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Ann Thorac Surg 2008;85:1503-1504. doi:10.1016/j.athoracsur.2007.10.049
© 2008 The Society of Thoracic Surgeons
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Correspondence

Proteasome Inhibitors in Myocardial Ischemia, Some Concerns

Saul R. Powell, PhD

The Feinstein Institute for Medical Research, The Albert Einstein School of Medicine, Department of Medicine, The Long Island Jewish Medical Center, 270-05 76th Ave, Room B-387, New Hyde Park, NY 11042

(Email: spowell{at}lij.edu).

To the Editor:

I read with great interest the article by Stansfield and coworkers [1] that reports observations suggesting that pretreatment of mice with the proteasome inhibitor, PS-519, decreases postischemic infarct size and preserves cardiac function through a mechanism that might be linked to changes in nuclear factor kappa B (NF{kappa}B) signaling. Considering the critical role of the ubiquitin proteasome system in cardiac pathophysiology [2], this is an important study; however, certain issues with the experimental design, as well as interpretation of these studies require comment. There is concern that simply showing changes in I{kappa}B levels and phosphorylation of p65 without measuring levels of total p65 may not be reflective of changes in activity of NF{kappa}B. For these changes to be meaningful, transcriptional activity of NF{kappa}B must be assessed, which is usually done by means of an electrophoretic mobility shift assay. However, of greater concern is the lack of assessment of proteasome activity in at least peripheral blood cells, if not in cardiac tissue. Without this data, it is unclear if a single dose of PS-519 had any effect on proteasome activity in any tissue (cardiac or blood), and thus if any of the observed effects are even related to proteasome inhibition, or if these are extracardiac effects. The authors cite Zollner and coworkers [3] study as the source of this treatment protocol, which examined proteasome inhibition in the inflammatory processes. At issue is that Zollner and coworkers [3] first measured proteasome activity only after 4 days of treatment, not 1 dose, and that only 20S-proteasome or the non-ATP-dependent activity was determined, which may not be reflective of the ATP-dependent degradation of ubiquitinated proteins by the 26S-proteasome [4]. For optimal interpretation of these studies, the authors should have assessed activity of the 26S-proteasome in both peripheral blood cells and heart. We have recently published a modification of the standard technique for analysis of both ATP-dependent and non-ATP-dependent activities of the proteasome in cardiac tissue, which simplifies this procedure [4].

The need for accurate assessment of proteasome activity is further exemplified by studies that show that proteasome may become dysfunctional as a result of myocardial ischemia [5]. Considering that significant inhibition of the proteasome is known to induce cellular apoptosis in a variety of tissues, including the heart [6], the wisdom of adding additional inhibition on top of pre-existing dysfunction is questionable. Using the isolated perfused heart preparation, which allows for assessment of direct effect of proteasome inhibitors on function, we have consistently observed that these compounds at best have little or no effect and may worsen postischemic function (reviewed in [2]), an observation recently confirmed by another group [7]. It is certainly conceivable that under the right conditions, the extracardiac anti-inflammatory effects of proteasome inhibition [3] could be beneficial. However, in light of a recent case report [8] of cardiac toxicity after bortezomib (Velcade; Millenium Pharmaceuticals Inc, Cambridge, MA) treatment for multiple myeloma, the prudent course would be to suggest caution before proposing use of proteasome inhibitors to treat myocardial infarction.


   References
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 References
 

  1. Stansfield WE, Moss NC, Willis MS, Tang R, Selzman C. Proteasome inhibition attenuates infarct size and preserves cardiac function in a murine model of myocardial ischemia-reperfusion injury Ann Thorac Surg 2007;84:120-125.[Abstract/Free Full Text]
  2. Powell SR. The ubiquitin proteasome system in cardiac physiology and pathology Am J Physiol Heart Circ Physiol 2006;291:1-19.
  3. Zollner TM, Podda M, Pien C, Elliott PJ, Kaufmann R, Boehncke WH. Proteasome inhibition reduces superantigen-mediated T cell activation and the severity of psoriasis in a SCID-hu model J Clin Invest 2002;109:671-679.[Medline]
  4. Powell SR, Davies KJA, Divald A. Optimal determination of heart tissue 26S proteasome activity requires maximal stimulating concentrations of ATP J Mol Cell Cardiol 2007;42:265-269.[Medline]
  5. Powell SR, Wang P, Katzeff HL, et al. Oxidized and ubiquitinated proteins may predict recovery of postischemic cardiac function. Essential role of the proteasome. Antioxid Redox Signal 2005;7538–5.
  6. Powell SR, Gurzenda EM, Mantell LL, Teichberg S, Maulik D. Association of increased ubiquinated proteins with cardiac apoptosis Antioxid Redox Signal 2000;2:103-112.[Medline]
  7. Cai Z, Semenza GL. PTEN activity is modulated during ischemia and reperfusion: involvement in the induction and decay of preconditioning Circ Res 2005;97:1351-1359.[Abstract/Free Full Text]
  8. Voortman J, Giaccone G. Severe reversible cardiac failure after bortezomib treatment combined with chemotherapy in a non-small cell lung cancer patient: a case report BMC Cancer 2006;6:129.[Medline]

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Ann. Thorac. Surg. 85: 1504-1504. [Full Text]



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S. R. Powell and A. Divald
The ubiquitin-proteasome system in myocardial ischaemia and preconditioning
Cardiovasc Res, October 27, 2009; (2009) cvp321v3.
[Abstract] [Full Text] [PDF]

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W. E. Stansfield and C. H. Selzman
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Ann. Thorac. Surg., April 1, 2008; 85(4): 1504 - 1504.
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