Response to Letter Regarding Article, “Protease-Activated Receptor-1 Contributes to Cardiac Remodeling and Hypertrophy”
We recently reported that a genetic absence of protease activated receptor-1 (PAR-1) improved cardiac function by reducing remodeling but did not affect infarct size in an in vivo mouse model of cardiac ischemia-reperfusion injury.1 In contrast, Strande and colleagues2 found that administration of the non–peptide PAR-1 antagonist SCH 79797 to rats significantly reduced infarct size in a similar cardiac ischemia-reperfusion model.
One can debate the pros and cons of pharmacological versus genetic approaches at length. Obviously, the best case scenario is that the results of both approaches match. In the case of the role of PAR-1 in infarct size, however, opposite results were observed. A concern with all pharmacological inhibitors is specificity. SCH 79797 was originally developed as an inhibitor of human PAR-1 by Schering-Plough; however, further development was halted by the company.3 Another anti-human PAR-1 compound developed by the same company called SCH 530348 is currently undergoing evaluation in the TRANSCENDENCE (Thrombin Receptor Antagonist for Clinical Event Reduction Over Standard Concomitant Therapies) phase II clinical trial.4 This is a multicenter randomized trial investigating the safety of various doses of SCH 530348 when used in the nonemergent percutaneous coronary intervention setting.4 Unfortunately, in most cases, researchers do not have access to pharmaceutical drugs that are being tested in clinical trials and we have to make do with discarded drugs. We suggested in our article1 that the difference between our data with PAR-1−/− mice and the results with SCH 79797 made be due to off-target effects of the compound that may occur in vivo. Importantly, a recent study5 demonstrated that SCH 79797 interfered with the growth of several human and mouse cell lines and that the antiproliferative activity of SCH 79797 was found to be independent of PAR-1.
We are continuing to explore the role of PAR-1 in cardiac ischemia-reperfusion injury and agree that the next step is to examine the effect of inhibition of PAR-1 in wild-type mice. However, we believe that the best approach is to compare the effect of more than one mouse PAR-1 inhibitor, such as a small molecule inhibitor and an anti-mouse PAR-1 antibody. Furthermore, these inhibitors must be shown to inhibit mouse PAR-1 signaling in cultured cells before testing in the cardiac ischemia-reperfusion injury model. In addition, experiments with the various PAR-1 inhibitors in both wild-type and PAR-1−/− mice would provide evidence of their specificity.
Source of Funding
This work was supported by grant HL084087 from the National Institutes of Health.
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