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Division of Cardiothoracic Surgery, University of North Carolina, 3040 Burnett Womack, CB #7065, Chapel Hill, NC 27599-7065
(Email: selzman{at}med.unc.edu).
We greatly appreciate the comments regarding our article [1] by Dr Powell, clearly a leader in the field of the cardiac proteasome [2]. His thoughts and critique are valid. We share some skepticism, despite human clinical trial data demonstrating safety and efficacy, that proteasome inhibition will be a panacea for ischemic heart disease. Although much of our effort has been directed towards a more focused approach to inhibition of nuclear factor-
B (NF-B) [3], we believe that manipulation of the proteasome offers some therapeutic opportunities in heart disease.
In regards to our experimental protocols and data interpretation, we are confident that PS-519 was efficacious in inhibiting the 26S proteasome and the metabolism of inhibitory B
(IB). The proteasome assay is fairly burdensome and is reliably done in only a few centers. Fair enough, we did not perform this study in our protocol. Yet, we (A. S. B.) have previously performed assays with PS-519 in pigs [4], and the pharmacokinetics of proteasome inhibition using PS-519 has been extensively studied in rodents and humans [5, 6]. These studies have demonstrated that at a dose of 1 mg/kg, proteasome inhibition in peripheral blood leukocytes is achieved at a level of approximately 80% to 90% in 30 to 60 minutes, with an approximate duration of action of 24 hours. We therefore elected to focus our studies on the cardiovascular physiology related to the specific hypothesis of the paper.
In demonstrating the effect of PS-519 on cardiac tissue, specifically its effects on the NF-B regulatory system, we elected to monitor levels of IB and phospho-p65. We did not believe that changes in total p65 would be detectable within the short timeframe of the experiment. Although we did not use electrophoretic mobility shift assay techniques to show changes in NF-B binding activity, we did demonstrate significant changes in the physiologically relevant downstream indicator of NF-B function, tumor necrosis factor-.
Dr Powell sites several articles that achieved different results using the proteasome inhibitor MG-132. MG-132 is known to be less specific in its inhibition of the 26S proteasome than lactacystin, which is similarly less specific than the lactacystin derivative PS-519. We agree that results and their interpretation are highly subject to the specificity of the inhibitor used.
Similarly, the articles sited by Dr Powell that achieved conflicting results used the Langendorff system for cardiac perfusion. We agree that there are important caveats in the interpretation of the two types of experiments. In vivo ischemia and reperfusion experiments are typically more complex and subject to more variables, but are generally more physiologically relevant than the isolated heart perfusion systems.
Again, we appreciate the opportunity to explain some of the decisions we made in pursuing this line of research and agree that more work remains in bringing proteasome inhibition therapies to cardiovascular disease.
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