordingly, we strongly support the notion put forward by Fukai3 that the ultimate vascular response to proteasome inhibition depends on multiple factors such as the stage of atherosclerotic lesion, cell type, means of administration, and dose of proteasome inhibitor. Future studies in appropriate models of atherosclerosis should take into account these parameters and in particular establish the degree of proteasome inhibition. However, in fact, the key question remains unanswered: Does targeting of the proteasome worsen atherosclerosis in any case?
Herrmann J, Saguner AM, Versari D, Peterson TE, Chade A, Olson M, Lerman LO, Lerman A. Chronic proteasome inhibition contributes to coronary atherosclerosis. Circ Res. 2007; 101: 865–874.
Chade AR, Herrmann J, Zhu X, Krier JD, Lerman A, Lerman LO. Effects of proteasome inhibition on the kidney in experimental hypercholesterolemia. J Am Soc Nephrol. 2005; 16: 1005–1012.
Fukai T. Targeting proteasome worsens atherosclerosis. Circ Res. 2007; 101: 859–861.
Meiners S, Ludwig A, Stangl V, Stangl K. Proteasome inhibitors: poisons and remedies. Med Res Rev. In press.